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Item 1. Business

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We are a clinical-stage, multi-platform biotechnology company focused on the development of first, only and best-in-class gene therapies, with direct on-target mechanism of action and clear clinical

endpoints, for rare and devastating diseases.

We have three clinical-stage ex vivo lentiviral vector (“LVV”) programs.

These include programs for Fanconi Anemia (“FA”), a genetic defect in the bone marrow

that reduces production of blood cells or promotes the production of faulty blood cells, Leukocyte Adhesion Deficiency-I (“LAD-I ” ), a genetic disorder that causes the immune system to malfunction, and

Pyruvate Kinase Deficiency (“PKD”), a rare red blood cell autosomal recessive disorder that results in chronic non-spherocytic hemolytic anemia.

Of these, both the Phase 2 FA program and the Phase 1/2 LAD-I program are in registration-enabling

studies in the United States (“U.S.”) and Europe (“EU”).

In addition, in the U.S., we have a clinical stage in vivo adeno-associated virus (“AAV”) program for Danon disease, a multi-organ

lysosomal-associated disorder leading to early death due to heart failure.

Additional discovery efforts on a gene therapy program for the less common FA subtypes C and G is ongoing.

We have global commercialization and development rights to all

of these product candidates under royalty-bearing license agreements.

We are a clinical-stage, multi-platform biotechnology company focused on the development of first, only and best-in-class gene therapies, with direct on-target mechanism of action and clear clinical endpoints,

for rare and devastating diseases.

We have three clinical-stage ex vivo lentiviral vector (“LV”) programs.

These include programs for Fanconi Anemia (“FA”), a genetic defect in the bone marrow that reduces production of blood cells or promotes

the production of faulty blood cells, Leukocyte Adhesion Deficiency-I (“LAD-I”), a genetic disorder that causes the immune system to malfunction and Pyruvate Kinase Deficiency (“PKD”), a rare red blood cell autosomal recessive disorder that

results in chronic non-spherocytic hemolytic anemia.

Of these, both the Phase 2 FA program and the Phase ½ LAD-I program are in potentially registration-enabling studies in the United States (“U.S.”) and Europe (“EU”).

Additional work on a gene

therapy program for the less common FA subtypes C and G is ongoing.

In the U.S., we also have a clinical stage in vivo adeno-associated virus (“AAV”) program for Danon disease, a multi-organ lysosomal-associated disorder leading to early death

due to heart failure.

The Danon program is currently in an ongoing Phase 1 trial.

Additionally, we have an AAV vector program targeting Plakophilin-2 Arrhythmogenic Cardiomyopathy (“PKP2-ACM”), an inheritable cardiac disorder that is

characterized by a progressive loss of cardiac muscle mass, severe right ventricular dilation, dysplasia, fibrofatty replacement of the myocardium and a high propensity to arrhythmias and sudden death.

As a result of our acquisition of

Renovacor, Inc.

(“Renovacor”), we are now able to utilize recombinant AAV9-based gene therapy designed to slow or halt progression of BAG3 Dilated Cardiomyopathy (“DCM”), which is the most common form of cardiomyopathy and is characterized by

progressive thinning of the walls of the heart resulting in enlarged heart chambers that are unable to pump blood.

We have global commercialization and development rights to all of these product candidates under royalty-bearing license

Effective December 2021, a decision was made to no longer pursue Rocket-sponsored clinical evaluation of RP-L401;

this program is to be returned to academic innovators.

Although we believe that gene

therapy may be beneficial to patients afflicted with this disorder, we have opted to focus available resources towards advancement of RP-A501, RP-L102, RP-L201 and RP-L301, based on the compelling clinical data to date and potential for

this program was returned to academic innovators.

Although we believe that gene therapy may be

beneficial to patients afflicted with this disorder, we have opted to focus available resources towards advancement of RP-A601, RP-A501, RP-L102, RP-L201, RP-L301, and BAG3-DCM based on the compelling clinical data to date and potential for

therapeutic advancement in these severe disorders of childhood and young adulthood.

Gene Therapy Overview

Genes are composed of sequences of deoxyribonucleic acid (“DNA”), which code for proteins that perform a broad range of physiologic functions in all living organisms.

Genes are composed of sequences of deoxyribonucleic acid (“DNA”), which provide the code for proteins that perform a broad range of physiologic functions in all living organisms.

Although genes are passed on

from generation to generation, genetic changes, also known as mutations, can occur in this process.

These changes can result in the lack of production of proteins or the production of altered proteins with reduced or abnormal function, which can

in turn result in disease.

Gene therapy is a therapeutic approach in which an isolated gene sequence or segment of DNA is administered to a patient, most commonly for the purpose of treating a genetic disease that is caused by

genetic mutations.

These changes can result in the lack of production of proteins or the production of altered proteins with reduced or abnormal function, which

can in turn result in disease.

Gene therapy is a therapeutic approach in which an isolated gene sequence or segment of DNA is administered to a patient, most commonly for the purpose of treating a genetic disease that is caused by genetic

Currently available therapies for many genetic diseases focus on administration of large proteins or enzymes and typically address only the symptoms of the disease.

Gene therapy aims to address the disease-causing effects of

absent or dysfunctional genes by delivering functional copies of the gene sequence directly into the patient’s cells, offering the potential for curing the genetic disease, rather than simply addressing symptoms.

Gene therapy aims to address the disease-causing effects of absent

or dysfunctional genes by delivering functional copies of the gene sequence directly into the patient’s cells, offering the potential for curing the genetic disease, rather than simply addressing symptoms.

We are using modified non-pathogenic viruses for the development of our gene therapy treatments.

Viruses are particularly well suited as delivery vehicles because they are adept at penetrating cells

and delivering genetic material inside a cell.

Viruses are particularly well suited as delivery vehicles because they are adept at penetrating cells and

delivering genetic material inside a cell.

In creating our viral delivery vehicles, the viral (pathogenic) genes are removed and are replaced with a functional form of the missing or mutant gene that is the cause of the patient’s genetic

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transgene, the modified virus is called a “viral vector.” The viral vector delivers the transgene into the targeted tissue or organ (such as the cells inside a patient’s bone marrow).

We have two types of viral vectors in development, LVV and

We believe that our LVV and AAV-based programs have the potential to offer a significant therapeutic benefit to patients that is durable (long-lasting).

The gene therapies can be delivered either (1) ex vivo (outside the body), in which case the patient’s cells are extracted and the vector is delivered to

these cells in a controlled, safe laboratory setting, with the modified cells then being reinserted into the patient, or (2) in vivo (inside the body), in which case the vector is injected directly into

the patient, either intravenously (“IV”) or directly into a specific tissue at a targeted site, with the aim of the vector delivering the transgene to the targeted cells.

We believe that scientific advances, clinical progress, and the greater regulatory acceptance of gene therapy have created a promising environment to advance gene therapy products as these products

are being designed to restore cell function and improve clinical outcomes, which in many cases include prevention of death at an early age.

The FDA approval of several gene therapies in recent years indicates that there is a regulatory pathway

forward for gene therapy products.

We have two types of viral vectors in development, LV and

We believe that our LV and AAV-based programs have the potential to offer a significant therapeutic benefit to patients that is durable (long-lasting).

The gene therapies can be delivered either (1) ex vivo (outside the body), in which case the patient’s cells are extracted and the vector is delivered to these cells in

a controlled, safe laboratory setting, with the modified cells then being reinserted into the patient, or (2) in vivo (inside the body), in which case the vector is injected directly into the patient,

either intravenously (“IV”) or directly into a specific tissue at a targeted site, with the aim of the vector delivering the transgene to the targeted cells.

We believe that scientific advances, clinical progress, and the greater regulatory acceptance of gene therapy have created a promising environment to advance gene therapy products as these products are being

designed to restore cell function and improve clinical outcomes, which in many cases include prevention of death at an early age.

The FDA approval of several gene therapies in recent years indicates that there is a regulatory pathway forward

for gene therapy products.

Essential Terminology

Set forth below is an abbreviated index of certain key terms and optimal ranges of values used in the discussion of LVV and AAV gene therapies.

Set forth below is an abbreviated index of certain key terms and optimal ranges of values used in the discussion of LV and AAV gene therapies.

Optimal Ranges

LVV Therapy (hematopoietic disorders)

LV Therapy (hematopoietic disorders)

CD34+ cell(s)

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Will depend on underlying disorder, generally > 1 million CD34+ cells/kg.

Vector copy number (VCN)

Vector copy number (VCN) [product]

The average number of gene copies per infused stem cell (as determined by DNA analysis;

this is an average ratio, not a precise value)

0.5 to 2 has been target in some LVV clinical studies (5.0 generally considered maximum)

0.5 to 2 has been target in some LV clinical studies (5.0 generally considered maximum)

Vector copy number (VCN)

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Pipeline Overview

The chart below shows the current phases of development of Rocket’s programs and product candidates for both LVV and AAV programs:

Descriptions of these conditions and the Rocket programs for each is set forth below.

LVV Programs .

Rocket’s LVV-based programs utilize third-generation, self-inactivating lentiviral vectors to target selected rare diseases.

Currently, Rocket is developing LVV programs to treat FA, LAD-I, and PKD.

AAV Program .

Overview of Danon Disease

The chart below shows the current phases of development of Rocket’s programs and product candidates:

Cardiovascular Programs

Danon Disease

Danon disease (“DD”) is a multi-organ lysosomal-associated disorder leading to early death due to heart failure.

DD is caused by mutations in the gene encoding lysosome-associated membrane protein 2

(“LAMP-2”), a mediator of autophagy.

DD is caused by mutations in the gene encoding lysosome-associated membrane

protein 2 (“LAMP-2”), a mediator of autophagy.

This mutation results in the accumulation of autophagic vacuoles, predominantly in cardiac and skeletal muscle.

Male patients often require heart transplantation and typically die in their teens or twenties

from progressive heart failure.

Along with severe cardiomyopathy, other DD-related manifestations can include skeletal muscle weakness, liver disease, and intellectual impairment.

There are no specific therapies available for the treatment of DD

and medications typically utilized for the treatment of congestive heart failure (CHF) are not believed to modify progression to end-stage CHF.

Male patients often require heart transplantation and typically die in their teens or

twenties from progressive heart failure.

Along with severe cardiomyopathy, other DD-related manifestations can include skeletal muscle weakness and intellectual impairment.

There are no specific therapies available for the treatment of DD and

medications typically utilized for the treatment of congestive heart failure (“CHF”) are not believed to modify progression to end-stage CHF.

Patients with end-stage CHF may undergo heart transplant, which currently is available to a minority

of patients, is associated with short- and long-term complications and is not curative of the disorder in the long-term.

RP-A501 is in clinical trials as an in vivo therapy for Danon disease, which is

of patients, is associated with significant short- and long-term complications and is not curative of the disorder in the long-term.

RP-A501 is in clinical trials as an in vivo therapy for DD, which is

estimated to have a prevalence of 15,000 to 30,000 patients in the U.S.

Rationale for Gene Therapy in Danon Disease

Danon disease is an autosomal dominant, rare inherited disorder characterized by progressive cardiomyopathy which is almost universally fatal in males even in settings where cardiac transplantation

DD is an X-linked dominant, monogenic rare inherited disorder characterized by progressive cardiomyopathy which is almost universally fatal in males even in settings where cardiac transplantation

is available.

Danon disease predominantly affects males early in life and is characterized by absence of LAMP2B expression in the heart and other tissues.

Pre-clinical models of Danon disease have

demonstrated that AAV-mediated transduction of the heart results in reconstitution of LAMP2B expression and improvement in cardiac function.

DD predominantly affects males early in life and is characterized by absence of LAMP2B expression in the heart and other tissues.

Preclinical models of DD have demonstrated that

AAV-mediated transduction of the heart results in reconstitution of LAMP2B expression and improvement in cardiac function.

We currently have one adeno-associated viral vector program targeting DD, RP-A501.

We have treated six patients in the RP-A501 Phase 1 clinical trial, which enrolled for adult and pediatric male DD

This includes a first cohort evaluating a low-dose (6.7e13 genome copies (vg)/kilogram (kg)) in adult/older adolescent patients aged 15 or greater (n=3), a second cohort evaluating a higher dose (1.1e14 vg/kg) in adult/older adolescent

patients aged 15 or greater (n=2), and we have initiated treatment in a pediatric cohort at a low dose level (6.7e13 vg/kg;

Data disclosed from our Phase 1 study of RP-A501 in November 2021 and January 2022 included safety and clinical activity results from the three patients treated with the low dose of 6.7e13 vg/kg and

from two patients treated with the higher dose of 1.1e14 vg/kg, and early safety information from the initial pediatric patient (pediatric cohort is age 8-14 years) treated with the low dose of 6.7e13 vg/kg.

Efficacy assessments include evaluation of New York Heart Association (NYHA) Functional Classification, which is the most commonly used heart failure classification system.

NYHA Class II is where a

patient exhibits a slight limitation of physical activity, is comfortable at rest, and ordinary physical activity results in fatigue, palpitation and/or dyspnea.

Class I is where a patient exhibits no limitation of physical activity and ordinary

physical activity does not cause undue fatigue, palpitation and/or dyspnea.

We have treated seven patients in the RP-A501 Phase 1 clinical trial, which enrolled adult/older adolescent and

pediatric male DD patients.

This includes a first cohort evaluating a low-dose (6.7e13 genome copies (gc)/kilogram (kg)) in adult/older adolescent patients aged 15 or greater (n=3), a second cohort evaluating a higher dose (1.1e14 gc/kg) in

adult/older adolescent patients aged 15 or greater (n=2), and a pediatric cohort at a low dose level (6.7e13 gc/kg;

As previously disclosed, a patient receiving therapy on the high dose cohort (1.1e14 gc/kg dose) had progressive heart

failure and underwent a heart transplant at month five following therapy.

This patient had more advanced disease than the four other adult/older adolescent patients who received treatment in the low and high dose cohorts, as evidenced by

diminished baseline left ventricle (“LV”) ejection fraction (35%) on echocardiogram and markedly elevated LV filling pressure prior to treatment.

The patient’s clinical course was characteristic of DD progression.

The patient is doing well

post-transplant.

Based on the initial efficacy observed in the low dose cohort and to mitigate complement-mediated safety concerns observed in the high dose cohort (thrombotic microangiopathy (“TMA”)) and in

agreement with the FDA, we are focusing on the low dose (6.7e13 gc/kg) and we will no longer administer doses of 1.1e14 gc/kg or higher in this trial.

Additional safety measures have been implemented and are reflected in the updated trial

These measures include exclusion of patients with end-stage heart failure, and a refined immunomodulatory regimen involving transient B- and T-cell mediated inhibition, with emphasis on preventing complement activation, while also

enabling lower steroid doses and earlier steroid taper, with all immunosuppressive therapy discontinued 2-3 months following administration of RP-A501.

We are conducting a variety of efficacy assessments in the Phase I clinical study to measure the prospect of benefit for patients.

These assessments include the following:

New York Heart Association (“NYHA”) Functional Classification is the most commonly used heart failure classification system.

NYHA Class II is where a patient exhibits a slight limitation of physical

activity, is comfortable at rest, and ordinary physical activity results in fatigue, palpitation and/or dyspnea.

Class I is where a patient exhibits no limitation of physical activity and ordinary physical activity does not cause undue

fatigue, palpitation and/or dyspnea.

Class III and IV are considered more severe or advanced heart failure.

Brain natriuretic peptide (“BNP”) is a blood-based evaluation and a key marker of heart failure with prognostic significance in CHF and cardiomyopathies.

Other efficacy

parameters include echocardiographic measurements of heart thickness, most notably the thickness of the left ventricular posterior wall (LVPW), and importantly, measurement of LAMP2B gene expression both via immunohistochemistry and Western blot,

as obtained via endomyocardial biopsy.

Biopsied heart tissue is also evaluated on electron microscopy for evidence of DD-associated tissue derangements, including the presence of autophagic vacuoles and disruption of myofibrillar architecture,

each of which are characteristic of DD-related myocardial damage.

In November 2021 and January 2022, data for the ongoing Phase 1 trial of RP-A501 was presented, including efficacy parameters for the low and high dose cohorts in patients aged 15 and older with at

least 12 months follow-up (n=5).

An improvement in NYHA Class (from II to I) was observed in three patients (two low-dose and one high-dose) who had closely monitored immunosuppression with follow-up greater than one year and stabilization was

observed in one low-dose patient without a closely monitored immunosuppressive regimen.

A substantial improvement in BNP, a key marker of heart failure, was observed in all three low-dose patients and one high-dose patient.

Among the three

low-dose patients, BNP decreased from a pretreatment baseline by 57% at 24 months, 79% at 18 months, and 75% at 15 months, respectively.

In one high-dose patient, BNP decreased from a pretreatment baseline by 67% at 12 months.

In patients with

closely monitored immunosuppression (two low-dose and one high-dose) left ventricular (LV) posterior wall thickness improved (average 23% decrease compared to pretreatment baseline) and ejection fraction improved or stabilized (average 20%

increase compared to pretreatment baseline) at 12 to 18 months on echocardiography.

Severe and progressive wall thickening is a hallmark of the hypertrophic cardiomyopathy of Danon Disease and is a major contributor to early mortality in male

Cardiac output remained normal for all patients with improved or stable left heart filling pressures as measured by cardiac catheterization.

Three low-dose patients and one high-dose patient demonstrated improvements in the 6-minute

walk test (6MWT).

One low-dose patient improved from a pretreatment baseline of 443 meters (m) to 467 m at 24 months.

The second low-dose patient improved from a pretreatment baseline of 405 m to 410 m at 18 months.

The third low-dose patient

improved from a pretreatment baseline of 427 m to 435 m at 15 months.

One high-dose patient improved from a pretreatment baseline of 436 m to 492 m at 12 months.

Evidence of sustained cardiac LAMP2B gene expression by immunohistochemistry and

Western blot with qualitative improvement of vacuoles and cardiac tissue architecture on electron microscopy was observed at both dose levels.

Sustained cardiac LAMP2B gene expression by immunohistochemistry was observed in all three patients

with a closely monitored immunosuppressive regimen.

Specifically, LAMP2B gene expression by immunohistochemistry in the low-dose (6.7e13 vg/kg) was 68% in one patient at Month 12 and 92% in another patient at Month 9.

In one patient who received

the high-dose (1.1e14 vg/kg), LAMP2B gene expression by immunohistochemistry was 100% at Month 12.

One of the patients receiving therapy on the high dose cohort had progressive heart failure and underwent a heart transplant at Month 5 following therapy.

This patient had more advanced disease than

the 4 other adult/older adolescent patients who received treatment in the low and high dose cohorts, as evidenced by diminished LV ejection fraction (35%) on echocardiogram and markedly elevated LV filling pressure prior to treatment.

clinical course was characteristic of DD progression.

Assessments regarding gene transduction from the explanted heart are summarized below:

Explanted Heart

Analysis of the explanted heart revealed significant fibrosis consistent with advanced DD.

Myocardial tissue from the explanted heart at 5 months post-treatment displayed 100% LAMP2B protein expression by immunohistochemistry throughout non-fibrotic cardiac regions including the ventricles and other essential targeted

RP-A501 was generally well tolerated at the 6.7e13 vg/kg dose level, or lower dose.

All observed adverse effects were reversible with no lasting sequelae.

Early transaminase and creatinine kinase

elevations returned to baseline or decreased.

No unexpected and serious drug product-related adverse events or severe adverse events were observed in this low dose cohort.

The most common adverse events were predominantly mild, not associated

with clinical symptoms and were related to elevated transaminases post-treatment.

Elevation in transaminases and creatinine kinases was observed in all three low-dose patients and returned to baseline levels within the first one to two months

Elevations in BNP are strongly associated with

worsening heart failure and poor outcomes in cardiovascular disease.

High sensitivity troponin I (“hsTnI”) is a blood-based evaluation and a key marker of cardiac injury, one that is (like BNP) frequently elevated in DD patients and has been shown to be markedly elevated

in patients with advanced stage disease.

Echocardiographic measurements of heart thickness, most notably, left ventricular mass (“LVM”) and maximal left ventricular wall thickness (“MLVWT”), indicate the degree of hypertrophy present in the

Kansas City Cardiovascular Questionnaire (“KCCQ”) is a validated, patient-reported outcomes assessment that measures a patients perception of their heart failure symptoms, impact of disease on physical

and social function, and the impact of their heart failure on overall health status and quality of life.

Assessment scores range from 0 (very poor health status) to 100 (excellent health status).

Changes in KCCQ score of +/- 5 points

are considered meaningful and have been shown to correlate with outcomes.

Histologic examination of endomyocardial biopsies via hematoxylin and eosin (“H&E”) histology and electron microscopy is used to detect evidence of DD-associated tissue derangements, including the

presence of autophagic vacuoles and disruption of myofibrillar architecture, each of which are characteristic of DD-related myocardial damage.

LAMP2B gene expression in endomyocardial biopsy samples is measured via both immunohistochemistry and Western blot and confirms the presence of LAMP2B protein in DD cardiac tissue following RP-A501

In May 2022 at the 25 th Annual Meeting of the American Society of Gene and Cell Therapy (“ASGCT”) we disclosed

data from our Phase I study that included safety and efficacy updates from the three patients treated with the low dose of 6.7e13 gc/kg and from two patients treated with the higher dose of 1.1e14 gc/kg, and initial safety information from the

two pediatric patients (pediatric cohort is age 8-14 years) treated with the low dose of 6.7e13 gc/kg.

We reported that RP-A501 continued to be well-tolerated at 12-24 months post treatment in both the high and low-dose adult/older adolescent cohorts (age ≥15 years).

As previously presented, there

were no drug product related SAEs observed in the low dose (6.3e13 gc/kg) adult/older adolescent cohort.

The most common adverse events were predominantly mild, not associated with clinical symptoms and were related to elevated transaminases

post-treatment.

There was also a transient and reversible decline in platelets observed in these three patients.

These changes were largely responsive to corticosteroids and other immunosuppressive therapies.

All patients were given oral steroids

to prevent or minimize potential immune-related events.

Corticosteroids were associated with transient exacerbation of DD-associated skeletal myopathy, which resolved upon discontinuation of steroid therapy.

At the higher dose administered

(1.1e14 vg/kg), additional immunosuppressive therapies were stipulated and administered to mitigate the immune response associated with RP-A501.

As disclosed in December 2020, one of the two patients receiving the 1.1e14 vg/kg dose had more

advanced heart failure than the others, and was the heaviest patients treated to-date (receiving the highest absolute AAV9 dose).

This patient experienced a non-persistent, immune-related event that was classified as a drug product-related

serious adverse event.

This thrombotic microangiopathy (TMA) event (which was later reclassified as a Sudden Unexpected Serious Adverse Reaction (SUSAR)) was believed to be likely due to immune-mediated complement activation, resulting in

reversible thrombocytopenia and acute kidney injury requiring eculizumab and transient hemodialysis.

This patient regained normal kidney function within three weeks.

(This event occurred in the same patient in whom RP-A501 was not associated with

clinical stabilization or improvement, and who required a heart transplant 5 months post-therapy).

Following transplant, this patient has been clinically stable and reports resolution of a baseline skeletal myopathy that was present prior to treatment.

Analysis of the explanted heart is described

Of note, this patient had more advanced heart failure at time of treatment;

the clinical protocol has been modified to exclude enrollment of DD with end-stage CHF/cardiomyopathy.

In May 2021, 5 months after details of this event were

disclosed and after recognition of complement-mediated TMA in other systemic AAV programs, the FDA placed the study on clinical hold.

In response to the FDA’s clinical hold, we amended the trial protocol in order to enable more defined mechanisms

for prevention, early recognition and management of complement-mediated adverse events.

The FDA lifted the clinical hold on August 16, 2021 and dosing of the pediatric cohort was initiated in the fourth quarter of 2021.

Based on the activity observed in the low dose cohort and to mitigate complement-mediated TMA (safety concerns observed in the high dose cohort) and in agreement with the FDA, we are focusing on the

low dose (6.7e13 vg/kg) and we will no longer administer doses of 1.1e14 vg/kg or higher in this trial.

Additional safety measures have been implemented and are reflected in the updated trial protocol.

These measures include exclusion of patients

with end-stage heart failure, and a refined immunosuppressive regimen involving transient B- and T-cell mediated inhibition, with emphasis on preventing complement activation, while also enabling lower steroid doses and earlier steroid taper,

with all immunosuppressive therapy discontinued 2-3 months following therapy.

As announced in January 2022, the initial pediatric patient received RP-A501 therapy (6.7e13 vg/kg dose level) without evidence of significant complement activation and

with stable platelet levels;

there was no worsening of the patient’s baseline DD-related skeletal myopathy during the weeks following RP-A501.

Elevation in transaminases and creatinine kinases was observed in all three low-dose adult/older adolescent cohort patients and returned to baseline levels within the first one to two months post-treatment.

There was also a

transient and reversible decline in platelets observed in two of three of these patients.

These changes were responsive to corticosteroids and other immunosuppressive therapies.

Two patients in the low dose cohort and one patient in the high

dose cohort experienced skeletal myopathy related to corticosteroid administration, which resolved with steroid taper.

As disclosed in 2020, one patient in the high dose cohort (the same patient who later went to cardiac transplant as described

above) experienced a non-persistent, immune-related event that was classified as a drug product-related serious adverse event.

This TMA event (which was later reclassified as a Sudden Unexpected Serious Adverse Reaction (“SUSAR”) was believed

to be likely due to immune-mediated complement activation, resulting in reversible thrombocytopenia and acute kidney injury requiring eculizumab and transient hemodialysis.

This patient received the highest absolute dose secondary to high

baseline weight and the higher (1.1e14 gc/kg) dose level.

The TMA resolved fully with supportive therapy and the patient regained normal kidney function within three weeks.

The patient’s progression to heart transplant is not associated with

this event, but instead due to advanced DD at the time of treatment.

Across the adult/older adolescent patients, no additional SAEs were observed following the first 2-4 months from treatment and all treatment-related adverse events were

reversible with no lasting renal, hepatic or other sequelae.

Initial safety assessment of the two pediatric patients showed normal-range platelets, diminished complement activation relative to the adult/older adolescent cohorts, and no

complement-related adverse events.

Corticosteroid taper commenced at day 10 following therapy for both pediatric patients and there was no significant worsening of the patients’ baseline DD-related skeletal myopathy during the weeks following

Of note, transaminases and parameters of liver inflammation (including blood levels of gamma-glutamyl transferase, bilirubin and coagulation parameters) were not significantly increased during the weeks following therapy.

All 4 adult/older adolescent (age ≥15 years) patients with observed immunomodulatory regimen compliance and preserved (>40%) left ventricular ejection fraction at baseline demonstrated

disease modification across molecular, echocardiographic, and functional parameters.

These patients demonstrated evidence of sustained cardiac LAMP2B expression by immunohistochemistry and reduced levels of autophagic vacuoles on histologic

Echocardiograms showed stabilized or decreased cardiac wall thickness with improved or stabilized ejection fraction in these patients.

Patients in the adult/older adolescent cohorts demonstrated sustained improvement or

stabilization in BNP and NYHA class, 6-minute walk test and reported increases in physical activity.

In September 2022, we presented interim data for the ongoing Phase 1 trial of RP-A501 at the Heart Failure Society of America (“HFSA”) meeting, including updated safety and initial efficacy parameters for the

pediatric cohort and longer-term efficacy parameters for the low and high dose adult/older adolescent cohort (patients aged 15 and older;

n=5) (data cut-off September 27, 2022).

This data was also presented in November 2022 at the 75 th American Heart Association (“AHA”) Annual Meeting.

During these presentations we provided incremental safety updates across cohorts.

As previously outlined, RP-A501 was generally well tolerated at the 6.7e13 gc/kg dose level and no unexpected and serious drug product-related adverse events or severe adverse events were observed in both adult/older adolescent

and pediatric low dose cohorts.

All observed adverse effects at both doses were reversible and no lasting sequelae were observed with follow-up of 2-3 years from treatment for the adult/older adolescent cohort and 6-11 months for the

pediatric cohort.

Any early transaminase and creatinine kinase elevations returned to baseline or decreased, and any transient exacerbation of DD-associated skeletal myopathy resolved upon discontinuation of corticosteroid therapy.

updated safety data presented at HFSA in September 2022 and AHA in November 2022 reconfirmed that RP-A501 was generally well tolerated at the low dose with a manageable safety profile across pediatric and adult/older adolescent cohorts.

In the pediatric cohort, an improvement in NYHA Class (from Class II to I) was reported in both patients after 6 and 9 months of follow-up post-RP-A501.

In the adult/older adolescent cohorts, improvement in NYHA

Class (from II to I) was observed in three patients (two low-dose and one high-dose) who had closely monitored immunomodulation and stabilization of NYHA Class was observed in one low-dose adult patient without a closely monitored

immunomodulatory regimen.

Substantial improvements (reductions) in BNP, a key marker of heart failure, were observed in both pediatric patients at 6 and 9 months of follow-up, with levels at these assessments less than 50% of baseline values.

Improvements (reductions) in hsTnI, a key marker of myocardial injury, were observed in both pediatric patients at 6 and 9 months of follow-up, with levels at these assessments less than 20% of baseline values.

In the adult/older adolescent

cohorts, reductions in hsTnI were observed in three low-dose patients and one high-dose patient, with reductions greater than 50% of baseline levels identified in these four patients on at least one assessment, and reductions sustained through

24-36 months of follow-up.

Reductions in BNP of at least 25% below baseline values were identified in three low-dose patients and one high-dose patient on at least one assessment.

In two of the adult/older adolescent patients, BNP levels were

modestly above baseline at the most recent assessment;

however baseline BNP levels were either within normal limits or mildly elevated for these two patients.

In adult/older adolescent cohort patients with closely monitored immunomodulation

(two low-dose and one high-dose) left ventricular (LV) posterior wall thickness improved (approximately 15-25% decrease compared to pretreatment baseline) and reductions in left ventricular mass were identified in four patients, including the

patient in the low-dose cohort for whom immunomodulation was not closely monitored.

Severe and progressive wall thickening is a hallmark of the hypertrophic cardiomyopathy of Danon disease and is a major contributor to early mortality in male

Evidence of sustained cardiac LAMP2B gene expression by immunohistochemistry with qualitative improvement of vacuoles and cardiac tissue architecture on standard H&E and electron microscopy was observed at both dose levels in four

of five patients in the adult/older adolescent cohorts and both patients in the pediatric cohort.

Sustained cardiac LAMP2B gene expression by immunohistochemistry was observed in all three adult/older adolescent patients with a closely

monitored immunomodulatory regimen through 24 months of follow-up.

Importantly, genetic correction (as evidenced by myocardial vector copy numbers (“VCNs”) and LAMP2 protein expression were accompanied by reductions in the relative area of

autophagic vacuoles relative to overall myocardial area, with decreases in this ratio of at least 20% relative to baseline identified in four adult/older adolescent cohort patients (three of whom had reductions of at least 50%).

reductions (>50% baseline) in vacuolar area were also identified in the one pediatric cohort patient for whom this parameter was evaluable at 6 months post-therapy.

In addition to the improvements identified in NYHA Class, improvements in

quality of life (“QOL”) as reported via the KCCQ were noted in three of the adult/older adolescent patients who had closely monitored immunomodulation, and both of the pediatric cohort patients;

KCCQ score at baseline was 50 for the initial

pediatric patient and was 93 at the most recent 9 month assessment;

KCCQ score at baseline was 52 for the second pediatric patient and was 81 at a preliminary 3 month assessment.

On December 22, 2022, we announced updates from our end-of-Phase 1 meeting with the FDA regarding RP-A501.

During the meeting, we reviewed the positive Phase 1 dataset with the FDA and proposed a

study design and endpoints for ongoing clinical development of the investigational gene therapy.

Following discussions with the FDA, we anticipate proceeding with a dose of 6.7e13 GC/kg, and we anticipate utilizing a single arm open-label trial

design with a robust natural history comparator, pursuant to the FDA’s acknowledgment of the challenges associated with executing a randomized controlled trial in Danon Disease.

The FDA has also expressed an openness to considering a

biomarker-based composite endpoint supported by functional and quality-of-life assessments as measures of patient benefit.

We look forward to continued dialogue with the FDA on the design for our proposed pivotal trial, including discussion of

appropriate external controls for the study and appropriate endpoints to support accelerated approval.

We are now in discussion with the FDA about a trial design that will enable evaluation of two pediatric patients treated with drug product

manufactured at our in-house cGMP AAV facility as an initial component of a modestly sized global pivotal study.

On January 9, 2023, we presented additional positive efficacy updates from our Phase I study of RP-A501 during the 41 st Annual J.P.

Morgan Healthcare Conference.

The data presented included several additional months of follow-up, which showed further improvements in key

biomarkers, echocardiographic and functional measures.

A summary of these updates is provided in the table below.

We also provided additional natural history comparator data, which showed the marked divergence of the course of Phase I

patients from that of untreated patients in terms of key biomarkers (BNP) and functional measures (NYHA Class).

Furthermore, RP-A501 continued to be well tolerated at 2-3 years post treatment in both adult /older adolescent high and low-dose cohorts and at 8 to 13 months in the pediatric cohort.

In the pediatric cohort, no significant immediate or delayed toxicities, significant skeletal myopathy, or late transaminase elevations

have been observed.

Improvement or Stabilization Observed Across Key Biomarker, Echo Findings and Functional Measures in Phase 1 RP-A501 study

Darker Green = improved;

Lighter Green = minimal change (stabilization)

Does not include pt 1007 in Ph1 trial who had advanced HF with EF<40% at enrollment and received HTx 5M following tx due to pre-existing advanced HF.

Patient is currently stable.

1 Patient 1008 echocardiographic parameters are M9 visit (M12 pending).

2 Patient 1002 NYHA class depicted for M30 visit (M36 pending).

3 Patient 1005 KCCQ score depicted for M24 visit (M30 pending).

In addition to these clinical updates, we also provided updates on our in-house manufacturing activities.

We have successfully produced 2 cGMP RP-A501 batches that have superior specifications to

Phase I material in both titer and full versus empty particles.

We believe the improved quality of our in-house manufactured product will allow for full dosing with lower total viral particles, potentially further optimizing the safety profile

Furthermore, we have agreement from the FDA on the continued utilization of HEK-293 cell-based process through commercialization as well as our comparability approach and potency assay.

Results from the ongoing Phase 1 Danon Disease trial represent one of the most comprehensive investigational gene therapy datasets for any cardiac condition.

RP-A501 was generally well tolerated

with evidence of durable treatment activity and improvement of Danon Disease for both pediatric patients with up to nine months of follow-up and four adult/older adolescent patients with up to 36 months of follow-up.

All adult/older adolescent

and pediatric patients who received a closely monitored immunomodulatory regimen showed improvements across tissue, laboratory, and imaging-based biomarkers, as well as in NYHA class (from II to I) and KCCQ scores with follow-up of six to 36

Anticipated Milestones

On February 7, 2023, we announced that RP-A501 received RMAT designation from the FDA.

We are very encouraged by the highly collaborative ongoing dialogue with the FDA for RP-A501 in Danon

Disease and subject to the continued dialogue and agreement with the FDA anticipate initiating the initial component of the global study in Q2 of 2023.

Plakophilin-2 Arrhythmogenic Cardiomyopathy (PKP2-ACM)

Arrhythmogenic cardiomyopathy (“ACM”) is an inheritable cardiac disorder that is characterized by a high propensity for arrhythmias and sudden death, a progressive loss of cardiac muscle mass, severe right

ventricular dilation, dysplasia, and fibrofatty replacement of the myocardium.

Most commonly, the cardiomyopathy initially manifests in the right ventricular free wall, so the disease was termed arrhythmogenic right ventricular

dysplasia/cardiomyopathy (ARVD/ARVC).

However, since left dominant and biventricular forms have also been observed, this has led more recently to the use of the term ACM.

Mutations in the PKP2 gene comprise the most frequent genetically

identified etiology of familial ACM.

PKP2 encodes for the protein Plakophilin-2, which is a component of the desmosome, an intercellular complex involved in cell-cell adhesion.

PKP2 is also involved in transcriptional regulation of calcium

signaling between cardiomyocytes.

Patients with mutations in PKP2 are typically heterozygous and demonstrate reduced expression of PKP2 in the myocardium.

Mean presentation is at the age of 35, and patients have a very high lifetime risk of

ventricular arrhythmias, structural ventricular abnormalities, and sudden cardiac death (“SCD”).

There are no specific available medical therapies available that have been shown to be highly effective for ACM, and current treatment protocols follow standard ventricular arrhythmia and cardiomyopathy

guidelines, which involve lifestyle modifications (i.e.

exercise limitation) and include drug treatments such as beta blockers, anti-arrhythmics and diuretics.

The use of these therapies is driven by the arrhythmia burden and severity of

cardiomyopathy.

These therapies do not modify the course of the disease, and generally provide only symptomatic and/or palliative support.

Upon diagnosis, a substantial percentage of patients receive an implantable cardiac defibrillator

(“ICD”) for primary or secondary prevention of ventricular arrhythmias and SCD.

Of note, ICDs are not curative, and breakthrough life-threatening arrythmias may persist with ongoing risk of death;

ICDs furthermore do not prevent the

progression to end-stage heart failure.

ICD firings, although lifesaving, are physically and emotionally traumatic events.

Patients whose condition progresses to end-stage heart failure are considered for cardiac transplantation which, while

curative of underlying disease, is itself associated with significant morbidity and mortality.

Hence there exists a high unmet medical need in this population.

PKP2-ACM is estimated to have a prevalence of 50,000 patients in the US and EU.

We currently have one adeno-associated viral vector program targeting PKP2-ACM, RP-A601, which is a recombinant AAVrh.74 vector expressing PKP2a.

PKP2-ACM is typically caused by heterozygous pathogenic

mutations in the PKP2 gene resulting in reduced PKP2 expression in the myocardium.

A once-administered gene therapy that addresses the root cause of the disease (PKP2 deficiency) early in the disease course, could mitigate the early

electrical remodeling and diminish the risk of life-threatening arrhythmias and SCD associated with ACM, potentially impeding the development of irreversible cardiac structural changes.

Prevention of syncopal episodes, life-threatening

arrythmias, SCD, ICD shocks and the resulting anxiety, discomfort and hospitalizations is anticipated to result in a vastly improved quality of life and survival benefit.

Furthermore, such an approach could spare patients the need for

lifelong adherence to multiple arrhythmia and heart failure drugs that are nonspecific for PKP2-ACM and are associated with their own side effects, enabling patients an opportunity to live without exercise restrictions and with diminished

concern for arrhythmias, palpitations, ICD shocks and progression to end-stage heart failure.

In nonclinical studies conducted by the Sponsor, RP-A601 has demonstrated efficacy in altering the natural history of PKP2-driven ACM.

PKP2 cKO animals treated with the study drug have exhibited extended

survival to the longest timepoint measured (5 months), reduced cardiac dilation and fibrofatty replacement / fibrosis of the myocardium, preserved LV function, and mitigation of the arrhythmic phenotype.

Untreated PKP2 cKO mice had a median

survival of approximately one month.

Anticipated Milestones

We have achieved pre-clinical proof-of-concept for RP-A601 in an animal model representative of PKP2-ACM, completed pharmacology and GLP toxicology studies, produced GMP drug product, and developed an

appropriate potency assay to support a Phase I study.

We anticipate filing an IND in Q2 of 2023.

BAG3 Dilated Cardiomyopathy

Dilated cardiomyopathy (“DCM”) is the most common form of cardiomyopathy and is characterized by progressive thinning of the walls of the heart resulting in enlarged heart chambers that are unable to pump

A familial association of DCM can be identified in 20-50% of DCM patients, with up to 40% of familial patients having an identifiable genetic cause.

Mutations in the BAG3 gene (BCL-2-associated athanogene 3) are among the more common

pathogenic genetic variants observed in familial DCM and these variants are highly penetrant, with approximately 80% of individuals with disease-causing genetic variants in the BAG3 gene developing DCM

at > 40 years of age.

BAG3 protein is associated with a variety of cellular functions including cardiac contractility, protein quality control (as a co-chaperone), cardiomyocyte structural support and anti-apoptosis.

BAG3 associated

dilated cardiomyopathy (BAG3-DCM) leads to early onset, rapidly progressing heart failure and significant mortality and morbidity.

We estimate that the prevalence of BAG3 - associated DCM in the United

States to be as many as 30,000 individuals.

Currently, DCM patients with a BAG3 mutation are treated with the standard of care for heart failure, which include angiotensin converting enzyme inhibitors, angiotensin

receptor blockers, neprilysin inhibitors, beta-adrenergic receptor antagonists, or beta-blockers, aldosterone antagonists and/or diuretics, along with certain lifestyle changes, and do not address the underlying cause of disease.

meet specific parameters may also undergo placement of an implantable cardioverter defibrillator, a cardiac resynchronization device or a combination of the two.

There is no current therapy directly targeting the underlying mechanism of BAG3

associated DCM, and patients diagnosed with BAG3 associated DCM appear to progress to end-stage heart failure and death more rapidly than patients with DCM not associated with BAG3 variants.

For example, approximately 19% of patients with BAG3

DCM require mechanical cardiac support, heart transplant, or have heart failure related death at 12 months after diagnosis, nearly twice the rate of similarly staged non-BAG3 DCM patients.

In December 2022 we completed our acquisition of Renovacor which provided Rocket with Renovacor’s most advanced program, a recombinant AAV9-based gene therapy designed to deliver a fully functional BAG3 gene

to augment BAG3 protein levels in cardiomyocytes and slow or halt progression of BAG3 DCM.

Initial proof of concept for AAV9-BAG3 has been demonstrated in studies of BAG3-knockout mouse models, which show treated mice have improved ejection

fraction versus untreated knockout mice and comparable ejection fraction to walk test controls at timepoints 4- and 6-weeks post injection.

Anticipated Milestones

We are in the process of evaluating the optimal development pathway for this program and plan to submit an IND for BAG3-DCM in the first half of 2024.

Hematology Programs

Fanconi Anemia Complementation Group A (FANCA)

Fanconi Anemia Overview

FA, a rare and life-threatening DNA-repair disorder, generally arises from a mutation in a single FA gene.

An estimated 60 to 70% of cases arise from mutations in the Fanconi-A (“FANCA”) gene, which

is the focus of our program.

An estimated 60 to 70% of cases arise from mutations in the Fanconi-A (“FANCA”) gene,

which is the focus of our program.

FA results in bone marrow failure, developmental abnormalities, myeloid leukemia, and other malignancies, often during the early years and decades of life.

Bone marrow aplasia, which is bone marrow that no longer

produces any or very few red and white blood cells and platelets leading to infections and bleeding, is the most frequent cause of early morbidity and mortality in FA, with a median onset before 10 years of age.

Leukemia is the next most common

cause of mortality, ultimately occurring in about 20% of patients later in life.

Bone marrow aplasia, which is bone marrow that no

longer produces any or very few red and white blood cells and platelets leading to infections and bleeding, is the most frequent cause of early morbidity and mortality in FA, with a median onset before 10 years of age.

Leukemia is the next most

common cause of mortality, ultimately occurring in about 20% of patients later in life.

Solid organ malignancies, such as head and neck cancers, can also occur, although at lower rates during the first two to three decades of life.

Although improvements in allogeneic (donor-mediated) hematopoietic stem cell transplant (“HSCT”), currently the most frequently utilized therapy for FA, have resulted in more frequent hematologic

correction of the disorder, HSCT is associated with both acute and long-term risks, including transplant-related mortality, graft versus host disease (“GVHD”), a sometimes fatal side effect of allogeneic transplant characterized by painful ulcers

in the GI tract, liver toxicity and skin rashes, as well as increased risk of subsequent cancers.

Our gene therapy program in FA is designed to enable a minimally toxic hematologic correction using a patient’s own stem cells during the early

years of life.

ulcers in the GI tract, liver toxicity and skin rashes, as well as increased risk of subsequent cancers.

Our gene therapy program in FA is designed to enable a minimally toxic hematologic correction using a patient’s own stem cells during the

early years of life.

We believe that the development of a broadly applicable autologous gene therapy can be transformative for these patients.

Current Therapy

Allogeneic HSCT may be curative for the hematologic manifestations of FA and is currently considered a standard-of-care in FA.

However, HSCT is limited in that not all patients

have a suitable donor and there is associated short term mortality and potential for acute and chronic GVHD with HSCT, especially in patients who do not receive an allograft from a sibling-human leukocyte antigen (“HLA”)-matched donor.

mortality following allogeneic HSCT continues to be in the 10 to 15% range due to infection, graft failure and other complications.

In a European Group for Blood and Marrow Transplant 2013 publication, a retrospective analysis detailed results

from 795 FA patients receiving HSCT from 1972 to 2010 in which Grade 2-4 Acute GVHD was reported in 19 to 36% of patients and Chronic GVHD was identified in 16 to 20% of patients.

HSCT likely increases the already high risk of subsequent solid tumor malignancies for patients with FA, most notably squamous carcinoma of the head and neck (“SCCHN”).

Based on the findings in one

series of data, HSCT was associated with a 4-fold increase in SCCHN risk relative to FA patients who did not receive a transplant, with cancers developing at an earlier age.

In another more recent but unpublished series, patients with HSCT who

developed GVHD had a 30+-fold increase in SCCHN risk.

Other therapies utilized for FA include androgens, corticosteroids, and hematopoietic growth factors, although the benefits of these therapies are considered modest and transient for the majority of

Side effects may also be considerable.

For androgens, for example, these include masculinization, short stature, hepatitis, liver adenomas and hepatocellular carcinoma.

Because of the severity of the disease and limitations with existing standards-of-care, additional, minimally-toxic therapies are urgently needed in FA, especially if these can be administered with

reduced short- and long-term toxicity relative to allogeneic HSCT.

Rationale for Gene Therapy in FA

Gene therapy has been considered a compelling investigative therapeutic option in FA since the genetic basis of the disorder was characterized and has been the subject of studies

in both preclinical models and in several clinical studies.

In addition to the monogenic nature of each patient’s disease.

We believe there are several critical factors that will help lead our gene therapy programs into the next generation of

promising therapy:

The ability of HSCT to cure the hematologic component of FA is proof-of-principle that gene therapy will work in FA .

If a sufficient number of hematopoietic stem cells (“HSCs”) with a

correct (non-FA) gene are able to engraft in the bone marrow of an FA patient, the blood component of FA can be eradicated, including both the risk of bone marrow failure and of leukemia.

We believe that gene therapy with a patient’s

own gene-corrected blood stem cells will work in a similar manner, but likely with fewer side effects than those resulting from an allogeneic transplant and with reduced long-term treatment cost burden.

Mosaicism in FA patients:

this is a condition in which a second mutation enables formation of a functional FA protein and leads to stabilization or correction of blood counts, in some cases enabling

decades of bone-marrow-failure free survival.

Mosaicism occurs because gene-corrected FA stem and progenitor cells have a selective advantage over uncorrected FA cells;

this phenomenon

has demonstrated that a modest number of gene corrected HSCs can repopulate a patient’s blood and bone marrow with corrected (non-FA) cells.

A comprehensive review of all known cases of somatic mosaicism has demonstrated a correlation

with lowered risk of both bone marrow failure and hematologic malignancy.

This selective advantage also has been demonstrated by the results of our initial FANCOLEN-I gene therapy study in Madrid, Spain, in which patients received

gene-corrected cells without any chemotherapy conditioning;

the percentage of blood and bone marrow cells containing the corrected FA gene has increased progressively over time.

These increases have been accompanied by increases in the

percentage of cells that are resistant to DNA-damaging agents, indicating a reversal of the FA phenotype in the blood and bone marrow of these patients.

Improved vector design, stem cell selection methods, cell harvest and transduction procedures have the potential to substantially improve the quality of autologous gene therapy cell products;

these improvements have been included in our programs .

As a result of these factors, we believe that there is reliable potential to confer disease correction at levels comparable to

allogeneic transplant, but without the chemotherapy conditioning and additional side effects associated with a transplant.

For example, stem cell selection methods utilized by our academic partners have increased both CD34+ cell yield and

purity, while retaining select non-CD34+ populations that may be essential for successful engraftment of gene-corrected cells in the bone marrow.

Rocket Clinical Study

Efforts underway at our partners have incorporated the recommendations of an international FA working group that convened November 2010 with the intent of consolidating medical and scientific

findings and optimizing future gene therapy clinical study design, with programs designed to overcome FA-specific gene therapy challenges.

Our partners have demonstrated the ability to successfully mobilize, and harvest target numbers of

hematopoietic stem and progenitor cells (“HSPCs”) generally acknowledged to be required for successful therapy.

This has been accomplished through the selection of younger patients, and mobilization with both granulocyte-colony stimulating factor

(“G-CSF”) and plerixa for drug products, which are both FDA-approved drugs that increase the number of bone marrow-derived stem cells circulating in the blood.

Improvements to cell processing, such as reduced transduction time requirements,

optimized transduction conditions, and modified HSPC selection processes, have also led to substantive improvements in cell recovery and in vivo VCN.

Improvements in the clinical and cell-processing components of our FA trials are expected to yield more robust and readily-identifiable disease-reversal.

These improvements include selection of

younger patients and identification of blood count profiles that are indicative of adequate stem cell populations capable of mobilization and engraftment in numbers sufficient for reversal of the disorder.

In contrast to the high doses of cytotoxic conditioning required for allogeneic transplant in most bone marrow disorders;

our expectation is that the selective growth advantage of gene-corrected

HSPCs in FA will enable treatment without conditioning agents to facilitate engraftment.

The engraftment of gene-corrected cells is likely to reduce the incidence of bone marrow failure.

In addition, gene-corrected cells are likely to diminish the replicative stress in FA bone marrow,

which has been increasingly implicated as a likely driver of the development or bone marrow failure or leukemia.

Each of our LVV-based programs utilize third-generation, self-inactivating lentiviral vectors to correct defects in patients’ HSCs, which are the cells found in bone marrow that are capable of

Each of our hematology programs utilize third-generation, self-inactivating lentiviral vectors to correct defects in patients’ HSCs, which are the cells found in bone marrow that are capable of

generating blood cells over a patient’s lifetime.

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In light of the efficacy seen in non-conditioned patients, the addressable annual market opportunity is now believed to be 400 to 500 patients collectively in the U.S.

We currently have one ex-vivo LVV-based program targeting FA, RP-L102.

We currently have one ex-vivo LV-based program targeting FA, RP-L102.

RP-L102 is our lead lentiviral vector-based program that we in-licensed from Centro de Investigaciones Energéticas,

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Curative Medicine at Stanford University School of Medicine (“Stanford”), the University of Minnesota, Great Ormond Street Hospital (“GOSH”) in London and Hospital Infantil de Nino Jesus (“HNJ”) in Spain.

The trial is expected to enroll a total

of ten patients from the U.S.

and EU with the first patient in this Phase 2 trial treated in December 2019.

Patients will receive a single intravenous infusion of RP-L102 that utilizes fresh cells and “Process B” which incorporates a modified

stem cell enrichment process, transduction enhancers, as well as commercial-grade vector and final drug product.

The trial has enrolled a total of ten

patients from the U.S.

Two additional patients were treated in the US Phase 1 study at Stanford such that a total of 12 patients have received RP-L102 on Rocket-sponsored clinical trials.

Patients receive a single intravenous infusion

of RP-L102 that utilizes fresh cells and “Process B” which incorporates a modified stem cell enrichment process, transduction enhancers, as well as commercial-grade vector and final drug product.

Resistance to mitomycin-C, a DNA damaging agent, in bone marrow stem cells at a minimum time point of one year post treatment is the primary endpoint for our ongoing Phase 2 study.

Per agreement with

the FDA and EMA, engraftment leading to bone marrow restoration exceeding a 10% mitomycin-C resistance threshold could support a marketing application for approval.

In December 2020, we presented updated interim data from our FA at the 62 nd American Society of Hematology (“ASH”)

Annual Meeting.

The FA data presented at the ASH Annual Meeting were from seven of the nine patients treated (out of twelve patients enrolled) as of October 2020 in both the U.S.

Phase 1 and global Phase 2 studies of RP-L102

Patients in these studies received a single intravenous infusion of “Process B” RP-L102 which incorporates a modified stem cell enrichment process, transduction enhancers, as well as commercial-grade vector.

Preliminary data from these

studies support “Process B” as a consistent and reproducible improvement over “Process A” which was used in earlier academic FA studies.

Seven patients had follow-up data of at least two-months and three of the seven patients had been followed for twelve-months or longer.

As patients are treated with gene therapy product without the

use of a conditioning regimen, the data indicated that RP-L102 was generally well-tolerated with no significant safety issues reported with infusion or post-treatment.

One drug related serious adverse event of Grade 2 transient infusion-related

reaction was observed.

In five out of the seven patients for whom there was follow-up data, evidence of preliminary engraftment was observed, with bone marrow (“BM”) vector copy numbers (“VCNs”) from 0.16 to 0.22 (long-term follow-up only) and

peripheral VCNs ranging from 0.01 (2-month follow-up) to 0.11 (long-term follow-up).

Further, two of the three patients with greater than 12-months follow-up showed evidence of increasing engraftment, mitomycin-C (“MMC”) resistance and stable

blood counts, which suggests a halt in the progression of bone marrow failure.

The third patient with greater than 12-month follow-up contracted Influenza B nine months post-treatment resulting in

progressive BM failure, for which, such patient received a successful bone marrow transplant at 18 months post-treatment.

In May 2021, we presented positive clinical data at the 24th Annual Meeting of the American Society of Gene and Cell Therapy (“ASGCT”).

The preliminary data from the Phase 1/2 trials presented in a

poster at ASGCT were from nine pediatric patients and showed increasing evidence of engraftment in at least six of the nine patients, including two patients with at least 15-months of follow-up and four patients with at least 6-months of

RP-L102 demonstrated a highly favorable tolerability profile with all subjects being treated without conditioning and with no sign of dysplasia.

One patient experienced a Grade 2 transient infusion-related reaction.

In December 2021, we presented encouraging clinical data at the 63rd Annual Meeting of the American Society of Hematology (ASH).

The preliminary results from the Phase 1/2 trials were presented in a

poster at ASH were from eleven pediatric patients and showed increasing evidence of engraftment in at least six of eight patients for whom there are at least 12 months of follow-up, including bone marrow progenitor cell resistance to mitomycin-C

(MMC) ranging from 16-63% in six patients (bone marrow cells in FA patients are highly sensitive to DNA-damaging agents including MMC;

this susceptibility to DNA damage is believed to mediate the FA-associated bone marrow failure and

predisposition to malignancy.

In addition to the development of MMC-resistance in BM hematopoietic cells, sustained peripheral VCN levels were seen in six of seven patients with at least 12-months of follow-up.

One patient experienced an

Influenza B infection approximately 9 months following treatment with concomitant progressive hematologic failure requiring allogeneic hematopoietic stem cell transplant, which was administered successfully;

the remaining patients have not

required transfusions.

Per agreement

with the FDA and EMA, engraftment leading to bone marrow restoration exceeding a 10% mitomycin-C resistance threshold could support a marketing application for approval.

In December 2021, we presented encouraging clinical data at the 63 rd Annual Meeting of the American Society of

Hematology (“ASH”).

The preliminary results from the Phase 1/2 trials presented in a poster at ASH were from eleven pediatric patients and showed increasing evidence of engraftment in at least six of eight patients for whom there are at least

12 months of follow-up, including bone marrow progenitor cell resistance to MMC ranging from 16-63% in six patients (bone marrow cells in FA patients are highly sensitive to DNA-damaging agents including MMC;

this susceptibility to DNA damage

is believed to mediate the FA-associated bone marrow failure and predisposition to malignancy.

In addition to the development of MMC-resistance in BM hematopoietic cells, sustained peripheral VCN levels were seen in six of seven patients with

at least 12-months of follow-up.

One patient experienced an Influenza B infection approximately 9 months following treatment with concomitant progressive hematologic failure requiring allogeneic hematopoietic stem cell transplant, which was

administered successfully;

the remaining patients have not required transfusions.

RP-L102 demonstrated a highly favorable tolerability profile with all subjects being treated without cytotoxic conditioning and no signs of dysplasia.

The only RP-L102 related serious adverse event to-date has been a Grade

2 transient infusion-related reaction in one patient.

RP-L102 related serious adverse event to-date has been a Grade 2 transient infusion-related reaction in one patient.

In May 2022, we presented topline data for RP-L102 at ASGCT’s 25 th Annual Meeting.

Five of nine evaluable

patients as of the April 4, 2022 cut-off date had increased resistance to MMC in bone marrow-derived colony forming cells, ranging from 21% to 42% at 12 to 18 months, increasing to 51% to 94% at 18 – 21 months.

The primary endpoint has been

achieved, based on a trial protocol in which statistical and clinical significance requires a minimum of five patients to attain increased MMC resistance at least 10% above baseline at two or more timepoints, and concomitant evidence of

genetic correction and clinical stabilization.

A sixth patient has displayed evidence of progressively increasing genetic correction as evidenced by peripheral VCN.

Three additional patients were less than 12 months post-treatment at the time

of presentation.

One patient had progressive bone marrow failure following therapy and underwent successful allogeneic transplant as previously disclosed.

The tolerability profile of RP-L102 appears favorable with no signs of dysplasia,

clonal dominance or oncogenic integrations;

as previously reported, one patient experienced a Grade 2 transient infusion-related reaction, which resolved.

In October 2022, we presented data for RP-L102 at the European Society for Cell and Gene Therapy 29 th

Annual Meeting, including the clinical activity results presented at the ASGCT 2022 meeting.

We also disclosed at least one of the additional three patients in our Phase 2 trial of RP-L102 for FA for whom there is less than 12 months of

follow-up has demonstrated initial evidence of engraftment (as demonstrated by bone marrow mitomycin-C resistance and VCN in blood and bone marrow) at levels comparable to those seen in the five patients for whom there is longer-term evidence

of progressive engraftment and phenotypic correction.

We also disclosed that one of the initial five patients in this trial who had evidence of engraftment developed a T-cell lymphoblastic lymphoma approximately 22 months after RP-L102

administration.

A surgical biopsy of the lymphoma indicated negligible gene markings (VCN of 0.003) at a juncture when concomitant VCN in blood and bone marrow were 0.26 and 0.42 respectively.

These findings conclusively indicate that the

lymphoma did not result from a LV-mediated insertion, as there were essentially no gene markings in the tumor (the very low but detectable VCN is likely the result of blood cells in the tumor specimen).

FA is a cancer-predisposition syndrome

and cancers may develop in patients under the age of 10.

Importantly, the patient tolerated induction chemotherapy for the lymphoma without significant complications and is currently in a complete response.

The presence of gene-corrected

hematopoietic cells may have contributed to this patient’s overall tolerance of chemotherapy.

In December 2022, we presented positive clinical data for RP-L102 at the 64 th Annual Meeting of ASH.

RP-L102 conferred phenotypic correction in at least six of 10 evaluable patients with ≥12 months of follow-up as demonstrated by increased resistance to MMC in bone marrow derived colony forming cells, concomitant genetic correction and

hematologic stabilization.

A seventh patient has displayed evidence of progressively increasing genetic correction as demonstrated by peripheral blood and bone marrow VCN’s, with recent development of MMC resistance and possible indicators of

hematologic stability after 36 months of follow-up.

The primary endpoint has been achieved, based on a trial protocol in which statistical and clinical significance requires a minimum of five patients to attain increased MMC resistance at

least 10% above baseline at two or more timepoints and concomitant evidence of genetic correction and clinical stabilization.

The safety profile of RP-L102 has been highly favorable, and the treatment, administered without any cytotoxic

conditioning, has been well tolerated.

No signs of bone marrow dysplasia, clonal dominance or insertional mutagenesis related to RP-L102 have been observed.

Anticipated Milestones

Based on achievement of the primary endpoint as defined in our pivotal Phase 2 study for FA, we have initiated FDA dialogue around biologics license application (“BLA”) filing plans for RP-L102 for the treatment

of FA and anticipate making such filing in Q4 of 2023.

Leukocyte Adhesion Deficiency-I (LAD-I)

Overview of LAD-I

LAD-I is a rare autosomal recessive disorder of white blood cell adhesion and migration, resulting from mutations in the ITGB2 gene encoding for the Beta-2 Integrin component,

Deficiencies in CD18 result in an impaired ability for neutrophils (a subset of infection-fighting white blood cells) to leave blood vessels and enter tissues where these cells are needed to combat infections.

As is the case with many rare

diseases, accurate estimates of incidence are difficult to confirm;

LAD-I is a rare autosomal recessive disorder of white blood cell adhesion and migration, resulting from mutations in the ITGB2 gene encoding for the Beta-2 Integrin component, CD18.

in CD18 result in an impaired ability for neutrophils (a subset of infection-fighting white blood cells) to leave blood vessels and enter tissues where these cells are needed to combat infections.

As is the case with many rare diseases,

accurate estimates of incidence are difficult to confirm;

however, several hundred cases have been reported to date.

Most LAD-I patients are believed to have the severe form of the disease.

Severe LAD-I is notable for recurrent, life-threatening infections and substantial infant mortality in patients who do not

receive an allogeneic HSCT.

Severe LAD-I is notable for recurrent,

life-threatening infections and substantial infant mortality in patients who do not receive an allogeneic HSCT.

Mortality for severe LAD-I has been reported as 60 to 75% by age two in the absence of allogeneic HCST.

Current Therapy

Allogeneic HSCT is the only known curative therapy, with survival rates of approximately 75% in recent studies.

Allogeneic HSCT in LAD-I has been associated with frequent severe

and chronic GVHD, and high rates of subsequent non-bacterial infections (most notably cytomegalovirus (“CMV”) and other viral and systemic fungal infections).

Because LAD-I is the result of mutations in a single gene (ITGB2), we are developing RP-L201, an LVV based program, to enable a potentially curative therapy utilizing patients’ own HSPCs, without the

dependency on the rapid identification of an appropriate donor required in allogeneic HSCT therapy.

It is anticipated that autologous therapy with RP-L201 will also enable definitive correction of this life-threatening disorder with reduced

short- and long-term toxicity relative to allogeneic HSCT.

Rationale for Gene Therapy in LAD-I

We believe there are two key reasons why gene therapy could have a transformative role in the treatment of LAD-I:

(1) the existence of evidence that even modest correction of the expression of the

genetic mutation will increase patient survival in the severe form of the disease, and (2) consistent and robust improvements in transduction and cell processing.

Of note, proprietary transduction protocols currently yield product VCNs ≥ 1 and

transduction efficiencies of > 50%.

In addition, with the addition of either of two transduction enhancing agents, at least a doubling of product VCN has been demonstrated in preliminary experiments.

We believe that combined with a relatively straightforward cell harvest procedure in LAD-I and the likely modest CD18 expression required for clinical impact, RP-L201 can yield a gene therapy product

that confers disease resolution comparable to allogeneic HSCT, and without the severe HSCT-associated acute and chronic toxicities.

Rocket Clinical Study

We currently have one ex -vivo program targeting LAD-I, RP-L201.

RP-L201 is a clinical program that we in-licensed from CIEMAT.

We have partnered with UCLA to

We have partnered with

UCLA to lead U.S.

clinical development efforts for the LAD-I program.

UCLA and its Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is serving as the lead U.S.

clinical research center for the registrational clinical trial for

LAD-I, and HNJ and GOSH serving as the lead clinical sites in Spain and London, respectively.

This study has received a $6.5 million CLIN2 grant award from the California Institute for Regenerative Medicine (“CIRM”) to support the clinical

development of gene therapy for LAD-I.

The ongoing open-label, single-arm, Phase 1/2 registration-enabling clinical trial of RP-L201 has treated four severe LAD-I patients to assess the safety and tolerability of

RP-L201 to date.

The first patient was treated at UCLA with RP-L201 in the third quarter 2019.

clinical research center for the registrational clinical

trial for LAD-I, and HNJ and GOSH serving as the lead clinical sites in Spain and London, respectively.

This study has received a $6.6 million CLIN2 grant award from the California Institute for Regenerative Medicine (“CIRM”) to support the

clinical development of gene therapy for LAD-I.

The open-label, single-arm, Phase 1/2 registration-enabling clinical trial of RP-L201 has treated nine severe LAD-I patients to assess the safety and tolerability of RP-L201

The first patient was treated at UCLA with RP-L201 in the third quarter of 2019.

Enrollment is now complete in both the Phase 1 and 2 portions of the study;

9 patients have received RP-L102 at 3 investigative centers in the US and

nine patients have received RP-L201 at 3 investigative centers in the U.S.

In December 2021, we presented positive clinical data at the 63rd Annual Meeting of ASH.

The ASH oral presentation included preliminary data from eight of nine severe LAD-I patients, as defined by

CD18 expression of less than 2%, who received RP-L201 treatment as of the November 8, 2021, data cut-off date.

Eight patients had follow-up data of at least three months, and four of the eight patients had been followed for 12 months or longer.

The ASH oral presentation included preliminary data from eight of nine severe LAD-I patients, as defined

by CD18 expression of less than 2%, who received RP-L201 treatment as of the November 8, 2021, data cut-off date.

Eight patients had follow-up data of at least three months, and four of the eight patients had been followed for 12 months or

All infusions of RP-L201 were well tolerated and no drug product-related serious adverse events were reported.

Evidence of preliminary efficacy was observed in all eight evaluable patients.

All eight patients demonstrated neutrophil CD18

expression that exceeded the 4-10% threshold associated with survival into adulthood and consistent with reversal of the severe LAD-I phenotype including six patients with at least 6 months of follow-up.

Peripheral blood VCN levels have been

stable and in the 0.54 – 2.94 copies per genome range.

All eight patients demonstrated neutrophil

CD18 expression that exceeded the 4-10% threshold associated with survival into adulthood and consistent with reversal of the severe LAD-I phenotype including six patients with at least 6 months of follow-up.

Peripheral blood VCN levels have

been stable and in the 0.54 – 2.94 copies per genome range.

No patients had LAD-I related infections requiring hospitalization after hematopoietic reconstitution post-RP-L201.

Additional updates presented in January 2022 included a ninth patient

achieving CD18 expression of 61% at 3 months, with the preliminary observation that all nine of nine patients have demonstrated 26% to 87% CD18 expression at timepoints ranging from 3 to 24 months following RP-L102, with stable CD18 expression

levels for each patient subsequent to month 3.

Additional updates presented in January 2022 included a ninth

patient achieving CD18 expression of 61% at 3 months, with the preliminary observation that all nine of nine patients have demonstrated 26% to 87% CD18 expression at timepoints ranging from 3 to 24 months following RP-L102, with stable CD18

expression levels for each patient subsequent to month 3.

In May 2022, we presented updated data at ASGCT’s 25th Annual Meeting.

The presentation included efficacy and safety interim data at three to 24 months of follow-up after infusion for all nine

treated patients and overall survival data, including survival data for the seven patients with at least 12 months of follow-up after infusion as of the March 9, 2022 cut-off date.

All patients, aged three months to nine years, demonstrated

sustained CD18 restoration and expression on more than 10% of neutrop hils (range:

20%-87%, median:

At one year, the overall survival without allogeneic hematopoietic stem cell transplantation across the cohort is 100% based on the

Kaplan-Meier estimate.

As of the data cut-off, all nine patients are alive and clinically stable.

All patients demonstrated a statistically significant reduction in the rate of all-cause hospitalizations and severe infections, relative to

pre-treatment.

Evidence of resolution of LAD-I-related skin rash and restoration of wound repair capabilities has been shown along with sustained phenotypic correction.

The tolerability profile of RP-L201 has been highly favorable in all

patients with no RP-L201-related adverse events.

Adverse events related to other study procedures, including busulfan conditioning, have been previously disclosed and consistent with the tolerability profiles of those agents and procedures.

In December 2022, we presented positive clinical data at the 64 th Annual Meeting of ASH.

The presentation

included previously disclosed top-line data at three to 24 months of follow-up after RP-L201 infusion for all patients and overall survival data for seven patients at 12 months or longer after infusion.

We observed 100% overall survival at 12

months post-infusion via Kaplan Meier estimate and a statistically significant reduction in all hospitalizations, infection and inflammatory-related hospitalizations and prolonged hospitalizations for all nine LAD-I patients with three to 24

months of available follow-up.

Data also shows evidence of resolution of LAD-I-related skin rash and restoration of wound repair capabilities.

The safety profile of RP-L201 has been highly favorable in all patients with no RP-L201-related

serious adverse events to date.

Anticipated Milestones

Based on the positive efficacy and safety data from the Phase 2 pivotal LAD-I trial, w e have initiated discussions with the FDA on BLA filing plans for RP-L201 for the

treatment of severe LAD-I and anticipate making such filing in Q2 of 2023.

Pyruvate Kinase Deficiency (PKD)

Overview of PKD

Red blood cell PKD is a rare autosomal recessive disorder resulting from mutations in the pyruvate kinase L/R (“PKLR”) gene encoding for a component of the red blood cell (“RBC”) glycolytic pathway.

PKD is characterized by chronic non-spherocytic hemolytic anemia, a disorder in which RBCs do not assume a normal spherical shape and are broken down, leading to decreased ability to carry oxygen to cells, with anemia severity that can range from

mild (asymptomatic) to severe forms that may result in childhood mortality or a requirement for frequent, lifelong RBC transfusions.

The pediatric population is the most commonly and severely affected subgroup of patients with PKD, and PKD often

results in splenomegaly (abnormal enlargement of the spleen), jaundice and chronic iron overload which is likely the result of both chronic hemolysis and the RBC transfusions used to treat the disease.

The variability in anemia severity is

believed to arise in part from the large number of diverse mutations that may affect the PKLR gene.

Red blood cell PKD is a rare autosomal recessive disorder resulting from mutations in the pyruvate kinase L/R (“PKLR”) gene encoding for a component of the red blood cell (“RBC”) glycolytic

range from mild (asymptomatic) to severe forms that may result in childhood mortality or a requirement for frequent, lifelong RBC transfusions.

The pediatric population is the most commonly and severely affected subgroup of patients with PKD,

and PKD often results in splenomegaly (abnormal enlargement of the spleen), jaundice and chronic iron overload which is likely the result of both chronic hemolysis and the RBC transfusions used to treat the disease.

The variability in anemia

severity is believed to arise in part from the large number of diverse mutations that may affect the PKLR gene.

Estimates of disease incidence have ranged between 3.2 and 51 cases per million in the white U.S.

and EU population.

Industry estimates suggest at

least 2,500 cases in the U.S.

estimates suggest at least 2,500 cases in the U.S.

and EU have already been diagnosed despite the lack of FDA-approved molecularly targeted therapies.

Market research indicates the application of gene therapy to broader populations could increase the market

opportunity from approximately 250 to 500 patients per year.

Current Therapy

Therapy for PKD is largely supportive, comprised of RBC transfusions and splenectomy for patients who require frequent transfusions.

Chronic RBC transfusions alleviate anemia symptoms, but are

associated with increased morbidity, predominantly from iron overload which may result in cirrhosis, which is a loss of liver cells and irreversible scarring of the liver, and cardiomyopathy, a chronic disease of the heart muscle that leads to a

larger and bulky but inefficient heart, if not diligently managed.

Iron chelation is often considered essential to offset the iron overload associated with chronic hemolysis and RBC transfusions.

Iron chelation entails continuous oral or injected

therapy, often for the duration of a patient’s lifetime and has been associated with diminished quality of life.

Splenectomy may confer a benefit in PKD, frequently yielding increased hemoglobin (“Hb”) levels of 1-2g/dL and a reduction in transfusion requirements.

However, some patients do not benefit from this

procedure, and it is estimated that a substantial proportion of PKD patients remain severely anemic or transfusion-dependent despite splenectomy.

Splenectomy does not eliminate hemolysis, iron overload or the need for iron chelation.

confers an increased susceptibility to serious bacterial infections, and potentially increases the risk of other PKD-associated or other complications such as venous thromboembolism and aplastic or hemolytic crises.

Allogeneic HSCT has been performed successfully for a small number of PKD patients, with reported correction of the clinical and laboratory features of the disorder.

Although reports of HSCT in PKD

suggest that correction of the genetic defect in hematopoietic stem cells may be curative of the disorder, HSCT requires identification of an appropriate HLA-matched donor, is associated with considerable short- and long-term complications

including transplant-related mortality and is not considered a standard-of-care in PKD.

Rationale for Gene Therapy in PKD

Patients with heterozygous PKLR mutations have 50% of normal enzyme activity and are phenotypically normal.

This suggests that it is not necessary for a therapy to achieve normal enzyme levels to

have a clinically meaningful effect.

In PKD-affected mice transplanted with normal marrow, the presence of 10% normal marrow was sufficient to restore normal red blood cells.

We have conducted experiments in which bone marrow cells from healthy

mice are transplanted into PKD affected mice and these results suggest that significant improvement in PKD may be achieved with 20% correction of bone marrow, and complete clinical resolution may likely be achieved when the percentage of bone

marrow gene-corrected cells is in the 20 to 40% range.

An additional study showed that a PKD-affected dog treated with an ex vivo gene therapy was rendered transfusion independent with a normalization of

lactate dehydrogenase, despite only partial gene correction.

Available therapies for PKD, such as splenectomy, are generally associated with an approximate 1.5g/dL increase in hemoglobin levels, and do not modify the underlying iron overload associated with

the disorder.

As indicated in the pre-clinical studies noted above, and more importantly, in the initial clinical results provided subsequently, gene therapy involving genetic correction of long-term stem and progenitor cells, offers a potential

for more comprehensive improvements in hemoglobin, with concomitant reduction in hemolysis and iron overload.

As demonstrated in natural history studies published during recent years, the majority of patients receiving splenectomy do not achieve

normal hemoglobin levels and hence there continues to be substantial need for therapies with potential to correct the underlying causes of the disorder and associated with hemoglobin corrections reaching or approaching normal range.

Rocket Clinical Study

We currently have one ex -vivo LVV-based program targeting PKD, RP-L301.

Market research indicates the application of gene therapy to broader populations could

increase the market opportunity from approximately 250 to 500 patients per year.

We currently have one ex -vivo LV-based program targeting PKD, RP-L301.

RP-L301 is a clinical stage program that we in-licensed from

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This program has been granted US and EMA orphan drug disease designation.

This global Phase 1 open-label, single-arm, clinical trial is expected to enroll six adult and pediatric PKD patients in the U.S.

The trial will be comprised of three cohorts to assess

RP-L301 in young pediatric (age 8-11), older pediatric (age 12-17) and adult populations.

The trial is designed to assess the safety, tolerability, and preliminary activity of RP-L301, and initial safety evaluation will occur in the adult cohort

before evaluation in pediatric patients.

This global Phase 1 open-label, single-arm, clinical trial is expected to enroll four to five adult and pediatric PKD patients in the U.S.

The trial will be comprised of two cohorts

to assess RP-L301 in pediatric (age 8-17) and adult populations.

The trial is designed to assess the safety, tolerability, and preliminary activity of RP-L301, and initial safety evaluation will occur in the adult cohort before evaluation in

pediatric patients.

Stanford will serve as the lead site in the U.S.

for adult and pediatric patients, HNJ will serve as the lead site in Europe for pediatrics, and Hospital Universitario Fundación Jiménez Díaz will serve as

the lead site in Europe for adult patients.

for adult and pediatric patients, HNJ will serve as the lead site in Europe for pediatrics, and Hospital Universitario Fundación Jiménez Díaz will serve as the lead site in

Europe for adult patients.

In July 2020, we treated the first patient in our clinical trial of RP-L301.

In December 2021, we presented positive clinical data at the 63 rd Annual Meeting of ASH.

The ASH poster presentation included preliminary data from two adult patients with severe anemia and

substantial transfusion requirements who were treated as of the November 3, 2021 cut-off date.

Each of these patients had experience extensive PKD-related disease complications including hepatic iron overload.

Both patients have had marked

improvement in hemoglobin levels, from baselines of 7.4 and 7.0 g/dL to 12-month values of 13.3 and 14.8 g/dL respectively;

this represents an improvement from severe (Hb <8g/dL) to normal levels.

Both patients have been transfusion

independent subsequent to post-treatment hematopoietic reconstitution.

Anemia resolution has been accompanied by marked improvement in additional markers of hemolysis, including bilirubin, erythropoietin, and reticulocyte counts.

RP-L301 has been

well tolerated in these adult patients, with no drug product related serious adverse events or infusion-related complications observed through 12-months post-treatment.

Both patients have reported improved quality of life (QOL) following

treatment with increases on FACT-An and additional designated QOL evaluations sustained through 12 months following therapy.

Infantile Malignant Osteopetrosis (IMO):

Overview of Infantile Malignant Osteopetrosis

IMO is a genetic disorder characterized by increased bone density and bone mass secondary to impaired bone resorption.

During normal growth and development small areas of bone are constantly being

broken down by special cells called osteoclasts, then made again by cells called osteoblasts.

In IMO, the cells that break down bone (osteoclasts) do not work properly, which leads to the bones becoming thicker and not as healthy.

Untreated IMO

patients may suffer from a compression of the bone-marrow space, which results in bone marrow failure, anemia, and increased infection risk due to the lack of production of white blood cells.

Untreated IMO patients may also suffer from a

compression of cranial nerves, which transmit signals between vital organs and the brain, resulting in blindness, hearing loss and other neurologic deficits.

IMO represents the autosomal recessive, severe variants of a group of disorders characterized by increased bone density and bone mass secondary to impaired bone resorption.

IMO typically presents in

the first year of life and is associated with severe manifestations leading to death within the first decade of life in the absence of allogeneic HSCT, although HSCT results have been limited to-date and notable for frequent graft failure, GVHD

and other severe complications.

Approximately 50% of IMO results from mutations in the TCIRG1 gene, resulting in cellular defects that prevent osteoclast bone resorption.

As a result of this defect, bone growth is markedly

It is estimated that IMO occurs in 1 out of 250,000-300,000 within the general global population, although incidence is higher in specific geographic regions including Costa Rica, parts of the Middle East, the Chuvash Republic of

Russia, and the Vasterbotten Province of Northern Sweden.

Effective December 2021, the Company made a decision to no longer pursue Rocket-sponsored clinical evaluation of RP-L401;

this program is to be returned to academic innovators.

The Company has opted

to focus available resources towards advancement of RP-A501, RP-L102, RP-L201 and RP-L301, based on the compelling clinical data to date and potential for therapeutic advancement in these severe disorders of childhood and young adulthood.

The ASH poster

presentation included preliminary data from two adult patients with severe anemia and substantial transfusion requirements who were treated as of the November 3, 2021 cut-off date.

Each of these patients had experience extensive PKD-related

disease complications including hepatic iron overload.

Both patients have had marked improvement in hemoglobin levels, from baselines of 7.4 and 7.0 g/dL to 12-month values of 13.3 and 14.8 g/dL respectively;

this represents an improvement from

severe (Hb <8g/dL) to normal levels.

Both patients have been transfusion independent subsequent to post-treatment hematopoietic reconstitution.

Anemia resolution has been accompanied by marked improvement in additional markers of hemolysis,

including bilirubin, erythropoietin, and reticulocyte counts.

RP-L301 has been well tolerated in these adult patients, with no drug product related serious adverse events or infusion-related complications observed through 12-months

post-treatment.

Both patients have reported improved QOL following treatment with increases on FACT-An and additional designated QOL evaluations sustained through 12 months following therapy.

In May 2022, we presented updated data at the 25 th Annual Meeting of the ASGCT.

The presentation included

data from two adult patients with severe or transfusion-dependent anemia as of the April 13, 2022 cut-off date.

At 18 months post-infusion, both patients had sustained transgene expression, normalized hemoglobin, improved hemolysis, no red

blood cell transfusion requirements post-engraftment and improved QOL both reported anecdotally and as documented via formal QOL assessments.

The tolerability profile of RP-L301 appears favorable, with no RP-L-301-related serious adverse

events through 18 months post-infusion.

Transient transaminase elevation was seen in both patients post-therapy/conditioning, with no clinical stigmata of liver injury and subsequent resolution without clinical sequelae.

The pediatric cohort

is currently enrolling.

In December 2022, we presented positive clinical data at the 64 th Annual Meeting of ASH.

The presentation included

positive updated data from two adult patients with significant anemia.

At 24 months post-infusion, both patients have robust and sustained efficacy demonstrated by normalized hemoglobin (from baseline levels in the 7.0-7.5 g/dL range), improved

hemolysis parameters, independence from red blood cell transfusions and improved quality of life both reported anecdotally and as documented via formal quality of life assessments.

The safety profile appears highly favorable, with no

RP-L301-related serious adverse events through 24 months post-infusion in both adult patients.

Insertion site analyses in peripheral blood and bone marrow in both adult patients up to 12 months post-RP-L301 demonstrated highly polyclonal

patterns and there has been no evidence of insertional mutagenesis.

Anticipated Milestones

Enrollment in the PKD adult and pediatric cohort is completed in the Phase 1 study.

Initiation of the phase 2 pivotal trial is anticipated in Q4 of 2023.

cGMP Manufacturing

Our new, 103,720 square foot manufacturing facility in Cranbury, New Jersey has been scaled up to manufacture AAV drug product for a planned Phase 2 pivotal study in Danon disease.

The facility also houses lab

space for research & development and quality.

We reached an understanding with the FDA on chemistry, manufacturing, and controls requirements to start AAV cGMP manufacturing at our in-house facility as well as potency assay plans for a

Phase 2 pivotal trial in Danon disease.

To further strengthen our manufacturing and commercial capabilities during 2022, we appointed Mayo Pujols, one of the most seasoned cell and gene therapy technical operations and manufacturing leaders in

the industry, as our Chief Technical Officer.

We seek to bring hope and relief to patients with devastating, undertreated, rare pediatric diseases through the development and commercialization of potentially curative first-in-class gene

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substantial unmet need, develop proprietary in-house analytics and manufacturing capabilities and continue to commence registration trials for our currently planned programs.

In the medium and long-term, we expect to submit our first biologics

license applications (“BLAs”) and establish our gene therapy platform and expand our pipeline to target additional indications that we believe to be potentially compatible with our gene therapy technologies.

In addition, during that time, we

believe that our currently planned programs will become eligible for priority review vouchers from the FDA that provide for expedited review.

We have assembled a leadership and research team with expertise in cell and gene therapy, rare disease

drug development and product approval.

In the medium and long-term, pending favorable data, we expect to

submit BLAs for the rest of our suite of clinical programs, and establish our gene therapy platform and expand our pipeline to target additional indications that we believe to be potentially compatible with our gene therapy technologies.

addition, during that time, we believe that our currently planned programs will become eligible for priority review vouchers from the FDA that provide for expedited review.

We have assembled a leadership and research team with expertise in cell

and gene therapy, rare disease drug development and product approval.

We believe that our competitive advantage lies in our disease-based selection approach, a rigorous process with defined criteria to identify target diseases.

We believe that this

approach to asset development differentiates us as a gene therapy company and potentially provides us with a first-mover advantage.

We believe that

this approach to asset development differentiates us as a gene therapy company and potentially provides us with a first-mover advantage.

Intellectual Property

We strive to protect and enhance the proprietary technology, inventions, and improvements that are commercially important to the development of our business, including seeking, maintaining, and

defending patent rights, whether developed internally or licensed from third parties.

We strive to protect and enhance the proprietary technology, inventions, and improvements that are commercially important to the development of our business, including seeking, maintaining,

and defending patent rights, whether developed internally or licensed from third parties.

We also rely on trade secrets relating to our proprietary technology platform and on know-how, continuing technological innovation and in-licensing

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drug designations, data exclusivity, market exclusivity, and patent term extensions where available.

Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our

Our commercial success may depend in part on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business;

defend and enforce our patents;

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and operate without infringing the valid enforceable patents and proprietary rights of third parties.

Our ability to stop third parties from making,

using, selling, offering to sell or importing its future products may depend on the extent to which we have rights under valid and enforceable patents or trade secrets that cover these activities.

Our ability to stop third parties from making, using,

selling, offering to sell or importing its future products may depend on the extent to which we have rights under valid and enforceable patents or trade secrets that cover these activities.

With respect to both licensed and company-owned

intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents

or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same.

We have developed and in-licensed numerous patents and patent applications and possess substantial know-how and trade secrets relating to the development and commercialization of gene therapy

Our proprietary intellectual property, including patent and non-patent intellectual property, is generally directed to gene expression vectors and methods of using the same for gene therapy.

As of February 22, 2022, our patent portfolio

includes both owned and in-licensed patent families relating to our product candidates and related technologies, discussed more fully below.

patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same.

We have developed and in-licensed numerous patents and patent applications and possess substantial know-how and trade secrets relating to the development and commercialization of gene therapy products.

proprietary intellectual property, including patent and non-patent intellectual property, is generally directed to gene expression vectors and methods of using the same for gene therapy.

As of February 22, 2023, our patent portfolio includes

both owned and in-licensed patent families relating to our product candidates and related technologies, discussed more fully below.

Fanconi Anemia

Our Fanconi Anemia program includes two in-licensed patent families.

The first family includes pending patents and pending applications in the U.S., Europe, Japan, China and other countries with

claims directed to polynucleotide cassettes and expression vector compositions containing Fanconi Anemia complementation group genes and methods for using such vectors to provide gene therapy in mammalian cells for treating Fanconi Anemia.

application was exclusively in-licensed from CIEMAT, Centro de Investigacion Biomedica En Red, (“CIBER”), Fundacion Instituto de investigacion Sanitaria Fundacion Jimenez Diaz, (“FIISFJD”), and Fundacion Para la Investigacion Biomedica del

Hospital Del Nino Jesus.

We expect any patents in this family, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2037, absent any patent term adjustments or extensions.

The second family includes pending U.S., Japanese, and European patent applications related to a portable platform for use in hematopoietic stem/progenitor cell-based gene therapy.

This patent family

was exclusively in-licensed from the Fred Hutchinson Cancer Research Center.

we expect any patents in this portfolio, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2036, absent

any patent term adjustments or extensions.

Pyruvate Kinase Deficiency (PKD)

Our PKD patent portfolio includes a pending patent application in the U.S., EU, Japan, China and other countries with claims directed to polynucleotide cassettes and expression vector compositions

containing pyruvate kinase genes and methods for using such vectors to provide gene therapy in mammalian cells for treating pyruvate kinase deficiency.

This application was exclusively in-licensed from CIEMAT, CIBER, and FIISFJD.

Our Fanconi Anemia patent portfolio includes granted patents in Australia and Japan and pending applications in the U.S., Europe, Japan, China and other countries with claims directed to polynucleotide cassettes

and expression vector compositions containing Fanconi Anemia complementation group genes and methods for using such vectors to provide gene therapy in mammalian cells for treating Fanconi Anemia.

These applications were exclusively in-licensed

from CIEMAT, Centro de Investigacion Biomedica En Red, (“CIBER”), Fundacion Instituto de investigacion Sanitaria Fundacion Jimenez Diaz, (“FIISFJD”), and Fundacion Para la Investigacion Biomedica del Hospital Del Nino Jesus.

We expect any

patents in this portfolio, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2037, absent any patent term adjustments or extensions.

patents in this family, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2037, absent any patent term adjustments or extensions.

Pyruvate Kinase Deficiency (PKD)

Our PKD patent portfolio includes granted patents in Europe, China, Hong Kong, Japan, Mexico, South Korea, and the United States and a pending patent application in the U.S., EU, Japan, China and other countries

with claims directed to polynucleotide cassettes and expression vector compositions containing pyruvate kinase genes and methods for using such vectors to provide gene therapy in mammalian cells for treating pyruvate kinase deficiency.

applications are exclusively in-licensed from CIEMAT, CIBER, and FIISFJD.

We expect any patents in this portfolio, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2037-2038,

absent any patent term adjustments or extensions.

Danon Disease

Our Danon disease patent portfolio includes both proprietary intellectual property and a patent family in-licensed from the University of California, San Diego, which includes patent applications in

the U.S., Europe, Japan, China and other countries with claims directed to the treatment of Danon disease.

We expect any patents in this portfolio, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are

paid, to expire in 2037 absent any patent term adjustments or extensions.

Our Danon disease patent portfolio includes both proprietary intellectual property and a patent family in-licensed from the University of California, San Diego, which includes patent applications in the U.S.,

Europe, Japan, China and other countries with claims directed to the treatment of Danon disease.

We expect any patents in this portfolio, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to

expire in 2037 absent any patent term adjustments or extensions.

We also own a U.S.

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patent issued in 2020.

Any patents, if issued, arising from any national stage applications filed from these patent applications, are expected to expire in 2039, absent any patent term adjustments or extensions, if the

appropriate maintenance, renewal, annuity, or other governmental fees are paid.

We have also filed a provisional patent application directed to methods for treatment of Danon disease.

Any patents, if issued, arising from this provisional patent

application, are expected to expire in 2041, absent any patent term adjustments or extensions, if the appropriate maintenance, renewal, annuity, or other governmental fees are paid.

Infantile Malignant Osteopetrosis (IMO)

Our IMO patent portfolio includes a pending PCT patent application with claims related to a method of manufacturing lentiviral vector used to transduce allogeneic HSCT.

We expect any patents arising

from any national stage applications filed from this PCT application, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2040, absent any patent term adjustments or extensions.

Any patents, if issued, arising from these patent applications, are expected to expire in 2039, absent any patent term adjustments or extensions, if the appropriate maintenance, renewal, annuity, or

other governmental fees are paid.

We have also filed additional patent applications directed to methods for treatment of Danon disease.

Any patents, if issued, arising from these patent applications, are expected to expire in 2040-2041, absent

any patent term adjustments or extensions, if the appropriate maintenance, renewal, annuity, or other governmental fees are paid.

Leukocyte Adhesion Deficiency (LAD-I)

Our patent portfolio includes pending patent applications in the U.S., EU, Japan, China and other countries with claims directed to transduction of allogeneic HSCT, which may be relevant to our LAD-I

We expect any patents arising from these patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2039, absent any patent term adjustments or extensions.

Our patent portfolio includes pending patent applications in the U.S., EU, Japan, China and other countries with claims directed to transduction of allogeneic HSCT, which may be relevant to our LAD-I program.

expect any patents arising from these patent applications, if issued, and if the appropriate maintenance, renewal, annuity, or other governmental fees are paid, to expire in 2039, absent any patent term adjustments or extensions.

Our objective is to continue to expand its portfolio of patents and patent applications in order to protect our gene therapy product candidates and manufacturing processes.

From time to time, we may

also evaluate opportunities to sublicense our portfolio of patents and patent applications that we own or exclusively license, and we may enter into such licenses from time to time.

The term of individual patents depends upon the legal term of

the patents in the countries in which they are obtained.

From time to time, we may also

evaluate opportunities to sublicense our portfolio of patents and patent applications that we own or exclusively license, and we may enter into such licenses from time to time.

The term of individual patents depends upon the legal term of the

patents in the countries in which they are obtained.

In most countries in which we file, the patent term is 20 years from the date of filing the non-provisional application.

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The term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration of a U.S.

patent as compensation for the patent term lost

during the FDA regulatory review process.

patent as compensation for the patent term lost during the

FDA regulatory review process.

The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent.

The length of the patent term extension is related to the length of time the drug is under

regulatory review.

The length of the patent term extension is related to the length of time the drug is under regulatory

A patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended.

Moreover, a patent can only

be extended once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product.

Moreover, a patent can only be

extended once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product.

Similar provisions are available in Europe and other foreign jurisdictions to extend the term of a patent that covers

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However, trade secrets can be difficult to protect.

We seek to protect our proprietary technology and processes, in

part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and third parties.

We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of

its premises and physical and electronic security of its information technology systems.

We seek to protect our proprietary technology and processes, in part, by

entering into confidentiality agreements with our employees, consultants, scientific advisors and third parties.

We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of its

premises and physical and electronic security of its information technology systems.

While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate

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In addition, our trade secrets may otherwise become known or be independently discovered by competitors.

To the extent that our consultants or collaborators use intellectual property owned by others in their work for us,

disputes may arise as to the rights in related or resulting know-how and inventions.

To the extent that our consultants or collaborators use intellectual property owned by others in their work for

us, disputes may arise as to the rights in related or resulting know-how and inventions.

Material Contracts

License Agreements with CIEMAT

In March 2016, we entered into a license agreement with CIEMAT, CIBER, and FIISFJD, (collectively, “CIEMAT”), granting us worldwide, exclusive rights to certain patents, know-how and other

intellectual property relating to lentiviral vectors containing the human PKLR gene solely within the field of treating PKD.

Under the terms of the agreement, we are obligated to use commercially reasonable efforts to (a) develop and obtain

regulatory approval for one or more products or processes covered by the licensed intellectual property, introduce such products or processes into the commercial market and then make them reasonably available to the public (b) develop or

commercialize at least one product or process covered by the licensed intellectual property in at least one country for at least two uninterrupted years following regulatory approval, and (c) use the licensed intellectual property in an adequate,

ethical and legitimate manner.

In exchange for the license, we are obligated to pay CIEMAT an up-front payment, royalty payments based on net sales of products or processes involving any of the licensed intellectual property, developmental and

regulatory milestone payments, and sublicense revenue payments.

In March 2016, we entered into a license agreement with CIEMAT, CIBER, and FIISFJD, (collectively, “CIEMAT”), granting us worldwide, exclusive rights to certain patents, know-how and other intellectual property

relating to lentiviral vectors containing the human PKLR gene solely within the field of treating PKD.

Under the terms of the agreement, we are obligated to use commercially reasonable efforts to (a) develop and obtain regulatory approval for

one or more products or processes covered by the licensed intellectual property, introduce such products or processes into the commercial market and then make them reasonably available to the public (b) develop or commercialize at least one

product or process covered by the licensed intellectual property in at least one country for at least two uninterrupted years following regulatory approval, and (c) use the licensed intellectual property in an adequate, ethical and legitimate

payments, and sublicense revenue payments.

We are responsible for prosecuting and maintaining the licensed patents at our expense, in cooperation with CIEMAT.

We also have the first responsibility to enforce and defend the

licensed patents against infringement and/or challenge, in cooperation with CIEMAT.

For five years following the effective date of the license agreement, we have a right of first refusal to license any improvements to the licensed intellectual

property obtained by CIEMAT at market value.

We also have the first responsibility to enforce and defend the licensed patents

against infringement and/or challenge, in cooperation with CIEMAT.

For five years following the effective date of the license agreement, we had a right of first refusal to license any improvements to the licensed intellectual property obtained

by CIEMAT at market value.

We are obligated to license (without charge) to CIEMAT for non-commercial use any improvements to the licensed intellectual property that we create.

As consideration for the licensed rights, we paid CIEMAT an initial upfront license fee of €0.03 million (approximately $0.03 million) which was expensed as research and development (“R&D”)

We are obligated to make aggregate milestone payments of up to €1.4 million (approximately $1.5 million) to CIEMAT upon the achievement of specified development and regulatory milestones.

With respect to any commercialized products covered

by the PKD license, we are obligated to pay a low to mid-single digit percentage royalty on net sales, subject to specified adjustments, by us or our sublicensees or affiliates.

In the event that we enter into a sublicense agreement with a

sublicensee, we will be obligated to pay a portion of any consideration received from such sublicensees in specified circumstances.

As consideration for the licensed rights, we paid CIEMAT an initial upfront license fee of €0.03 million (approximately $0.03 million) which was expensed as research and development (“R&D”) costs.

obligated to make aggregate milestone payments of up to €1.4 million (approximately $1.5 million) to CIEMAT upon the achievement of specified development and regulatory milestones.

With respect to any commercialized products covered by the PKD

license, we are obligated to pay a low to mid-single digit percentage royalty on net sales, subject to specified adjustments, by us or our sublicensees or affiliates.

In the event that we enter into a sublicense agreement with a sublicensee, we

will be obligated to pay a portion of any consideration received from such sublicensees in specified circumstances.

We may terminate this agreement at any time by providing CIEMAT with 90 days advance notice.

The license is in effect for a duration for each of the countries defined in this agreement for as long as

a license right exists that covers the licensed product or process in such country, or until the end of any additional legal protection that should be obtained for the license rights in each country.

In July 2016, we entered into a license agreement with CIEMAT granting us worldwide, exclusive rights to certain patents, know-how, data and other intellectual property relating

to lentiviral vectors containing the FA-A gene solely within the field of human therapeutic uses of VSV-G packaged integration component lentiviral vectors for FA type-A gene therapy.

This license is only sublicensable with the prior consent of

CIEMAT, not to be unreasonably withheld.

Under the terms of the agreement, we are obligated to use commercially reasonable efforts to (a) develop and obtain regulatory approval for one or more products or processes covered by the licensed

intellectual property, introduce such products or processes into the commercial market and then make them reasonably available to the public (b) develop or commercialize at least one product or process covered by the licensed intellectual

property in at least one country for at least two uninterrupted years following regulatory approval, and (c) use the licensed intellectual property in an adequate, ethical and legitimate manner.

In exchange for the license, we are obligated to

pay CIEMAT an up-front payment, royalty payments based on net sales of products or processes involving any of the licensed intellectual property, regulatory and financing milestone payments, and sublicense revenue payments.

We are responsible for

prosecuting and maintaining the licensed patents at our expense, in cooperation with CIEMAT.

The license is in effect for a duration for each of the countries defined in this agreement for as long as a license

right exists that covers the licensed product or process in such country, or until the end of any additional legal protection that should be obtained for the license rights in each country.

In July 2016, we entered into a license agreement with CIEMAT granting us worldwide, exclusive rights to certain patents, know-how, data and other intellectual property relating to lentiviral vectors containing

the FA-A gene solely within the field of human therapeutic uses of VSV-G packaged integration component lentiviral vectors for FA type-A gene therapy.

This license is only sublicensable with the prior consent of CIEMAT, not to be unreasonably

Under the terms of the agreement, we are obligated to use commercially reasonable efforts to (a) develop and obtain regulatory approval for one or more products or processes covered by the licensed intellectual property, introduce

such products or processes into the commercial market and then make them reasonably available to the public (b) develop or commercialize at least one product or process covered by the licensed intellectual property in at least one country for

at least two uninterrupted years following regulatory approval, and (c) use the licensed intellectual property in an adequate, ethical and legitimate manner.

In exchange for the license, we are obligated to pay CIEMAT an up-front payment,

royalty payments based on net sales of products or processes involving any of the licensed intellectual property, regulatory and financing milestone payments, and sublicense revenue payments.

We are responsible for prosecuting and maintaining

the licensed patents at our expense, in cooperation with CIEMAT.

We also have the first responsibility to enforce and defend the licensed patents against infringement and/or challenge, in cooperation with CIEMAT.

five years following the effective date of the license agreement, we have a right of first refusal to license any improvements to the licensed intellectual property obtained by CIEMAT at market value.

We are obligated to license (without charge)

to CIEMAT for non-commercial use any improvements to the licensed intellectual property that we create.

For five years following the

effective date of the license agreement, we have a right of first refusal to license any improvements to the licensed intellectual property obtained by CIEMAT at market value.

We are obligated to license (without charge) to CIEMAT for

non-commercial use any improvements to the licensed intellectual property that we create.

As consideration for the licensed rights, we paid CIEMAT an initial upfront license fee of €0.1 million (approximately $0.1 million), which was expensed as R&D costs.

We are obligated to make

aggregate milestone payments of up to €5.0 million (approximately $6.0 million) to CIEMAT upon the achievement of specified development and regulatory milestones.

With respect to any commercialized products covered by the license, we are

obligated to pay a mid-single digit percentage royalty on net sales, subject to specified adjustments, by us or our sublicensees or affiliates.

In the event that we enter into a sublicense agreement with a sublicensee, we will be obligated to pay

a portion of any consideration received from such sublicensees in specified circumstances.

We are obligated to make aggregate

milestone payments of up to €5.0 million (approximately $6.0 million) to CIEMAT upon the achievement of specified development and regulatory milestones.

With respect to any commercialized products covered by the license, we are obligated to pay

a mid-single digit percentage royalty on net sales, subject to specified adjustments, by us or our sublicensees or affiliates.

In the event that we enter into a sublicense agreement with a sublicensee, we will be obligated to pay a portion of

any consideration received from such sublicensees in specified circumstances.

We may terminate this agreement at any time by providing CIEMAT with 90 days’ advance notice.

The license is in effect for a duration for each of the countries defined in this agreement for as long

as a license right exists that covers the licensed product or process in such country, or until the end of any additional legal protection that should be obtained for the license rights in each country.

The license is in effect for a duration for each of the countries defined in this agreement for as long as a license

right exists that covers the licensed product or process in such country, or until the end of any additional legal protection that should be obtained for the license rights in each country.

License Agreement for LAD-I with CIEMAT and UCLB

We entered into a license agreement in November 2017, effective September 2017, with CIEMAT and UCL Business PLC (“UCLB”), collectively referred to as (“Licensors”), granting us worldwide, exclusive

rights to certain patents, know-how and other intellectual property relating to lentiviral vectors containing the human LAD-I gene solely within the field of treating LAD-I.

certain patents, know-how and other intellectual property relating to lentiviral vectors containing the human LAD-I gene solely within the field of treating LAD-I.

Under the terms of the agreement, we are obligated to use commercially

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licensed intellectual property in an adequate, ethical and legitimate manner.

In exchange for the license, we are obligated to pay Licensors an up-front payment, royalty payments in the mid-single digit percentages based on net sales of products

or processes involving any of the licensed intellectual property, developmental and regulatory milestone payments, and sublicense revenue payments.

We are responsible for prosecuting and maintaining the licensed patents at our expense, in

cooperation with Licensors.

In exchange for the license, we are obligated to pay Licensors an up-front payment, royalty payments in the mid-single digit percentages based on net sales of

products or processes involving any of the licensed intellectual property, developmental and regulatory milestone payments, and sublicense revenue payments.

We are responsible for prosecuting and maintaining the licensed patents at our expense,

in cooperation with Licensors.

We also have the first responsibility to enforce and defend the licensed patents against infringement and/or challenge, in cooperation with Licensors.

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agreement, we have a right of first refusal to license any improvements to the licensed intellectual property obtained by Licensors at market value.

We are obligated to license (without charge) to Licensors for non-commercial use any improvements

to the licensed intellectual property that we create.

We are obligated to license (without charge) to Licensors for non-commercial use any

improvements to the licensed intellectual property that we create.

As consideration for the licensed rights, we paid Licensors an initial upfront license fee of €0.03 million (approximately $0.04 million), which was expensed as R&D costs.

We are obligated to

make aggregate payments of up to €1.4 million (approximately $1.5 million) to Licensors upon the achievement of specified development and regulatory milestones.

With respect to any commercialized products covered by the LAD-I license, we are

obligated to pay a mid-single digit percentage royalty on net sales, subject to specified adjustments, by us or our sublicensees or affiliates.

In the event that we enter into a sublicense agreement with a sublicensee, we will be obligated to pay

a portion of any consideration received from such sublicensees in specified circumstances.

We are obligated to make aggregate

payments of up to €1.4 million (approximately $1.5 million) to Licensors upon the achievement of specified development and regulatory milestones.

With respect to any commercialized products covered by the LAD-I license, we are obligated to pay

a mid-single digit percentage royalty on net sales, subject to specified adjustments, by us or our sublicensees or affiliates.

In the event that we enter into a sublicense agreement with a sublicensee, we will be obligated to pay a portion of

any consideration received from such sublicensees in specified circumstances.

We may terminate this agreement at any time by providing the Licensors with 90 days advance notice.

The license is in effect for a duration for each of the

countries defined in this agreement for as long as a license right exists that covers the licensed product or process in such country, or until the end of any additional legal protection that should be obtained for the license rights in each

The license is in effect for a duration for each of the countries defined in this

agreement for as long as a license right exists that covers the licensed product or process in such country, or until the end of any additional legal protection that should be obtained for the license rights in each country.

License Agreement for Danon Disease with UCSD

In February 2017, we entered into a license agreement with The Regents of the University of California, represented by its San Diego campus (“UCSD”), under which UCSD granted us an exclusive,

sublicensable, worldwide license to certain intellectual property rights for the treatment of lysosomal storage diseases, including Danon disease.

In exchange for the license, we became obligated to make an up-front payment, certain clinical and

commercial milestone payments, royalty payments (on net sales of products covered by a valid claim within the licensed intellectual property), maintenance fees and sublicense revenue payments.

The upfront license fee of $0.05 million was expensed to R&D costs in the 2020 consolidated statements of operations.

We are obligated to make aggregate milestone payments of up to $1.5 million

to UCSD upon the achievement of specified development and regulatory milestones for the treatment of Danon disease.

A reduced schedule of milestone payments applies to achieving the same milestones for additional indications.

With respect to any

commercialized products covered by the agreement, we are obligated to pay a low single digit percentage royalty on net sales, subject to specified adjustments.

If we enter into a sublicense agreement with a sublicensee, we will be obligated to

pay a portion of any consideration received from such sublicensees in specified circumstances.

We are also subject to certain diligence milestones for development of a product using the intellectual property licensed from UCSD under this

In February 2017, we entered into a license agreement with The Regents of the University of California, represented by its San Diego campus (“UCSD”), under which UCSD granted us an exclusive, sublicensable,

worldwide license to certain intellectual property rights for the treatment of lysosomal storage diseases, including Danon disease.

In exchange for the license, we became obligated to make an up-front payment, certain clinical and commercial

milestone payments, royalty payments (on net sales of products covered by a valid claim within the licensed intellectual property), maintenance fees and sublicense revenue payments.

Rocket paid an upfront license fee of $0.05 million.

obligated to make aggregate milestone payments of up to $1.5 million to UCSD upon the achievement of specified development and regulatory milestones for the treatment of Danon disease.

A reduced schedule of milestone payments applies to

achieving the same milestones for additional indications.

With respect to any commercialized products covered by the agreement, we are obligated to pay a low single digit percentage royalty on net sales, subject to specified adjustments.

enter into a sublicense agreement with a sublicensee, we will be obligated to pay a portion of any consideration received from such sublicensees in specified circumstances.

We are also subject to certain diligence milestones for development of

a product using the intellectual property licensed from UCSD under this agreement.

The term of the license agreement with UCSD is through the expiration of the licensed patents, some of which are still in the pending application phase.

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(“RGNX”), pursuant to which we obtained an exclusive license for all U.S.

patents and patent applications related to

RGNX’s NAV AAV-9 vector for the treatment of Danon disease in humans by in vivo gene therapy using AAV-9 to deliver any known LAMP2 transgene isoforms and all possible combinations of LAMP2 transgene

isoforms (the “Field”), as well as an exclusive option to license (the “Option Right”) all U.S.

patents and patent applications related to RGNX’s NAV AAV-9

vector for the treatment of Danon disease in humans by in vivo gene therapy using AAV-9 to deliver any known LAMP2 transgene isoforms and all possible combinations of LAMP2 transgene isoforms (the

“Field”), as well as an exclusive option to license (the “Option Right”) all U.S.

patents and patent applications for two additional NAV AAV vectors in the Field (each, a “Licensed Patent” and collectively, the “Licensed Patents”).

In consideration for the rights granted to us under the license agreement, we made an upfront payment to RGNX of $7.0 million which was expensed to R&D costs in the 2018 consolidated statements

of operations.

In consideration for the rights granted to us under the license agreement, we made an upfront payment to RGNX of $7.0 million which was expensed to R&D costs in the 2018 consolidated statement of operations.

A fee of $2.0 million per additional vector would be due if we exercise our Option Right to purchase additional vectors.

The license agreement provides for royalties payable to RGNX in the high-single digits to low-teens on net

sales levels of products incorporating the Licensed Patents (the “Licensed Products”) during the royalty term.

If successful, we will be required to make milestone payments to RGNX of up to $13.0 million for each Licensed Product upon the

achievement of specified clinical development and regulatory milestones in the U.S.

In addition, we shall pay RGNX 20% of the payment fees received from a priority review voucher issued in connection with or otherwise related to a

Licensed Product.

The license agreement provides for royalties payable to RGNX in the high-single digits to low-teens on net sales levels of

products incorporating the Licensed Patents (the “Licensed Products”) during the royalty term.

If successful, we will be required to make milestone payments to RGNX of up to $13.0 million for each Licensed Product upon the achievement of

specified clinical development and regulatory milestones in the U.S.

In addition, we shall pay RGNX 20% of the payment fees received from a priority review voucher issued in connection with or otherwise related to a Licensed Product.

These royalty obligations are subject to specified reductions if additional licenses from third parties are required.

We must also pay RGNX a portion of all non-royalty sublicense income (if any) received from sublicensees.

paid a $1.0 million license fee payment under the RGNX agreement upon the dosing of the first Danon patient in 2019 which was expensed to R&D costs in the 2019 consolidated statements of operations.

There were no additional milestones

achieved or related payments made during the years ended December 31, 2021 and 2020.

The biotechnology and pharmaceutical industries, including in the field of gene therapy, are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary

products and novel therapies.

We paid a $1.0

million license fee payment under the RGNX agreement upon the dosing of the first Danon patient in 2019.

There were no additional milestones achieved or related payments made during the years ended December 31, 2022 and 2021.

At-the-Market Offering Program

On February 28, 2022, we entered into the Sales Agreement with Cowen with respect to an at-the-market offering program pursuant to which we may offer and sell, from time to time at our sole discretion, shares

through Cowen as our sales agent.

The shares to be offered and sold under the Sales Agreement are being offered and sold pursuant to our shelf registration statement on Form S-3 (File No.

We filed a prospectus supplement with the

SEC on February 28, 2022, in connection with the offer and sale of the shares and have agreed to pay Cowen a cash commission of 3.0% of gross proceeds from the sale of the shares, pursuant to the Sales Agreement.

We also agreed to provide

Cowen with customary indemnification and contribution rights and will also reimburse Cowen for certain expenses incurred in connection with the Sales Agreement.

Through December 31, 2022, we have sold

3.3 million shares of common stock pursuant to the at-the-market offering program for gross proceeds of $48.0 million, less commissions of $1.4 million for net proceeds of $46.6 million.

The biotechnology and pharmaceutical industries, including in the field of gene therapy, are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products and

novel therapies.

While we believe that our experience and scientific knowledge provides it with competitive advantages, we face potential competition from many different sources, including larger and better-funded pharmaceutical and

biotechnology companies, new market entrants and new technologies, as well as from academic institutions, government agencies and private and public research institutions, which may in the future develop products to treat the indications targeted

by our pipeline that have not yet been conceived.

Any product candidates that we successfully develop and commercialize will compete with existing therapies such as bone marrow transplantation and new therapies that may become available in the

We believe that the key competitive factors affecting the success of our product candidates, if approved, are likely to be efficacy, safety, convenience, price, pharmaco-economic value, tolerability and the availability of coverage and

adequate reimbursement from governmental authorities and other third-party payors.

In addition, we intend to develop single treatment curative therapies for clinical indications that address mortality or high morbidity, which could differentiate

us from potential competitors developing alternative competitive therapies that may require chronic or repetitive treatment.

targeted by our pipeline that have not yet been conceived.

Any product candidates that we successfully develop and commercialize will compete with existing therapies such as bone marrow transplantation and new therapies that may become

available in the future.

of coverage and adequate reimbursement from governmental authorities and other third-party payors.

In addition, we intend to develop single treatment curative therapies for clinical indications that address mortality or high morbidity, which

could differentiate us from potential competitors developing alternative competitive therapies that may require chronic or repetitive treatment.

Other early-stage companies may also compete through collaborative arrangements with large and established companies.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may

result in even more resources being concentrated among a smaller number of companies developing gene therapies.

These companies also compete with us in recruiting and retaining qualified scientific and management personnel and establishing

clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in

even more resources being concentrated among a smaller number of companies developing gene therapies.

These companies also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial

sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

We anticipate that we will face intense and increasing competition as new drugs and therapeutic modalities enter the market and advanced technologies become available.

Our commercial opportunity

could be reduced or eliminated if our potential competitors develop and commercialize products that are safer, more effective, have fewer adverse effects, are more convenient or are less expensive than any products that we may develop.

potential competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for our products.

Our commercial opportunity could be reduced

or eliminated if our potential competitors develop and commercialize products that are safer, more effective, have fewer adverse effects, are more convenient or are less expensive than any products that we may develop.

Our potential competitors

also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for our products.

Manufacturing

Our gene therapy platform has two main components:

the production of LVV vectors and AAV vectors and the target cell transduction process, which results in drug product.

We will commence GMP

manufacturing at our facility in Cranbury, New Jersey in 2022.

the production of LV vectors and AAV vectors and the target cell transduction process, which results in drug product.

We commenced GMP manufacturing at our

facility in Cranbury, New Jersey in 2022.

We plan to supplement our own direct manufacturing capabilities with third-party manufacturers for our AAV programs.

For our LVV programs, we currently rely on third-party

manufacturers to produce the plasmids, vectors, cell banks and final drug product for our clinical trials.

For our LV programs, we currently rely on third-party manufacturers to produce the

plasmids, vectors, cell banks and final drug product for our clinical trials.

We manage such production with our vendors on a purchase order basis in accordance with applicable master service and supply agreements.

have long-term agreements with these manufacturers.

We have long-term agreements

with these manufacturers.

Whenever possible, we procure materials from redundant and multiple sources to mitigate risk.

If any of our existing third-party suppliers should become unavailable to us for any reason, we

believe that there are a number of potential replacements, although we might experience a delay in our ability to obtain alternative suppliers.

We also do not have any current contractual relationships for the manufacture of commercial supplies

of our product candidates if they become registered.

If any of our existing third-party suppliers should become unavailable to us for any reason, we believe that there are a

number of potential replacements, although we might experience a delay in our ability to obtain alternative suppliers.

We also do not have any current contractual relationships for the manufacture of commercial supplies of our product

candidates if they become registered.

With respect to commercial production of our product candidates in the future, we plan to pursue multiple options including direct manufacturing as well as outsourcing production of the active

pharmaceutical (drug substance) ingredients and final drug product manufacturing (drug product) to contract manufacturing organizations if these products are approved and registered for marketing authorization by the applicable regulatory bodies.

We expect to continue to develop drug candidates that can be produced in a cost-effective manner through direct manufacturing or at contract manufacturing facilities.

Should a supplier or

manufacturer on which we have relied to produce a product candidate provide us with a faulty product or such product is later recalled, or should we experience such problems for our own products produced through direct manufacturing, we would

likely experience delays and additional costs, each of which could be significant.

Should a supplier or manufacturer on which

we have relied to produce a product candidate provide us with a faulty product or such product is later recalled, or should we experience such problems for our own products produced through direct manufacturing, we would likely experience

delays and additional costs, each of which could be significant.

Government Regulation

FDA Regulation and Marketing Approval

In the U.S., the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (“FDCA”), and biologics under the Public Health Service Act, the regulations promulgated under both laws and other

federal, state, and local statutes and regulations.

state, and local statutes and regulations.

Failure to comply with the applicable U.S.

regulatory requirements at any time during the product development process, approval process or after approval may subject an applicant to

administrative or judicial sanctions and non-approval of product candidates.

These sanctions could include, among other things, the imposition by the FDA of a clinical hold on trials, the FDA’s refusal to approve pending applications or related

supplements, withdrawal of an approval, untitled or warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, restitution, disgorgement, civil penalties, or criminal

Such actions by government agencies could also require us to expend a large amount of resources to respond to the actions.

regulatory requirements at any time during the product development process, approval process or after approval may subject an applicant to administrative or

judicial sanctions and non-approval of product candidates.

These sanctions could include, among other things, the imposition by the FDA of a clinical hold on trials, the FDA’s refusal to approve pending applications or related supplements,

withdrawal of an approval, untitled or warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, restitution, disgorgement, civil penalties, or criminal prosecution.

actions by government agencies could also require us to expend a large amount of resources to respond to the actions.

Any agency or judicial enforcement action could have a material adverse effect on us.

The FDA and comparable regulatory agencies in state and local jurisdictions and in foreign countries impose substantial requirements upon the clinical development, approval, manufacture, distribution

and marketing of pharmaceutical products.

The FDA and comparable regulatory agencies in state and local jurisdictions and in foreign countries impose substantial requirements upon the clinical development, approval, manufacture, distribution and

marketing of pharmaceutical products.

These agencies and other federal, state and local entities regulate R&D activities and the testing, manufacture, quality control, safety, effectiveness, labeling, packaging, storage, distribution,

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product candidates, before they may be legally marketed in the U.S.

Within the FDA, the FDA’s Center for Biologics Evaluation and Research (“CBER”) regulates gene therapy products and has published guidance documents with respect to the development these types of

The FDA also has published guidance documents related to, among other things, gene therapy products in general, their preclinical assessment, observing subjects involved in gene therapy studies for delayed adverse events, potency

testing, and chemistry, manufacturing and control information in gene therapy INDs.

Within the FDA, the FDA’s Center for Biologics Evaluation and Research (“CBER”) regulates gene therapy products and has published guidance documents with respect to the development of these

types of products.

potency testing, and chemistry, manufacturing and control information in gene therapy INDs.

The process required by the FDA before a biologic may be marketed in the United States generally involves the following:

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submission of an IND, which allows clinical trials to begin unless FDA objects within 30 days;

performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the proposed drug or biologic for its intended use or uses conducted in accordance with FDA regulations

and Good Clinical Practices (“GCP”), which are international ethical and scientific quality standards meant to ensure that the rights, safety and well-being of trial participants are protected, and that the integrity of the data is

Practices (“GCP”), which are international ethical and scientific quality standards meant to ensure that the rights, safety and well-being of trial participants are protected, and that the integrity of the data is maintained;

preparation and submission to the FDA of a BLA;

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review of the product by an FDA advisory committee, where appropriate or if applicable;

satisfactory completion of pre-approval inspection of manufacturing facilities and clinical trial sites at which the product, or components thereof, are produced to assess compliance with current Good

Manufacturing Practice (“cGMP”) requirements, and if applicable, the FDA’s current Good Tissue Practice (“cGTP”) requirements, and of selected clinical trial sites to assess compliance with GCP requirements;

requirements, and if applicable, the FDA’s current Good Tissue Practice (“cGTP”) requirements, and of selected clinical trial sites to assess compliance with GCP requirements;

FDA approval of a BLA which must occur before a biologic can be marketed or sold.

Preclinical Studies

Preclinical studies include laboratory evaluation of the purity and stability of the manufactured drug substance or active pharmaceutical ingredient and the formulated drug or drug product, as well

as in vitro and animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use.

The conduct of preclinical studies is subject to federal regulations and requirements,

including GLP regulations.

The results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical studies, among other things, are submitted to the FDA as

part of an IND.

Companies usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity and must also develop additional information about the

chemistry and physical characteristics of the drug and finalize a process for manufacturing the drug in commercial quantities in accordance with (“cGMP”) requirements.

The manufacturing process must be capable of consistently producing quality

batches of the drug candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality, and purity of the final drug product.

Additionally, appropriate packaging must be selected and tested, and

stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

Preclinical studies include laboratory evaluation of the purity and stability of the manufactured drug substance or active pharmaceutical ingredient and the formulated drug or drug product, as well as in vitro

and animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use.

The conduct of preclinical studies is subject to federal regulations and requirements, including

GLP regulations.

The results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data, or literature and plans for clinical studies, among other things, are submitted to the FDA as part of

Companies usually must complete some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity and must also develop additional information about the chemistry and

physical characteristics of the drug and finalize a process for manufacturing the drug in commercial quantities in accordance with (“cGMP”) requirements.

The manufacturing process must be capable of consistently producing quality batches of the

drug candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality, and purity of the final drug product.

Additionally, appropriate packaging must be selected and tested, and stability

studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

IND and Clinical Trials

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCP requirements.

Clinical trials are

conducted under written study protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Prior to commencing the first clinical trial, an

initial IND, which contains the results of preclinical testing along with other information, such as information about product chemistry, manufacturing and controls and a proposed protocol, must be submitted to the FDA.

The IND automatically

becomes effective 30 days after receipt by the FDA unless the FDA within the 30-day time period raises concerns or questions about the drug product or the conduct of the clinical trial and imposes a clinical hold.

A clinical hold may also be

imposed at any time while the IND is in effect.

Clinical trials are conducted

under written study protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

Prior to commencing the first clinical trial, an initial

IND, which contains the results of preclinical testing along with other information, such as information about product chemistry, manufacturing and controls and a proposed protocol, must be submitted to the FDA.

The IND automatically becomes

effective 30 days after receipt by the FDA unless the FDA within the 30-day time period raises concerns or questions about the drug product or the conduct of the clinical trial and imposes a clinical hold.

A clinical hold may also be imposed at

any time while the IND is in effect.

In such a case, the IND sponsor must resolve any outstanding concerns with the FDA before the clinical trial may begin or re-commence.

Accordingly, submission of an IND may or may not result in the

FDA allowing clinical trials to commence or continue.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules

are subject to oversight of institutional biosafety committees(“IBC’s”), as set forth in the National Institutes for Health(“NIH”), Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.

Accordingly, submission of an IND may or may not result in the FDA

allowing clinical trials to commence or continue.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject

to oversight of institutional biosafety committees(“IBC’s”), as set forth in the National Institutes for Health(“NIH”), Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.

Under the NIH Guidelines, recombinant and synthetic nucleic acids are defined as:

(i) molecules that are constructed by joining nucleic acid molecules and that can replicate in a living cell (i.e., recombinant

(i) molecules that are constructed by joining nucleic acid molecules and that can replicate in a living cell (i.e., recombinant nucleic

(ii) nucleic acid molecules that are chemically or by other means synthesized or amplified, including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules (i.e., synthetic

nucleic acids);

synthetic nucleic acids);

or (iii) molecules that result from the replication of those described in (i) or (ii).

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an

IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

The IBC assesses the safety of the research and identifies any potential risk to public health

or the environment, and such review may result in some delay before initiation of a clinical trial.

While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH

funding of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a

local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

The IBC assesses the safety of the research and identifies any potential risk to public health or

the environment, and such review may result in some delay before initiation of a clinical trial.

While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding

of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

A sponsor who wishes to conduct a clinical trial outside the U.S.

may, but need not, obtain FDA authorization to conduct the clinical trial under an IND.

If a foreign clinical trial is not conducted

under an IND, the sponsor may submit data from the clinical trial to the FDA in support of a BLA or IND so long as the clinical trial is conducted in compliance with GCP, and the FDA is able to validate the data from the study through an onsite

If a foreign clinical trial is not conducted under an

IND, the sponsor may submit data from the clinical trial to the FDA in support of a BLA or IND so long as the clinical trial is conducted in compliance with GCP, and the FDA is able to validate the data from the study through an onsite

inspection if the agency deems it necessary.

A separate submission to the existing IND must be made for each successive clinical trial to be conducted during product development.

Further, an independent Institutional Review Board (“IRB”) for

each site at which the clinical trial will be conducted must review and approve the clinical trial before it commences at that site.

Further, an independent Institutional Review Board (“IRB”) for each site at

which the clinical trial will be conducted must review and approve the clinical trial before it commences at that site.

Informed written consent must also be obtained from each trial subject.

Regulatory authorities, including the

FDA, or IRB, or the sponsor, may suspend or terminate a clinical trial at any time on various grounds, including a finding that the participants are being exposed to an unacceptable health risk or that the clinical trial is not being conducted in

accordance with FDA requirements.

Regulatory authorities, including the FDA, or IRB,

or the sponsor, may suspend or terminate a clinical trial at any time on various grounds, including a finding that the participants are being exposed to an unacceptable health risk or that the clinical trial is not being conducted in accordance

with FDA requirements.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

This group provides

authorization as to whether or not a trial may move forward at designated check points based on access to certain data from the trial and may recommend halting the clinical trial if it determines that there is an unacceptable safety risk for

subjects or other grounds, such as no demonstration of efficacy.

This group provides authorization

as to whether or not a trial may move forward at designated check points based on access to certain data from the trial and may recommend halting the clinical trial if it determines that there is an unacceptable safety risk for subjects or

other grounds, such as no demonstration of efficacy.

Human clinical trials for BLA approval typically involve a three-phase process, although some phases may overlap or be combined.

Phase 1, the initial clinical evaluations, consists of administering

the drug and testing for safety and tolerated dosages and in some indications such as rare disease, as preliminary evidence of efficacy in humans.

Phase 2 involves a study to evaluate the effectiveness of the drug for a particular indication and

to determine optimal dosage and dose interval and to identify possible adverse side effects and risks in a larger patient group.

When a product is found safe, and initial efficacy is established in Phase 2, it is then evaluated in Phase 3

clinical trials.

Phase 1, the initial clinical evaluations, consists of administering the drug and

testing for safety and tolerated dosages and in some indications such as rare disease, as preliminary evidence of efficacy in humans.

Phase 2 involves a study to evaluate the effectiveness of the drug for a particular indication and to

determine optimal dosage and dose interval and to identify possible adverse side effects and risks in a larger patient group.

When a product is found safe, and initial efficacy is established in Phase 2, it is then evaluated in Phase 3 clinical

Phase 3 trials consist of expanded multi-location testing for efficacy and safety to evaluate the overall benefit-to-risk index of the investigational drug in relationship to the disease treated.

The results of preclinical and

human clinical testing are submitted to the FDA in the form of a BLA for approval to commence commercial sales.

All clinical trials must be conducted in accordance with FDA regulations, GCP requirements and their protocols in order for the data to be considered reliable for regulatory

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed

successfully within any specified period, or at all.

The results of preclinical and human

clinical testing are submitted to the FDA in the form of a BLA for approval to commence commercial sales.

All clinical trials must be conducted in accordance with FDA regulations, GCP requirements and their protocols in order for the data to be considered reliable for regulatory purposes.

Progress reports detailing

the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period,

Government regulation may delay or prevent marketing of product candidates or new drugs for a considerable period of time and impose costly procedures upon our activities.

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Sponsors of clinical trials of FDA-regulated products, including drugs, are required to register and disclose certain clinical trial information.

Information related to the product, patient

population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made public as part of the registration.

Sponsors are also obligated to disclose the results of their clinical trials after

Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved up to a maximum of two years.

Competitors may use this publicly available information to gain knowledge

regarding the progress of development programs.

Information related to the product, patient population, phase of

investigation, study sites and investigators, and other aspects of the clinical trial is then made public as part of the registration.

Sponsors are also obligated to disclose the results of their clinical trials after completion.

Disclosure of

the results of these trials can be delayed until the new product or new indication being studied has been approved up to a maximum of two years.

Competitors may use this publicly available information to gain knowledge regarding the progress of

development programs.

The BLA Approval Process

In order to obtain approval to market a drug in the U.S., a marketing application must be submitted to the FDA that provides data establishing to the FDA’s satisfaction the safety and effectiveness

of the investigational drug for the proposed indication.

The application includes all relevant data available from pertinent non-clinical or preclinical studies and clinical trials, including negative or ambiguous results as well as positive

findings, together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.

Data can come from company-sponsored clinical trials intended to test the safety and

effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators that meet GCP requirements.

In order to obtain approval to market a drug in the U.S., a marketing application must be submitted to the FDA that provides data establishing to the FDA’s satisfaction the safety and effectiveness of the

investigational drug for the proposed indication.

The application includes all relevant data available from pertinent non-clinical or preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings,

together with detailed information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things.

Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a

use of a product, or from a number of alternative sources, including studies initiated by investigators that meet GCP requirements.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points.

These points may be prior to submission of an IND, at the

End-of-Phase 1 or 2, and before a BLA is submitted.

These points may be prior to submission of an IND, at the End-of-Phase 1 or 2,

and before a BLA is submitted.

Meetings at other times may be requested.

These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice and for

the sponsor and the FDA to reach agreement on the next phase of development.

The results of product development, non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed

labeling and other relevant information are submitted to the FDA as part of a BLA requesting approval to market the product for its intended indication.

The FDA reviews all BLAs submitted to ensure that they are sufficiently complete for

substantive review before it accepts them for filing.

These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice and for the sponsor and the

FDA to reach agreement on the next phase of development.

The results of product development, non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and

other relevant information are submitted to the FDA as part of a BLA requesting approval to market the product for its intended indication.

The FDA reviews all BLAs submitted to ensure that they are sufficiently complete for substantive review

before it accepts them for filing.

It may request additional information rather than accept a BLA for filing.

In this event, the BLA must be resubmitted with the additional information.

The resubmitted application also is

subject to review before the FDA accepts it for filing.

The FDA has 60 days from its receipt of a BLA to conduct an initial review to determine whether the application will be accepted for filing based on the agency’s threshold determination that

the application is sufficiently complete to permit substantive review.

The FDA reviews a BLA to determine, among other things, whether the proposed product is safe and potent, or effective, for its intended use, and has an acceptable purity

profile, and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, safety, strength, quality, potency and purity.

The FDA has agreed to specific performance goals on the review of BLA’s.

The resubmitted application also is subject to review

before the FDA accepts it for filing.

The FDA has 60 days from its receipt of a BLA to conduct an initial review to determine whether the application will be accepted for filing based on the Agency’s threshold determination that the application

is sufficiently complete to permit substantive review.

The FDA reviews a BLA to determine, among other things, whether the proposed product is safe and potent, or effective, for its intended use, and has an acceptable purity profile, and

whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, safety, strength, quality, potency and purity.

The FDA has agreed to specific performance goals on the review of BLAs.

Specifically, FDA under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act, or PDUFA, as amended, the FDA has 10 months, from the filing date, in which to complete its initial review of an original BLA and

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FDA has committed to reviewing such resubmissions in two to six months depending on the type of information included.

The FDA may refer applications for novel drug products or drug products that present difficult

questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation, and a recommendation as to whether the application should be approved and, if so, under what

The FDA may refer applications for novel drug products or drug products that present

difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation, and a recommendation as to whether the application should be approved and, if so, under

what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving a BLA, the FDA typically will inspect the facilities at which the product is manufactured.

The FDA will not approve the product unless it determines that the manufacturing processes

and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

The FDA will not approve the product unless it determines that the manufacturing processes and

facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving a BLA, the FDA may inspect one or more clinical sites to assure

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list their HCT/Ps with the FDA and, when applicable, to evaluate donors through appropriate screening and testing.

If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it typically will

outline the deficiencies and often will request additional testing or information.

If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it typically

will outline the deficiencies and often will request additional testing or information.

This may significantly delay further review of the application.

If the FDA finds that a clinical site did not conduct the clinical trial in accordance with GCP,

the FDA may determine the data generated by the clinical site should be excluded from the primary efficacy analyses provided in the BLA.

Additionally, notwithstanding the submission of any requested additional information, the FDA ultimately may

decide that the application does not satisfy the regulatory criteria for approval.

If the FDA finds that a clinical site did not conduct the clinical trial in accordance with

GCP, the FDA may determine the data generated by the clinical site should be excluded from the primary efficacy analyses provided in the BLA.

Additionally, notwithstanding the submission of any requested additional information, the FDA

ultimately may decide that the application does not satisfy the regulatory criteria for approval.

The FDA may require, or companies may pursue, additional clinical trials after a product is approved.

These so-called Phase 4 or post-approval trials may be made a condition to be satisfied for

continuing drug approval.

These so-called Phase 4 or post-approval trials may be made a condition to be satisfied for continuing drug

The results of Phase 4 trials can confirm the effectiveness of a product candidate and can provide important safety information.

In addition, the FDA has authority to require sponsors to conduct post-marketing trials to

specifically address safety issues identified by the agency.

In addition, the FDA has authority to require sponsors to conduct post-marketing trials to specifically

address safety issues identified by the agency.

See “Post-Marketing Requirements” below.

The FDA also has authority to require a Risk Evaluation and Mitigation Strategy (“REMS”), from manufacturers to ensure that the benefits of a drug outweigh its risks.

A sponsor may also voluntarily

propose a REMS as part of the BLA submission.

A sponsor may also voluntarily propose a

REMS as part of the BLA submission.

The need for a REMS is determined as part of the review of the BLA.

Based on statutory standards, elements of a REMS may include “Dear Doctor letters,” a medication guide, more elaborate targeted

educational programs, and in some cases distribution and use restrictions, referred to as elements to assure safe use (“ETASU”).

ETASU can include, but are not limited to, special training or certification for prescribing or dispensing,

dispensing only under certain circumstances, special monitoring and the use of patient registries.

Based on statutory standards, elements of a REMS may include “Dear Doctor letters,” a medication guide, more elaborate targeted educational

programs, and in some cases distribution and use restrictions, referred to as elements to assure safe use (“ETASU”).

ETASU can include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only

under certain circumstances, special monitoring and the use of patient registries.

These elements are negotiated as part of the BLA approval, and in some cases the approval date may be delayed.

Once adopted, REMS are subject to

periodic assessment and modification.

Changes to some of the conditions established in an approved application, including changes in indications, labeling, manufacturing processes or facilities, require submission and FDA approval of a

new BLA or BLA supplement before the change can be implemented.

Once adopted, REMS are subject to periodic

assessment and modification.

Changes to some of the conditions established in an approved application, including changes in indications, labeling, manufacturing processes or facilities, require submission and FDA approval of a new BLA or

BLA supplement before the change can be implemented.

A BLA supplement for a new indication typically requires clinical data similar to that in the original application, and the FDA uses the same procedures and actions in reviewing BLA

supplements as it does in reviewing BLAs.

Even if a product candidate receives regulatory approval, the approval may be limited to specific disease states, patient populations and dosages, or might contain significant limitations on use in

the form of warnings, precautions or contraindications, or in the form of onerous risk management plans, restrictions on distribution or use, or post-marketing trial requirements.

Further, even after regulatory approval is obtained, later

discovery of previously unknown problems with a product may result in restrictions on the product, including safety labeling or imposition of a REMS, the requirement to conduct post-market studies or clinical trials or even complete withdrawal of

the product from the market.

Even if a product candidate receives regulatory approval, the approval may be limited to specific disease states, patient populations and dosages, or might contain significant limitations on use in the form of

warnings, precautions or contraindications, or in the form of onerous risk management plans, restrictions on distribution or use, or post-marketing trial requirements.

Further, even after regulatory approval is obtained, later discovery of

previously unknown problems with a product may result in restrictions on the product, including safety labeling or imposition of a REMS, the requirement to conduct post-market studies or clinical trials or even complete withdrawal of the

product from the market.

Delay in obtaining, or failure to obtain, regulatory approval for our products, or obtaining approval but for significantly limited use, would harm our business.

In addition, we cannot predict what adverse

governmental regulations may arise from future U.S.

In addition, we cannot predict what adverse governmental

regulations may arise from future U.S.

or foreign governmental action.

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Under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Amendments, a portion of a product’s U.S.

patent term that was lost during clinical

development and regulatory review by the FDA may be restored by returning up to five years of patent life for a patent that covers a new product or its use.

This period is generally one-half the time between the effective date of an IND (falling

after issuance of the patent) and the submission date of a BLA, plus the time between the submission date of a BLA and the approval of that application, provided that the sponsor acted with diligence.

Patent term restorations, however, cannot

extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended and the extension must be applied for prior to expiration of the patent.

Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

patent term that was lost during clinical development and

regulatory review by the FDA may be restored by returning up to five years of patent life for a patent that covers a new product or its use.

This period is generally one-half the time between the effective date of an IND (falling after issuance

of the patent) and the submission date of a BLA, plus the time between the submission date of a BLA and the approval of that application, provided that the sponsor acted with diligence.

Patent term restorations, however, cannot extend the

remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended and the extension must be applied for prior to expiration of the patent.

and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

Market Exclusivity

The Affordable Care Act, or ACA, signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009, or the BPCIA, which created an abbreviated

approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-approved reference biological product.

Bio similarity, which requires that there be no clinically meaningful differences between the biological

product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical trial or trials.

Interchangeability requires that a product is biosimilar to the reference product

and the product must demonstrate that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been

previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

However, complexities associated with the larger, and often more complex, structure of biological

products, as well as the process by which such products are manufactured, pose significant hurdles to implementation that are still being worked out by the FDA.

The Affordable Care Act, or ACA, signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009, or the BPCIA, which created an abbreviated approval

pathway for biological products shown to be similar to, or interchangeable with, an FDA-approved reference biological product.

Bio similarity, which requires that there be no clinically meaningful differences between the biological product and

the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical trial or trials.

Interchangeability requires that a product is biosimilar to the reference product and the

product must demonstrate that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously

administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

However, complexities associated with the larger, and often more complex, structure of biological products, as

well as the process by which such products are manufactured, pose significant hurdles to implementation that are still being worked out by the FDA.

A reference biological product is granted four (4) and twelve (12) year exclusivity periods from the time of first licensure of the product.

FDA will not accept an application for a biosimilar or

interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product, and FDA will not approve an application for a biosimilar or interchangeable product based on the

reference biological product until twelve (12) years after the date of first licensure of the reference product.

FDA will not accept an application for a biosimilar or interchangeable

product based on the reference biological product until four years after the date of first licensure of the reference product, and FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological

product until twelve (12) years after the date of first licensure of the reference product.

“First licensure” typically means the initial date the particular product at issue was approved in the United States.

Date of first

licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or

manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of

administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

Therefore, one must

determine whether a new product includes a modification to the structure of a previously approved product that results in a change in safety, purity, or potency to assess whether the licensure of the new product is a first licensure that triggers

its own period of exclusivity.

Date of first licensure does not

include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of

the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing

schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

Therefore, one must determine whether a new

product includes a modification to the structure of a previously approved product that results in a change in safety, purity, or potency to assess whether the licensure of the new product is a first licensure that triggers its own period of

Whether a subsequent application, if approved, warrants exclusivity as the “first licensure” of a biological product is determined on a case-by-case basis with data submitted by the sponsor.

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individuals in the U.S., or more in cases in which there is no reasonable expectation that the cost of developing and making a biologic product available in the U.S.

for treatment of the disease or condition will be recovered from sales

of the product).

for treatment of the disease or condition will be recovered from sales of the

Orphan product designation must be requested before submitting a BLA.

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designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation,

the product is entitled to orphan product exclusivity, meaning that FDA may not approve any other applications to market the same drug or biologic product for the same indication for seven years, except in limited circumstances, such as a showing

of clinical superiority to the product with orphan exclusivity or if the party holding the exclusivity fails to assure the availability of sufficient quantities of the drug to meet the needs of patients with the disease or condition for which the

drug was designated.

Competitors, however, may receive approval of different products for the same indication than that for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which

the orphan product has exclusivity.

If a product with orphan status receives the first FDA approval for the disease or condition for which it has such

designation, the product is entitled to orphan product exclusivity, meaning that FDA may not approve any other applications to market the same drug or biologic product for the same indication for seven years, except in limited circumstances,

such as a showing of clinical superiority to the product with orphan exclusivity or if the party holding the exclusivity fails to assure the availability of sufficient quantities of the drug to meet the needs of patients with the disease or

condition for which the drug was designated.

Competitors, however, may receive approval of different products for the same indication than that for which the orphan product has exclusivity or obtain approval for the same product but for a

different indication for which the orphan product has exclusivity.

Orphan medicinal product status in the EU has similar, but not identical, benefits.

Pediatric exclusivity is another type of non-patent marketing exclusivity in the U.S.

and, if granted, provides for the attachment of an additional six months of marketing protection to the term of

any existing regulatory exclusivity, including the non-patent exclusivity.

and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing

regulatory exclusivity, including the non-patent exclusivity.

This six-month exclusivity may be granted if a BLA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.

Rare Pediatric Disease Designation and Priority Review Vouchers

Under the FDCA, the FDA incentivizes the development of drugs and biological products that meet the definition of a “rare pediatric disease,” defined to mean a serious or life-threatening disease in

which the serious of life-threatening manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals in the United States or affects more than 200,000 in the United States and for

which there is no reasonable expectation that the cost of developing and making in the United States a drug or biological product for such disease or condition will be received from sales in the United States of such drug or biological product.

The sponsor of a product candidate for a rare pediatric disease may be eligible for a voucher that can be used to obtain a priority review for a subsequent human drug or biological product application after the date of approval of the rare

serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals in the United States or affects more than 200,000 in the United States and for which

there is no reasonable expectation that the cost of developing and making in the United States a drug or biological product for such disease or condition will be received from sales in the United States of such drug or biological product.

sponsor of a product candidate for a rare pediatric disease may be eligible for a voucher that can be used to obtain a priority review for a subsequent human drug or biological product application after the date of approval of the rare

pediatric disease drug or biological product, referred to as a priority review voucher (“PRV”).

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FDA is authorized to expedite the review of BLAs in several ways.

Under the Fast Track program, the sponsor of a biologic product candidate may request FDA to designate the product for a specific

indication as a Fast Track product concurrent with or after the filing of the IND.

Biologic products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to

address unmet medical needs for the condition.

Under the Fast Track program, the sponsor of a biologic product candidate may request FDA to designate the product for a specific indication as a

Fast Track product concurrent with or after the filing of the IND.

Biologic products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet

medical needs for the condition.

Fast Track designation applies to the combination of the product candidate and the specific indication for which it is being studied.

In addition to other benefits, such as the ability to have

greater interactions with FDA, FDA may initiate review of sections of a Fast-Track BLA before the application is complete, a process known as rolling review.

Any product submitted to FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as regenerative

medicine advanced therapy (“RMAT”) designation, priority review and accelerated approval.

To qualify for RMAT designation, the product candidate must be a regenerative medicine therapy, which is defined

as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part

1271 of Title 21, Code of Federal Regulations;

In addition to other benefits, such as the ability to have greater

interactions with FDA, FDA may initiate review of sections of a Fast-Track BLA before the application is complete, a process known as rolling review.

Any product submitted to FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as regenerative medicine

advanced therapy (“RMAT”) designation, priority review and accelerated approval.

To qualify for RMAT designation, the product candidate must be a regenerative medicine therapy, which is defined as a cell

therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of

Title 21, Code of Federal Regulations;

is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition;

and preliminary clinical evidence indicates that the product has the potential to address unmet

medical needs for such disease or condition.

and preliminary clinical evidence indicates that the product has the potential to address unmet medical

needs for such disease or condition.

A gene therapy product may meet the definition of a regenerative medicine therapy for purposes of RMAT designation.

A BLA for a product candidate that has received

RMAT designation may be eligible for priority review or accelerated approval through use of surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of

A BLA for a product candidate that has received RMAT

designation may be eligible for priority review or accelerated approval through use of surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of

Benefits of RMAT designation also include early interactions with FDA to discuss any potential surrogate or intermediate endpoint to be used to support accelerated approval.

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or post-approval monitoring of all patients treated with such therapy prior to its approval.

A product candidate including one that received Fast Track or RMAT designation is eligible for priority review if it treats a serious condition and, if

approved, it would be a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious condition compared to available therapies.

FDA aims to complete its review of priority review applications

within six months as opposed to 10 months for standard review.

Additionally, a biologic product may be eligible for accelerated approval if it is designed to treat a serious or life-threatening disease or condition and demonstrates an effect on a surrogate

endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity

and prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, FDA may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and

well-controlled post-marketing clinical trials.

In addition, FDA currently requires, unless otherwise informed by the agency, pre-approval of promotional materials intended for dissemination or publication

within 120 days of marketing approval .

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the

time period for FDA review or approval may not be shortened.

A product candidate including one that received Fast Track or RMAT designation is eligible for priority review if it treats a serious condition and, if approved, it would

be a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious condition compared to available therapies.

FDA aims to complete its review of priority review applications within six months as

opposed to 10 months for standard review.

Additionally, a biologic product may be eligible for accelerated approval if it is designed to treat a serious or life-threatening disease or condition and demonstrates an effect on a surrogate endpoint that is

reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity and prevalence

of the condition and the availability or lack of alternative treatments.

As a condition of approval, FDA may require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well-controlled

post-marketing clinical trials.

In addition, FDA currently requires, unless otherwise informed by the agency, pre-approval of promotional materials intended for dissemination or publication within 120 days

of marketing approval .

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA

review or approval may not be shortened.

Fast Track designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

Post-Marketing Requirements

Following approval of a new product, a pharmaceutical company and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and recordkeeping

activities, reporting to the applicable regulatory authorities of adverse experiences with the product, providing the regulatory authorities with updated safety and efficacy information, product sampling and distribution requirements, and

complying with promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved

labeling, or off-label use, limitations on industry-sponsored scientific and educational activities and requirements for promotional activities involving the internet.

Although physicians may, in their independent professional medical judgment,

prescribe legally available drugs for off-label uses, manufacturers typically may not market or promote such off-label uses.

Modifications or enhancements to the product or its labeling or changes of the site of manufacture are often subject to

the approval of the FDA and other regulators, who may or may not grant approval or may include a lengthy review process.

Following approval of a new product, a pharmaceutical company and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and recordkeeping activities,

reporting to the applicable regulatory authorities of adverse experiences with the product, providing the regulatory authorities with updated safety and efficacy information, product sampling and distribution requirements, and complying with

promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling, or

off-label use, limitations on industry-sponsored scientific and educational activities and requirements for promotional activities involving the internet.

Although physicians may, in their independent professional medical judgment, prescribe

legally available drugs for off-label uses, manufacturers typically may not market or promote such off-label uses.

Modifications or enhancements to the product or its labeling or changes of the site of manufacture are often subject to the

approval of the FDA and other regulators, who may or may not grant approval or may include a lengthy review process.

Prescription drug advertising is subject to federal, state, and foreign regulations.

In the U.S., the FDA regulates prescription drug promotion, including direct-to-consumer

In the U.S., the FDA regulates prescription drug promotion, including direct-to-consumer advertising.

Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use.

Any distribution of prescription drug products and pharmaceutical samples must comply with the U.S.

Prescription Drug Marketing

Act, a part of the FDCA.

Drug Supply Chain Security Act and the

Prescription Drug Marketing Act, both are parts of the FDCA.

In the U.S., once a product is approved, its manufacturing is subject to comprehensive and continuing regulation by the FDA.

The FDA regulations require that products be manufactured in specific

approved facilities and in accordance with cGMP.

cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and

correct any deviations from cGMP.

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies and are subject to

periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Additionally, manufacturers and other parties involved in the supply chain for prescription drug products must also comply with

product tracking and racing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the U.S.

Accordingly, manufacturers must continue

to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

The FDA regulations require that products be manufactured in specific approved

facilities and in accordance with cGMP.

cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any

deviations from cGMP.

unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Additionally, manufacturers and other parties involved in the supply chain for prescription drug products must also comply with product

tracking and racing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the U.S.

Accordingly, manufacturers must continue to

expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

These regulations also impose certain organizational, procedural and documentation requirements with respect to manufacturing and quality

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where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such

product or may result in restrictions on a product, manufacturer, or holder of an approved BLA, including, among other things, recall or withdrawal of the product from the market.

In addition, the manufacturer and/or holder of an approved BLA are

subject to annual product and establishment fees.

product or may result in restrictions on a product, manufacturer, or holder of an approved BLA, including, among other things, recall, withdrawal of the product from the market, or refusal of importation.

In addition, the manufacturer and/or

holder of an approved BLA are subject to annual product and establishment fees.

These fees are typically increased annually.

The FDA also may require post-marketing testing, also known as Phase 4 testing, to monitor the effects of an approved product or place conditions on an approval via a REMS that could restrict the

distribution or use of the product.

Discovery of previously unknown problems with a product or the failure to comply with applicable FDA requirements can have negative consequences, including adverse publicity, judicial or administrative

enforcement, untitled or warning letters from the FDA, mandated corrective advertising or communications with doctors, withdrawal of approval, and civil or criminal penalties, among others.

Newly discovered or developed safety or effectiveness

data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures.

Also, new government requirements, including those

resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

The FDA also may require post-marketing testing, also known as Phase 4 testing, to monitor the effects of an approved product or place conditions on an approval via a REMS that could restrict the distribution or

use of the product.

or warning letters from the FDA, mandated corrective advertising or communications with doctors, withdrawal of approval, and civil or criminal penalties, among others.

Newly discovered or developed safety or effectiveness data may require

changes to a product’s approved labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures.

Also, new government requirements, including those resulting from

new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

Coverage and Reimbursement

Sales of any products for which we receive regulatory approval for commercial sale will depend in part on the availability of reimbursement from third-party payors, including government healthcare

program administrative authorities, managed care organizations, private health insurers, and other entities.

Patients who are prescribed medications for the treatment of their conditions, and their prescribing physicians, generally rely on

third-party payors to reimburse all of part of the costs associated with their prescription drugs.

Patients are unlikely to use our products unless coverage is provided, and reimbursement is adequate to cover a significant portion of the cost of

our products.

Sales of any products for which we receive regulatory approval for commercial sale will depend in part on the availability of reimbursement from third-party payors, including government healthcare program

administrative authorities, managed care organizations, private health insurers, and other entities.

Patients who are prescribed medications for the treatment of their conditions, and their prescribing physicians, generally rely on third-party

payors to reimburse all of part of the costs associated with their prescription drugs.

Patients are unlikely to use our products unless coverage is provided, and reimbursement is adequate to cover a significant portion of the cost of our

Therefore, our products, once approved, may not obtain market acceptance unless coverage is provided, and reimbursement is adequate to cover a significant portion of the cost of our products.

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reimbursement rate that the payor will pay for the drug product once coverage is approved.

Third-party payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the

FDA-approved drugs for a particular indication.

A decision by a third-party payor not to cover our product candidates could reduce physician utilization of our products once approved.

Moreover, a third-party payor’s decision to provide coverage

for a drug product does not imply that an adequate reimbursement rate will be approved.

Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in

product development.

Third-party payors may limit coverage to specific drug products on an approved list, also known as a formulary, or otherwise subject it to a health

technology assessment.

In either case, payer coverage rules might exclude certain FDA-approved drugs for a particular indication.

A decision by a third-party payor not to cover our product candidates could reduce physician utilization of our

products once approved.

Moreover, a third-party payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.

Adequate third-party reimbursement may not be available to enable us to

maintain price levels sufficient to realize an appropriate return on our investment in product development.

Additionally, coverage and reimbursement for drug products can differ significantly from payor to payor.

One third-party payor’s decision to cover a particular drug product or service does not ensure that other payors will

also provide coverage for the medical product or service or will provide coverage at an adequate reimbursement rate.

As a result, the coverage determination process will require us to provide scientific and clinical support for the use of our

products to each payor separately and will be a time-consuming process.

One third-party payor’s

decision to cover a particular drug product or service does not ensure that other payors will also provide coverage for the medical product or service or will provide coverage at an adequate reimbursement rate.

As a result, the coverage

determination process will require us to provide scientific and clinical support for the use of our products to each payor separately and will be a time-consuming process.

The containment of healthcare costs has become a priority of federal, state, and foreign governments, and the prices of drugs have been a focus in this effort.

Third-party payors are increasingly

challenging the prices charged for drug products and medical services, examining the medical necessity, and reviewing the cost effectiveness of drug products and medical services, in addition to questioning safety and efficacy.

third-party payors do not consider our products to be cost-effective compared to other available therapies, they may not cover our products after FDA approval or, if they do, the level of payment may not be sufficient to allow us to sell our

products at a profit.

Third-party payors are increasingly challenging the

prices charged for drug products and medical services, examining the medical necessity, and reviewing the cost effectiveness of drug products and medical services, in addition to questioning safety and efficacy.

If these third-party payors do

not consider our products to be cost-effective compared to other available therapies, they may not cover our products after FDA approval or, if they do, the level of payment may not be sufficient to allow us to sell our products at a profit.

The American Recovery and Reinvestment Act of 2009 provided funding for the federal government to compare the effectiveness of different treatments for the same illness.

The plan for the research was

published in 2012 by the Department of Health and Human Services, the Agency for Healthcare Research and Quality and the National Institutes for Health, and periodic reports on the status of the research and related expenditures will be made to

Although the results of the comparative effectiveness studies are not intended to mandate coverage policies for public or private payors, it is not clear what effect, if any, the research will have on the sales of our product

candidates, if any such product or the condition that it is intended to treat is the subject of a study.

It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s product could adversely affect the sales

of our product candidates, once approved.

If third-party payors do not consider our products to be cost-effective compared to other available therapies, they may not cover our products after approval as a benefit under their plans or, if they do,

the level of payment may not be sufficient to allow us to sell our products on a profitable basis.

The plan for the research was published

in 2012 by the Department of Health and Human Services, the Agency for Healthcare Research and Quality and the National Institutes for Health, and periodic reports on the status of the research and related expenditures will be made to Congress.

such product or the condition that it is intended to treat is the subject of a study.

It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s product could adversely affect the sales of our product

candidates, once approved.

payment may not be sufficient to allow us to sell our products on a profitable basis.

In addition, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.

The requirements governing drug pricing vary widely from country to

For example, the EU provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

A member state may approve a specific price for the medicinal product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

There can be no assurance that

any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

The requirements governing drug pricing vary widely from country to country.

example, the EU provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

state may approve a specific price for the medicinal product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

There can be no assurance that any

country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

Historically, products launched in the EU do not follow price

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Anti-Kickback and False Claims Laws and Other Regulatory Matters

In the U.S., among other things, the research, manufacturing, distribution, sale and promotion of drug products and medical devices are potentially subject to regulation and enforcement by various

federal, state and local authorities in addition to the FDA, including the Centers for Medicare & Medicaid Services, other divisions of the U.S.

Department of Health and Human Services (e.g., the Office of Inspector General), the Drug

Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency, state Attorneys General and other state and local

In the U.S., among other things, the research, manufacturing, distribution, sale and promotion of drug products and medical devices are potentially subject to regulation and enforcement by various federal, state

and local authorities in addition to the FDA, including the Department of Justice, Centers for Medicare & Medicaid Services, other divisions of the U.S.

Department of Health and Human Services (e.g., the Office of Inspector General), the

Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency, state Attorneys General and other state and local

government agencies.

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similar state laws.

Pricing and rebate programs must comply with the Medicaid Drug Rebate Program requirements of the Omnibus Budget Reconciliation Act of 1990, as amended, and the Veterans Health Care Act of 1992, as amended.

If products are

made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply.

All of these activities are also potentially subject to federal and state consumer protection and

unfair competition laws.

The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage, and security requirements intended to

prevent the unauthorized sale of pharmaceutical products.

The Federal Anti-Kickback Statute makes it illegal for any person or entity, including a prescription drug manufacturer (or a party acting on its behalf) to knowingly and willfully, directly or

indirectly, in cash or in kind, solicit, receive, offer, or pay any remuneration that is intended to induce the referral of business, including the purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of,

any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as Medicare or Medicaid.

special pricing to both the Veterans Administration and other Federal agencies, as well as to certain safety net providers, referred to as 340B covered entities.

If products are made available to authorized users of the Federal Supply Schedule

of the General Services Administration, additional laws and requirements apply.

All of these activities are also potentially subject to federal and state consumer protection and unfair competition laws.

The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage, and security requirements intended to prevent the

unauthorized sale of pharmaceutical products.

The Federal Anti-Kickback Statute makes it illegal for any person or entity, including a prescription drug manufacturer (or a party acting on its behalf) to knowingly and willfully, directly or indirectly, in

cash or in kind, solicit, receive, offer, or pay any remuneration that is intended to induce the referral of business, including the purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of, any good,

facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as Medicare or Medicaid.

The term “remuneration” has been broadly interpreted to include anything of value.

Federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and formulary managers on the other.

Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and formulary managers on the other.

Although there are a number of statutory exceptions and

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needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, the ACA codified case law that a claim including items or services resulting from a violation of the Federal

Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the Federal False Claims Act.

Violations of this law are punishable by up to five years in prison, criminal fines, administrative civil money penalties, and exclusion

from participation in federal healthcare programs.

In addition, a claim including items or services resulting from a violation of the Federal Anti-Kickback Statute constitutes

a false or fraudulent claim for purposes of the Federal False Claims Act.

Violations of this law are punishable by up to five years in prison, criminal fines, administrative civil money penalties, and exclusion from participation in federal

healthcare programs.

In addition, many states have adopted laws similar to the Federal Anti-Kickback Statute.

Some of these state prohibitions apply to the referral of patients for healthcare services reimbursed by

any insurer, not just federal healthcare programs such as Medicare and Medicaid.

Due to the breadth of these federal and state anti-kickback laws, and the potential for additional legal or regulatory change in this area, it is possible that our

future business activities, including our sales and marketing practices and/or our future relationships with physicians and the medical community might be challenged under anti-kickback laws, which could harm us.

Federal false claims and false statement laws, including the civil False Claims Act, prohibits any person or entity from, among other things, knowingly presenting, or causing to be presented, for

payment to federal programs (including Medicare and Medicaid) claims for items or services, including drugs, that are false or fraudulent.

Although we would not submit claims directly to payors, manufacturers can be held liable under these laws

if they are deemed to “cause” the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information to customers or promoting a product off-label.

In addition, our future activities relating to the

reporting of wholesaler or estimated retail prices for our products, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state, and third-party reimbursement for our products, and the

sale and marketing of our products, are subject to scrutiny under this law.

Some of these state prohibitions apply to the referral of patients for healthcare services reimbursed by any insurer, not just federal

healthcare programs such as Medicare and Medicaid.

Due to the breadth of these federal and state anti-kickback laws, and the potential for additional legal or regulatory change in this area, it is possible that our future business activities,

including our sales and marketing practices and/or our future relationships with physicians and the medical community might be challenged under anti-kickback laws, which could harm us.

Federal false claims and false statement laws, including the civil False Claims Act, prohibits any person or entity from, among other things, knowingly presenting, or causing to be presented, for payment to

federal programs (including Medicare and Medicaid) claims for items or services, including drugs, that are false or fraudulent.

Although we would not submit claims directly to payors, manufacturers can be held liable under these laws if they

are deemed to “cause” the submission of false or fraudulent claims by, for example, providing inaccurate billing or coding information to customers or promoting a product off-label.

In addition, our future activities relating to the reporting

of wholesaler or estimated retail prices for our products, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state, and third-party reimbursement for our products, and the sale and

marketing of our products, are subject to scrutiny under this law.

For example, pharmaceutical companies have been found liable under the Federal Civil False Claims Act in connection with their off-label promotion of drugs.

Penalties for

a civil False Claims Act violation include three times the actual damages sustained by the government, plus mandatory civil penalties for each separate false claim, the potential for exclusion from participation in federal healthcare programs,

Penalties for a

civil False Claims Act violation include three times the actual damages sustained by the government, plus mandatory civil penalties for each separate false claim, the potential for exclusion from participation in federal healthcare programs,

and, although the Federal False Claims Act is a civil statute, conduct that results in a False Claims Act violation may also implicate various federal criminal statutes.

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enacted laws modeled after the Federal False Claims Act.

Additionally, HIPAA created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare

benefit program, including private third-party payors and knowingly and willfully falsifying, concealing, or covering up a material fact or making any materially false, fictitious, or fraudulent statement in connection with the delivery of or

payment for healthcare benefits, items or services.

Additionally, HIPAA created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit

program, including private third-party payors and knowingly and willfully falsifying, concealing, or covering up a material fact or making any materially false, fictitious, or fraudulent statement in connection with the delivery of or payment

for healthcare benefits, items or services.

There are also an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information.

Many of these laws contain

ambiguities as to what is required to comply with the laws.

Many of these laws contain ambiguities as to what is required to

comply with the laws.

For example, federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs.

addition, as discussed below, a similar federal requirement under the Physician Payments Sunshine Act, requires certain manufacturers to track and report to the federal government certain payments provided to physicians and teaching hospitals

made in the previous calendar year, as well as certain ownership and investment interests held by physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors) and their immediate family members.

These laws may

affect our sales, marketing, and other promotional activities by imposing administrative and compliance burdens on us.

In addition, given the lack of clarity with respect to these laws and their implementation, our reporting actions could be

subject to the penalty provisions of the pertinent state and federal authorities.

Effective January 1, 2022, these reporting obligations extend to include transfers of value made to certain non-physician providers such as physician assistants and

nurse practitioners.

In addition, as discussed below, a similar

federal requirement under the Physician Payments Sunshine Act, requires certain manufacturers to track and report to the federal government certain payments provided to physicians and teaching hospitals made in the previous calendar year, as

well as certain ownership and investment interests held by physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors) and their immediate family members.

These laws may affect our sales, marketing, and other

promotional activities by imposing administrative and compliance burdens on us.

In addition, given the lack of clarity with respect to these laws and their implementation, our reporting actions could be subject to the penalty provisions of the

pertinent state and federal authorities.

Effective January 1, 2022, these reporting obligations extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.

In addition, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information

Technology for Economic and Clinical Health Act, and their respective implementing regulations, including the Final Omnibus Rule published on January 25, 2013, imposes specified requirements relating to the privacy, security, and transmission of

individually identifiable health information on certain types of individuals and organizations.

In addition, certain state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other

and from HIPAA in significant ways and may not have the same effect, thus complicating compliance efforts.

HIPAA, as amended by the Health Information Technology for

Economic and Clinical Health Act, and their respective implementing regulations, including the Final Omnibus Rule published on January 25, 2013, imposes specified requirements relating to the privacy, security, and transmission of individually

identifiable health information on certain types of individuals and organizations.

In addition, certain state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other and from

HIPAA in significant ways and may not have the same effect, thus complicating compliance efforts.

The failure to comply with regulatory requirements subjects us to possible legal or regulatory action.

Depending on the circumstances, failure to meet applicable regulatory requirements can result in

significant criminal, civil and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in federal healthcare programs, such as Medicare and Medicaid, injunctions, recall or seizure of products, total or partial

suspension of production, denial or withdrawal of product approvals, refusal to allow us to enter into supply contracts, including government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future

earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

We plan to develop a comprehensive compliance program that establishes internal controls to facilitate adherence to the law and program requirements to which we will or may

become subject because we intend to commercialize products that could be reimbursed under a federal healthcare program and other governmental healthcare programs.

Depending on the circumstances, failure to meet applicable regulatory requirements can

result in significant criminal, civil and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in federal healthcare programs, such as Medicare and Medicaid, injunctions, recall or seizure of products, total

or partial suspension of production, denial or withdrawal of product approvals, refusal to allow us to enter into supply contracts, including government contracts, contractual damages, reputational harm, administrative burdens, diminished

profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

We plan to develop a comprehensive compliance program that establishes internal controls to facilitate adherence to the law and program requirements to which we will or may become subject

because we intend to commercialize products that could be reimbursed under a federal healthcare program and other governmental healthcare programs.

Changes in law or the interpretation of existing law could impact our business in the future by requiring, for example:

(i) changes to our manufacturing arrangements;

(ii) additions or modifications

to product labeling;

(ii) additions or modifications to product

(iii) the recall or discontinuation of our products;

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Healthcare Legislative Reform

In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system that could impact our ability to sell our

products profitably.

In particular, in 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, was enacted, which, among other things, subjected

biologic products to potential competition by lower-cost biosimilars;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled,

implanted or injected;

In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system that could impact our ability to sell our products

products to potential competition by lower-cost biosimilars;

addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or

increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;

extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed

care organizations;

extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care

organizations;

subjected manufacturers to new annual fees and taxes for certain branded prescription drugs;

created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (increased to 70%

pursuant to the Bipartisan Budget Act of 2018, effective as of January 1, 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the

manufacturer’s outpatient drugs to be covered under Medicare Part D;

created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (increased to 70% pursuant

to the Bipartisan Budget Act of 2018, effective as of January 1, 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s

outpatient drugs to be covered under Medicare Part D;

and provided incentives to programs that increase the federal government’s comparative effectiveness research.

Since its enactment, there have been judicial, Congressional, and executive challenges to certain aspects of the ACA.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial

challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February

15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that

limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage

through Medicaid or the ACA.

It is unclear how other healthcare reform measures of the Biden administration or other efforts, if any, to challenge, repeal or replace the ACA will impact our business.

In addition, other legislative changes have been proposed and adopted since the ACA was enacted.

In addition, other legislative changes have been proposed and adopted since the ACA was enacted including:

In August 2011, President Obama signed into law the Budget Control Act of 2011, which, among other things, created the Joint Select Committee on Deficit Reduction to recommend to Congress proposals for deficit reduction of at least

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went into effect in April 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2030 unless additional action is taken by Congress.

Pursuant to the Coronavirus Aid, Relief, and Economic

Security Act, also known as the CARES Act, as well as subsequent legislation, these reductions have been suspended from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.

Then, a 1% payment reduction will occur beginning

April 1, 2022 through June 30, 2022, and the 2% payment reduction will resume on July 1, 2022.

In January 2013, the American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the

government to recover overpayments to providers from three to five years.

On April 13, 2017, CMS published a final rule that gives states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits

required under the ACA for plans sold through such marketplaces.

benefits required under the ACA for plans sold through such marketplaces.

On May 30, 2018, the Right to Try Act, was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial

and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical

trial and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access

There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.

On May 23, 2019, CMS published a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.

On December 20, 2019, former President Trump signed into law the Further Consolidated Appropriations Act (H.R.

1865), which repealed the Cadillac tax, the health insurance provider tax, and the medical device excise tax.

impossible to determine whether similar taxes could be instated in the future.

There has been increasing legislative and enforcement interest in the United States with respect to specialty drug pricing practices.

Specifically, there have been several recent U.S.

Congressional

inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient

programs, and reform government program reimbursement methodologies for drugs.

At a federal level, President Biden signed an Executive Order on July 9, 2021 affirming the administration’s policy to (i) support legislative reforms that would lower

the prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and biosimilars;

Congressional inquiries and

proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs,

and reform government program reimbursement methodologies for drugs.

At a federal level, President Biden signed an Executive Order on July 9, 2021 affirming the administration’s policy to (i) support legislative reforms that would lower the

prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and biosimilars;

and (ii) support

the enactment of a public health insurance option.

Among other things, the Executive Order also directs HHS to provide a report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the price

that the Federal government pays for drugs, and address price gouging in the industry;

and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription

Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.

FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and

submit importation plans for drugs from Canada.

On September 25, 2020, CMS stated drugs imported by states under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report

these drugs for “best price” or Average Manufacturer Price purposes.

Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these drugs.

If implemented,

importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.

Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation, or MFN, Model under

which Medicare Part B reimbursement rates would have been calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross

domestic product per capita.

However, on August 6, 2021 CMS announced a proposed rule to rescind the Most Favored Nations rule.

Additionally, on November 30, 2020, HHS published a regulation removing safe harbor protection for price reductions

from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the

point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and recent

legislation imposed a moratorium on implementation of the rule until January 1, 2026.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden

administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

In addition, there have been several changes to the 340B drug pricing program, which imposes ceilings on prices that drug manufacturers can charge for medications sold to certain health care

On December 27, 2018, the District Court for the District of Columbia invalidated a reimbursement formula change under the 340B drug pricing program, and CMS subsequently altered the FYs 2019 and 2018 reimbursement formula on

specified covered outpatient drugs (“SCODs”).

The court ruled this change was not an “adjustment” which was within the Secretary’s discretion to make but was instead a fundamental change in the reimbursement calculation.

However, most recently,

on July 31, 2020, the U.S.

Court of Appeals for the District of Columbia Circuit overturned the district court’s decision and found that the changes were within the Secretary’s authority.

On September 14, 2020, the plaintiffs-appellees filed a

Petition for Rehearing En Banc (i.e., before the full court), but was denied on October 16, 2020.

Plaintiffs-appellees filed a petition for a writ of certiorari at the Supreme Court on February 10, 2021.

On Friday July 2, 2021, the Supreme Court

granted the petition.

It is unclear how these developments could affect covered hospitals who might purchase our future products and affect the rates we may charge such facilities for our approved products in the future, if any.

number of these, and other proposed measures will require authorization through additional legislation to become effective, Congress has indicated that it may continue to seek new legislative and/or administrative measures to control drug costs.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient

reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

We expect that the healthcare reform measures that have been adopted and may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price

that we receive for any approved product and could seriously harm our future revenues.

Among other things, the Executive Order also directs HHS to provide a report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the

price that the Federal government pays for drugs, and address price gouging in the industry;

and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare

Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.

FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states

to build and submit importation plans for drugs from Canada.

On September 25, 2020, CMS stated drugs imported by states under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers

would not report these drugs for “best price” or Average Manufacturer Price purposes.

Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these

If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.

Additionally, on November 30, 2020, HHS published a regulation removing safe harbor protection

for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price

reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to court order, the removal and addition of the aforementioned safe harbors

were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2032.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective,

and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

Most recently, on August 16, 2022, President Biden signed the Inflation Reduction Act (“IRA”) which provides for (i) the government to set or negotiate prices for select high-cost Medicare

Part D (beginning in 2026) and Medicare Part B drugs (beginning in 2028) that are more than nine years (for small-molecule drugs) or 13 years (for biological products) from their FDA approval, (ii) manufacturers to pay a rebate for Medicare

Part B and Part D drugs when prices increase faster than inflation beginning in 2022 for Medicare Part D and 2023 for Medicare Part B drugs, and (iii) Medicare Part D redesign which replaces the current coverage gap provisions and establishes a

$2,000 cap for out-of-pocket limits costs for Medicare beneficiaries beginning in 2025, with manufacturers being responsible for 10% of costs up to the $2,000 cap and 20% after that cap is reached.

Implementation of the IRA is expected to be

carried out through upcoming actions by regulatory authorities, the outcome of which is uncertain.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement

constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

We expect that the healthcare reform measures that have been adopted and may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we

receive for any approved product and could seriously harm our future revenues.

Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private third-party payors.

There have been, and likely will continue to be, legislative and regulatory proposals at the foreign, federal, and state levels directed at broadening the availability of healthcare and containing or

lowering the cost of healthcare.

There have been, and likely will continue to be, legislative and regulatory proposals at the foreign, federal, and state levels directed at broadening the availability of healthcare and containing or lowering

the cost of healthcare.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our product.

Such reforms could have an

adverse effect on anticipated revenue from product candidates that we may successfully develop and for which we may obtain regulatory approval and may affect our overall financial condition and ability to develop product candidates.

Such reforms could have an adverse

effect on anticipated revenue from product candidates that we may successfully develop and for which we may obtain regulatory approval and may affect our overall financial condition and ability to develop product candidates.

European Union Drug Review and Approval

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In the EU, an applicant for authorization of a clinical trial must obtain prior approval from the national competent authority of the EU Member States in which the clinical trial is to be conducted.

Furthermore, the applicant may only start a clinical trial at a specific study site after the relevant independent ethics committee has issued a favorable opinion.

In April 2014, the EU adopted the new Clinical Trials Regulation (EU) No 536/2014,

which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022.

the applicant may only start a clinical trial at a specific study site after the relevant independent ethics committee has issued a favorable opinion in accordance with the laws of the Member State(s) concerned.

In April 2014, the EU adopted

the new Clinical Trials Regulation (EU) No 536/2014, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022.

It overhauls the system of approvals for clinical trials in the EU.

Specifically, the new legislation, which is directly applicable in all EU Member States (meaning that

no national implementing legislation in each EU Member State is required), aims at simplifying and streamlining the approval of clinical trials in the EU.

For instance, the new Clinical Trials Regulation provides for a streamlined application

procedure via a single-entry point (instead of submitting applications separately to each national competent authority and ethics committee in the Member States in which the trial will be conducted) and strictly defined deadlines for the

assessment of clinical trial applications.

The Clinical Trials Regulation also makes it more efficient for EU Member States to evaluate and authorize applications together, via the Clinical Trials Information System.

The transitory provisions of

the new Clinical Trials Regulation offer sponsors the possibility to choose between the requirements of the previous Clinical Trials Directive and the Clinical Trials Regulation if the request for authorization of a clinical trial is submitted in

the year after the new Clinical Trials Regulation became applicable.

If the sponsor chooses to submit under the Clinical Trials Directive, the clinical trial continues to be governed by the Directive until three years after the new Clinical

Trials Regulation became applicable.

If a clinical trial continues for more than three years after the Clinical Trials Regulation became applicable, the Clinical Trials Regulation will at that time begin to apply to the clinical trial.

Specifically, the new legislation, which is

directly applicable in all EU Member States (meaning that no national implementing legislation in each EU Member State is required), aims at simplifying and streamlining the approval of clinical trials in the EU.

For instance, the new Clinical

Trials Regulation provides for a streamlined application procedure via a single-entry point (instead of submitting applications separately to each national competent authority and ethics committee in the Member States in which the trial will be

conducted) and strictly defined deadlines for the assessment of clinical trial applications.

The Clinical Trials Regulation also makes it more efficient for EU Member States to evaluate and authorize applications together, via the Clinical

Trials Information System.

The transitory provisions of the new Clinical Trials Regulation offer sponsors the possibility to choose between the requirements of the previous Clinical Trials Directive and the Clinical Trials Regulation if the

request for authorization of a clinical trial is submitted in the year after the new Clinical Trials Regulation became applicable i.e.

January 31, 2023.

As of January 31, 2023, all applications need to be submitted under and in accordance with

the Clinical Trial Regulation.

If the sponsor chooses to submit under the Clinical Trials Directive, the clinical trial continues to be governed by the Directive and the relevant implementing legislation in each EU Member State, as required,

until three years after the new Clinical Trials Regulation became applicable.

If a clinical trial continues for more than three years after the Clinical Trials Regulation became applicable, the Clinical Trials Regulation will at that time begin

to apply to the clinical trial.

The implementation of the Clinical Trial Regulation may require us to take additional steps and procedures to ensure that our clinical trials comply with applicable laws.

Marketing Authorization

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There are two types of marketing authorizations:

(1) the centralized authorization,

which is issued by the European Commission through the centralized procedure based on the opinion of the Committee for Medicinal Products for Human Use (“CHMP”), a body of the EMA, and which is valid throughout the entire territory of the

European Economic Area, or EEA (comprising the EU Member States plus Norway, Iceland and Liechtenstein);

and (2) national marketing authorizations, which is issued by the competent authorities of the Member States of the EU and only authorize

marketing in that Member State’s national territory and not the EEA as a whole.

The centralized procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced therapy medicinal products (i.e., gene-therapy,

somatic cell-therapy, and tissue-engineered medicines) and medicinal products containing a new active substance indicated for the treatment of HIV / AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune diseases and other immune

dysfunctions and viral diseases.

The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic, scientific, or technical innovation or

which are in the interest of public health.

(1) the centralized authorization, which is issued

by the European Commission through the centralized procedure based on the opinion of the Committee for Medicinal Products for Human Use (“CHMP”), a body of the EMA, and which is valid throughout the entire territory of the European Economic

Area, or EEA (comprising the EU Member States plus Norway, Iceland and Liechtenstein);

and (2) national marketing authorizations, which is issued by the competent authorities of the Member States of the EU and only authorize marketing in that

Member State’s national territory and not the EEA as a whole, including the harmonized issuance of marketing authorizations in several Member States upon the initial application (“Decentralized Procedure”) or subsequently after the issuance of

the initial national marketing authorization (“Mutual Recognition Procedure”) in accordance with the procedures set forth in Regulation (EC) 1234/2008..

The centralized procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced therapy medicinal products (i.e., gene-therapy, somatic

cell-therapy, and tissue-engineered medicines) and medicinal products containing a new active substance indicated for the treatment of HIV / AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune diseases and other immune dysfunctions

and viral diseases.

in the interest of public health.

Gene therapy products are a type of advanced therapy medicinal product (“ATMP”) in the EU.

The scientific evaluation of marketing authorization applications for ATMPs is primarily performed by a

specialized scientific committee called the Committee for Advanced Therapies (“CAT”).

The CAT prepares a draft opinion on the quality, safety, and efficacy of the ATMP which is the subject of the marketing authorization application, which is sent

for final approval to the CHMP.

The scientific evaluation of marketing authorization applications for ATMPs is primarily performed by a specialized

scientific committee called the Committee for Advanced Therapies (“CAT”).

The CAT prepares a draft opinion on the quality, safety, and efficacy of the ATMP which is the subject of the marketing authorization application, which is sent for final

approval to the CHMP.

The CHMP recommendation is then sent to the European Commission, which adopts a decision binding in all EEA Member States.

The maximum timeframe for the evaluation of a marketing authorization application for an

ATMP is 210 days from receipt of a valid application, excluding clock stops when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CAT and/or CHMP.

The maximum timeframe for the evaluation of a marketing authorization application for an ATMP is

210 days from receipt of a valid application, excluding clock stops when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CAT and/or CHMP.

Clock stops may extend the

timeframe of evaluation of an application considerably beyond 210 days.

Where the CHMP gives a positive opinion, the EMA provides the opinion together with supporting documentation to the European Commission, who make the final decision to grant

a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.

Accelerated assessment may be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of

public health and, in particular, from the viewpoint of therapeutic innovation.

If the CHMP accepts such a request, the timeframe of 210 days for assessment will be reduced to 150 days (excluding clock stops), but it is possible that the CHMP may

revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.

The development and evaluation of a gene therapy medicinal product must be

considered in the context of the relevant EU guidelines, and the EMA may issue new guidelines concerning the development and marketing authorization for gene therapy medicinal products and require that we comply with these new guidelines.

Where the CHMP gives a positive opinion, the EMA provides the opinion together with supporting documentation to the European Commission, who make the final decision to

grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.

Accelerated assessment may be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view

of public health and, in particular, from the viewpoint of therapeutic innovation.

If the CHMP accepts such a request, the timeframe of 210 days for assessment will be reduced to 150 days (excluding clock stops), but it is possible that the

CHMP may revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.

The development and evaluation of a gene therapy medicinal product

must be considered in the context of the relevant EU guidelines, and the EMA may issue new guidelines concerning the development and marketing authorization for gene therapy medicinal products and require that we comply with these new

National marketing authorizations are for products not falling within the mandatory scope of the centralized procedure.

Where a product has already been authorized for marketing in a Member State of

the EU, this marketing authorization can be recognized in another Member States through the mutual recognition procedure.

If the product has not received a national marketing authorization in any Member State at the time of application, it can be

approved simultaneously in various Member States through the decentralized procedure.

Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the Member States in which an authorization is

sought, one of which is selected by the applicant as the Reference Member State (“RMS”).

If the RMS proposes to authorize the product, and the other Member States do not raise objections, the product is granted a national marketing authorization

in all the Member States where the authorization was sought.

Under the above-described procedures, before granting the MAA, the EMA or the competent authorities of the Member States of the EU make an assessment of the risk-benefit balance of the product on the

basis of scientific criteria concerning its quality, safety, and efficacy.

Now that the UK (which comprises Great Britain and Northern Ireland) has left the EU, Great Britain will no longer be covered by centralized marketing authorizations (under the Northern Ireland

Protocol, centralized marketing authorizations will continue to be recognized in Northern Ireland).

All medicinal products with a current centralized marketing authorization were automatically converted to Great Britain marketing authorizations

on January, 1 2021.

Where a product has already been authorized for marketing in a Member State of the EU, this

marketing authorization can be recognized in another Member States through the mutual recognition procedure.

If the product has not received a national marketing authorization in any Member State at the time of application, it can be approved

simultaneously in various Member States through the decentralized procedure.

Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the Member States in which an authorization is sought, one

of which is selected by the applicant as the Reference Member State (“RMS”).

If the RMS proposes to authorize the product, and the other Member States do not raise objections, the product is granted a national marketing authorization in all the

Member States where the authorization was sought.

Harmonization throughout all concerned Member States is achieved through procedures set forth in Regulation (EC) 1234/2008, including in cases of differences on the assessment between the

relevant authorities of Member States.

Under the above-described procedures, before granting the MAA, the EMA or the competent authorities of the Member States of the EU make an assessment of the risk-benefit balance of the product on the basis of

scientific criteria concerning its quality, safety, and efficacy.

Now that the UK (which comprises Great Britain and Northern Ireland) has left the EU, Great Britain will no longer be covered by centralized marketing authorizations (under the Northern Ireland Protocol,

centralized marketing authorizations will continue to be recognized in Northern Ireland).

All medicinal products with a current centralized marketing authorization were automatically converted to Great Britain marketing authorizations on

January, 1 2021.

For a period of two years from January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, the UK medicines regulator, may rely on a decision taken by the European Commission on the approval of a new

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Regulatory exclusivity

In the EU, innovative products authorized for marketing (i.e., reference products) may qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing

authorization.

The data exclusivity period prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing

authorization in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its

product in the EU until ten years have elapsed from the initial authorization of the reference product.

The ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the

marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing

In the EU, innovative products authorized for marketing (i.e., reference products) may qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization.

the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU

until ten years have elapsed from the initial authorization of the reference product.

The ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing

authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing

Even if an innovative medicinal product gains the prescribed period of data exclusivity, however, another company may market another version of the product if such company obtained marketing authorization based on a marketing

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The criteria for designating an orphan medicinal product in the EU, are similar in principle to those in the U.S.

Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as

orphan if the following criteria are fulfilled:

Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as orphan if

the following criteria are fulfilled:

(i) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;

(ii) either (a) such condition affects no more than five in 10,000 persons

in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in its development;

and (iii) there exists no

satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined in Regulation

(EC) 847/2000.

(ii) either (a) such condition affects no more than five in 10,000 persons in the

EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify the necessary investment in its development;

and (iii) there exists no satisfactory

method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined in Regulation (EC)

Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic

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Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The ten-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan

designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

The ten-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for

example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

Otherwise, orphan medicine marketing exclusivity may be revoked only in very select cases, such as if:

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In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.

The PRIority MEdicines

(PRIME), scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation, where the marketing authorization application will be made through the

centralized procedure.

Eligible products must target conditions for which where is an unmet medical need, i.e., there is no satisfactory method of diagnosis, prevention or treatment in the EU or, if there is, the new medicine will bring a major

therapeutic advantage) and they must show potential to benefit patients with unmet medical needs based on early clinical data.

Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger

Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development

program elements, and accelerated marketing authorization application assessment once a dossier has been submitted.

Importantly, a dedicated contact and rapporteur from the EMA’s CHMP or Committee for Advanced Therapies are appointed early in

PRIME scheme facilitating increased understanding of the product at the EMA’s committee level.

A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall

development and regulatory strategies.

The PRIority MEdicines (PRIME), scheme is

intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation, where the marketing authorization application will be made through the centralized

advantage) and they must show potential to benefit patients with unmet medical needs based on early clinical data.

Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies.

benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements,

and accelerated marketing authorization application assessment once a dossier has been submitted.

Importantly, a dedicated contact and rapporteur from the EMA’s CHMP or Committee for Advanced Therapies are appointed early in PRIME scheme

facilitating increased understanding of the product at the EMA’s committee level.

A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and

regulatory strategies.

Where, during the course of development, a medicine no longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn.

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In June 2016, the electorate in the UK voted in favor of leaving the EU (commonly referred to as “Brexit”), and the UK formally left the EU on January 31, 2020.

There was a transition period during

which EU pharmaceutical laws continued to apply to the UK, which expired on December 31, 2020.

However, the EU and the UK have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has

been formally applicable since May 1, 2021.

There was a transition period during which EU

pharmaceutical laws continued to apply to the UK, which expired on December 31, 2020.

However, the EU and the UK have concluded a trade and cooperation agreement, or TCA, which was provisionally applicable since January 1, 2021 and has been

formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued but

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now repealed Clinical Trials Directive 2001/20/EC into national law through the Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended).

The extent to which the regulation of clinical trials in the UK will mirror the new Clinical

Trials Regulation now that has come into effect is not yet known, however the Medicines and Healthcare products Regulatory Agency (“MHRA”), the UK medicines regulator, has opened a consultation on a set of proposals designed to improve and

strengthen the UK clinical trials legislation.

Such consultation is open until 14 March 2022.

The extent to which the regulation of clinical trials in the UK will mirror the new

Clinical Trials Regulation now that has come into effect is not yet known, however the Medicines and Healthcare products Regulatory Agency (“MHRA”), the UK medicines regulator, has opened a consultation on a set of proposals designed to improve

and strengthen the UK clinical trials legislation.

Such consultation was open until 14 March 2022.

Human Capital

As of December 31, 2021, we had 151 full-time employees, of whom 148 were located in the United States, two in Spain and one in Switzerland.

We also leverage temporary workers to

provide flexibility for our business needs.

As of December 31, 2022, we had 240 full-time employees, of whom 230 were located in the United States, five in Spain, two in Switzerland and one each in the UK, Sweden and Portugal.

leverage temporary workers to provide flexibility for our business needs.

None of our employees are represented by a labor union or covered by a collective bargaining agreement.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing, and integrating our existing and new employees, advisors and

The principal purposes of our equity and cash incentive plans are to attract, retain and reward personnel through the granting of stock-based and cash-based compensation awards, in order to increase stockholder value and the success

of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

Our human capital resources objectives include, as applicable, identifying, attracting, recruiting, retaining, incentivizing, developing, and integrating our existing and new employees,

advisors, and consultants.

and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.

We believe that developing a diverse, equitable and inclusive culture is critical to continuing to attract and retain the top talent necessary to deliver on our growth strategy.

As such, we are

investing in the creation of a work environment where our employees can feel inspired to deliver their workplace best every day.

All employees are responsible for upholding the Rocket Behaviors and the Rocket Code of Conduct, which form the

foundation of our policies and practices.

As such, we are investing in

creating and maintaining a diverse, inclusive and safe work environment where our employees can feel inspired to deliver their workplace best every day.

All employees are responsible for upholding the Rocket Behaviors and the Rocket Code of

Conduct, which form the foundation of our policies and practices.

Corporate Information

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and changed its name to Rocket Pharmaceuticals, Inc.

Our principal executive offices are located at 9 Cedarbrook Drive, Cranbury, NJ 08512, and our telephone number is (646) 440-9100.

Our principal

executive offices are located at 9 Cedarbrook Drive, Cranbury, NJ 08512, and our telephone number is (609) 659-8001.

Our internet address is www.rocketpharma.com.

We use our website as means of disclosing material non-public

information and for complying with our disclosure obligations under Regulation FD.

We make available on our website, free of charge, our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to

those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (“SEC”).

reports can be accessed through the Investors section of our website.

We use our website as means of disclosing material non-public information and for

complying with our disclosure obligations under Regulation FD.

We make available on our website, free of charge, our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to those reports

filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission (“SEC”).

Our SEC reports can

be accessed through the Investors section of our website.

The SEC maintains a website that contains reports, proxy and information statements and other information regarding our filings at www.sec.gov.

The information found on our

website is not incorporated by reference into this report or any other report we file with or furnish to the SEC.

The information found on our website is

not incorporated by reference into this report or any other report we file with or furnish to the SEC.

Our common stock is listed on the NASDAQ Global Market under the symbol “RCKT.”

We operate in an industry that involves numerous risks and uncertainties.

You should carefully consider the following information about these risks, together with the other

information appearing elsewhere in this Annual Report, including our financial statements and related notes hereto.

The occurrence of any of the following risks could have a material adverse effect on our business, financial condition, results of

operations and future growth prospects.

The risks and uncertainties described below may change over time and other risks and uncertainties, including those that we do not currently consider material, may impair our business.

circumstances, the market price of our common stock could decline.

In these circumstances, the market price of our common stock could decline.

Risks Related to Current Novel Coronavirus (COVID-19) Pandemic

The outbreak of the novel strain of coronavirus, SARS-CoV-2, which causes COVID-19, could adversely impact our business, including our preclinical and clinical

Public health crises such as pandemics or similar outbreaks could adversely impact our business.

Throughout 2021 and into 2022, COVID-19 has spread extensively throughout the world and in the United

In response to the spread of COVID-19 and its variants, most of our corporate employees converted to working remotely part-time, with a smaller number of employees whose roles require them to be on-site full-time working at our Cranbury,

As a result of the ongoing COVID-19 outbreak, or similar pandemics, we have and may in the future experience disruptions that could severely impact our business, preclinical studies, and clinical

trials, including:

delays or difficulties in enrolling patients in our clinical trials;

delays or difficulties in clinical site initiation, including difficulties in recruiting clinical site investigators and clinical site staff;

diversion of healthcare resources from the conduct of clinical trials such as patient follow up visits, the diversion of hospitals ability to serve as our clinical trial sites and hospital staff supporting the conduct of our clinical

interruption of clinical trial activities, such as clinical trial site data monitoring, due to limitations on travel imposed or recommended by federal or state governments, employers and others or interruption of clinical trial subject

visits and study procedures (particularly any procedures that may be deemed non-essential), which may impact the integrity of subject data and clinical study endpoints;

delays or difficulties in the buildout of our in-house manufacturing;

delays or difficulties in securing manufacturing slots or materials;

delays or difficulties in advancing preclinical research requiring in-person laboratory work at our facility at academic partners or contract research facilities;

interruption or delays in the operations of the FDA and comparable foreign regulatory agencies, which may impact approval timelines.

These and other factors arising from the COVID-19 pandemic could worsen in areas that are already afflicted with COVID-19, could continue to spread to additional areas, or could return to areas where

the pandemic has been partially contained, each of which could further adversely impact our ability to conduct clinical trials and our business generally, and could have a material adverse impact on our operations and financial condition and

The extent to which the outbreak may impact our business, preclinical studies and clinical trials will depend on future developments, which are highly uncertain and cannot be predicted with

confidence, such as the ultimate geographic spread of the disease, the identification of new variants of the virus, the duration of the outbreak, travel restrictions and actions to contain the outbreak or treat its impact, such as social

distancing and quarantines or lock-downs in the United States and other countries, business closures or business disruptions and the effectiveness of actions taken in the United States and other countries to contain and treat the disease.

addition, a recession, depression, or other sustained adverse market event resulting from the spread of the coronavirus could materially and adversely affect our business and the value of our common stock.

Since the beginning of the COVID-19 pandemic, three vaccines for COVID-19 have been granted Emergency Use Authorization by the FDA, and two of those later received marketing approval.

vaccines may be authorized or approved in the future.

The resultant demand for vaccines and potential for manufacturing facilities and materials to be commandeered under the Defense Production Act of 1950, or equivalent foreign legislation, may

make it more difficult to obtain materials or manufacturing slots for the products needed for our clinical trials, which could lead to delays in these trials.

The ultimate impact of the current pandemic, or any other health epidemic, is highly uncertain and subject to change.

We do not yet know the full extent of potential delays or impacts on our

business, our clinical and preclinical programs, our clinical, preclinical, research, manufacturing, and regulatory activities, healthcare systems or the global economy.

However, these effects could have a material adverse impact on our

operations, and we will continue to monitor the situation closely.

Risks Related to Our Financial Condition and Capital Needs

Risks Related to Our Financial Condition

We have a history of operating losses, and we may not achieve or sustain profitability.

We anticipate that we will continue to incur losses for the

foreseeable future.

If we fail to obtain additional funding to conduct our planned research and development efforts, we could be forced to delay, reduce, or eliminate our product development programs or commercial development efforts.

We are an early-stage gene therapy company with a limited operating history on which to base your investment decision.

Gene therapy product development is a highly speculative undertaking and

involves a substantial degree of risk.

Our operations to date have been limited primarily to organizing and staffing our company, business planning, raising capital, acquiring, and developing product and technology rights, building out our

R&D and manufacturing capabilities, and conducting preclinical and clinical R&D activities for our product candidates.

We have never generated any revenue from product sales.

We have not obtained regulatory approvals for any of our

product candidates and have funded our operations to date through proceeds from sales of our stock.

We have incurred net losses since our inception.

We incurred net losses of $169.1 million, $139.7 million and $77.3 million for the years ended December 31, 2021, 2020 and 2019, respectively.

December 31, 2021, we had an accumulated deficit of $491.9 million.

Substantially all our operating losses have resulted from costs incurred in connection with our R&D programs, buildout of our manufacturing capabilities and from general and

administrative (“G&A”) costs associated with our operations.

We expect to continue to incur significant expenses and operating losses over the next several years and for the foreseeable future as we intend to continue to conduct R&D,

clinical trials, regulatory compliance activities, internal and external manufacturing activities, and, if any of our product candidates is approved, sales and marketing activities that, together with anticipated G&A expenses, will likely

result in us continuing to incur significant losses for the foreseeable future.

Our limited operating history may make it difficult for us to evaluate the success of our business to date and to assess our future viability.

Our operations to date have predominantly focused on organizing and staffing our company, business planning, raising capital, acquiring our technology, administering, and expanding our gene therapy

platforms, identifying potential product candidates, undertaking research, preclinical studies and clinical trials of our product candidates, building out our R&D and manufacturing capabilities, and establishing licensing arrangements and

collaborations.

We have not yet completed clinical trials of our product candidates, obtained marketing approvals, manufactured a commercial-scale product, or conducted sales and marketing activities necessary for successful commercialization.

Consequently, any predictions made about our future success or viability may not be as accurate as they could be if we had a longer operating history.

We are currently a drug discovery and clinical stage company and at a later point we may need

to transition to a commercial stage company.

We cannot guarantee that we will be successful in this transition.

Changes in tax law could adversely affect our business and financial condition.

The rules dealing with U.S.

federal, state, and local income taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service and the U.S.

Treasury Department.

Changes to tax laws (which changes may have retroactive application) could adversely affect us or holders of our common stock.

In recent years, many such changes have been made and changes are likely to continue to occur in

Future changes in tax laws could have a material adverse effect on our business, cash flow, financial condition or results of operations.

We urge investors to consult with their legal and tax advisers regarding the implications of

potential changes in tax laws on an investment in our common stock.

The amount of and our ability to use net operating losses and research and development credits to offset future taxable income may be subject to certain limitations and

Federal net operating losses generated in taxable years beginning after December 31, 2017 generally may not be carried back to prior taxable years, and while such federal net operating losses

generated in taxable years beginning after December 31, 2017 will not be subject to expiration, the deduction for such net operating loss in any taxable year will be limited to 80% of our taxable income in such year, where taxable income is

determined without regard to the net operating loss deduction itself.

However, the Coronavirus Aid, Relief and Economic Security Act repeals the 80% limitation on the utilization of such federal net operating losses for taxable years beginning

after December 31, 2017 and beginning before January 1, 2021 and allows for federal net operating losses generated in taxable years beginning after December 31, 2017 and before January 1, 2021 to be carried back to each of the five taxable years

preceding the taxable year in which the loss arises.

This change in law temporarily allowing for the carryback of federal net operating losses is not expected to produce any material benefit for the issuer.

In general, under Sections 382 and 383

of the Internal Revenue Code, a corporation that undergoes an “ownership change” is subject to limitations on its ability to utilize its pre-change net operating losses, or NOLs or tax credits, or credits, (including federal research and

development tax credits) to offset future taxable income or taxes.

For these purposes, an ownership change generally occurs where the aggregate stock ownership of one or more stockholders or groups of stockholders who owns at least 5% of a

corporation’s stock increases its ownership by more than 50 percentage points over its lowest ownership percentage within a specified testing period.

Future changes in our stock ownership, many of which are outside of our control, could result in

an ownership change under Sections 382 and 383 of the Internal Revenue Code and limit our ability to utilize our NOLs and credits.

Our NOLs or credits may also be impaired under state law.

Accordingly, we may not be able to utilize a material

portion of our NOLs or credits if we undergo an ownership change prior to the utilization of all such NOLs or credits.

Risks Related to Capital Needs

We may need to raise additional funding, which may not be available on acceptable terms, or at all.

Failure to obtain this necessary capital when needed may

force us to delay, limit or terminate certain of our licensing activities, product development efforts or other operations.

We expect to require substantial future capital in order to expand our gene therapy platforms, advance preclinical and clinical development for our current product candidates and other future product

candidates, if any, and potentially commercialize these product candidates.

We expect our spending levels to increase in connection with our preclinical and clinical activities.

Also, if we obtain marketing approval for any of our current or

future product candidates, we expect to incur significant expenses related to product sales, medical affairs, marketing, manufacturing, and distribution.

Furthermore, we expect to incur additional costs associated with operating as a public

company, particularly as we no longer qualify as an emerging growth company or smaller reporting company and are subject to certain disclosure and compliance requirements as a large accelerated filer that we were not previously subject to.

Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations.

If we are unable to raise capital when needed or on acceptable terms, we could be forced to delay, limit or terminate our product

development efforts or other operations.

Furthermore, to the extent we raise additional capital by issuing equity securities, our stockholders will experience substantial additional dilution.

Our operations have consumed significant amounts of cash since inception.

As of December 31, 2021, our cash, cash equivalents and investments were $388.7 million.

Our future capital requirements will

depend on many factors, including:

the timing of enrollment, commencement, completion, and results of our preclinical studies and clinical trials;

costs for seeking regulatory approval for our product candidates in the U.S., Europe and other jurisdictions;

the production of LVV and AAV gene therapy product candidates to support preclinical and clinical needs;

the results of our preclinical studies for our current product candidates and any subsequent clinical trials;

the scope, progress, results, and costs of researching and developing our product candidates, and conducting preclinical studies and clinical trials;

the costs, timing, and outcome of regulatory review of our product candidates;

the costs of future activities, including product sales, medical affairs, marketing, manufacturing, and distribution, for any of our product candidates for which we receive marketing approval;

the costs of manufacturing clinical-grade and commercial-grade product to support our clinical trials and commercial launch, if approved;

the ability to receive additional non-dilutive funding, including grants from organizations and foundations;

the revenue, if any, received from commercial sale of its products, should any of its product candidates receive marketing approval;

the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims;

our ability to establish and maintain collaborations on favorable terms, if at all;

the extent to which we acquire or in-license other product candidates and technologies;

the timing, receipt, and amount of sales of, or milestone payments related to our royalties on, current or future product candidates, if any.

Many of these factors are outside of our control.

Identifying potential product candidates and conducting preclinical testing and clinical trials is a time-consuming, expensive

and uncertain process that takes years to complete, and we may never generate the necessary data or results required to obtain regulatory and marketing approval and achieve product sales.

In addition, our product candidates, if approved, may not

achieve commercial success.

Accordingly, we will need to continue to rely on additional financing to achieve our business objectives.

To the extent that additional capital is raised through the sale of equity or equity-linked securities, the issuance of those securities could result in substantial dilution for our current

stockholders and the terms may include liquidation or other preferences that adversely affect the rights of our current stockholders.

Adequate additional financing may not be available to us on acceptable terms, or at all.

We also could be

required to seek funds through arrangements with partners or otherwise that may require us to relinquish rights to our intellectual property, our product candidates or otherwise agree to terms unfavorable to us.

We have never generated any revenue from product sales and may never be profitable.

Our ability to generate revenue and achieve profitability depends on our ability, alone or with strategic collaboration partners, to successfully complete the development of, and obtain the

regulatory, pricing and reimbursement approvals necessary to commercialize our product candidates.

We do not anticipate generating revenues from product sales for the foreseeable future, if ever.

Our ability to generate future revenues from

product sales depends heavily on our success in:

completing research and preclinical and clinical development of our product candidates;

seeking and obtaining regulatory and marketing approvals for product candidates for which we successfully complete clinical studies;

developing a sustainable, commercial-scale, reproducible, and transferable manufacturing process for our vectors and product candidates;

establishing and maintaining supply and manufacturing relationships with third parties that can provide adequate (in amount and quality) products and services to support preclinical and clinical development and the market demand for

our product candidates, if approved;

launching and commercializing product candidates for which we obtain regulatory and marketing approval, either by collaborating with a partner or, if launched independently, by establishing a sales force, marketing and distribution

infrastructure;

obtaining sufficient pricing and reimbursement for our product candidates from private and governmental payors;

obtaining market acceptance of our product candidates and gene therapy as a viable treatment option;

addressing any competing technological and market developments;

identifying and validating new gene therapy product candidates;

negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter;

maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets and know-how.

Even if one or more of the product candidates that we will develop is approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product

Our expenses could increase beyond expectations if we are required by the FDA, the EMA, or other regulatory agencies, domestic or foreign, to perform clinical and other studies in addition to those that we currently anticipate.

we generate revenues from the sale of any approved products, we may not become profitable and may need to obtain additional funding to continue operations.

Risks Related to Clinical Development and Product Regulatory Matters

Risks Related to Clinical Development of our Product Candidates

We may encounter substantial delays in commencement, enrollment or completion of our clinical trials or may fail to demonstrate safety and efficacy to the satisfaction of

applicable regulatory authorities, which could prevent us from commercializing our current and future product candidates on a timely basis, if at all.

Before obtaining marketing approval from regulatory authorities for the sale of our current and future product candidates, we must conduct extensive clinical trials to demonstrate the safety and

efficacy of our product candidates.

Clinical trials are expensive, time-consuming, and outcomes are uncertain.

Our experience with clinical trials has been limited.

We have initiated Rocket-sponsored clinical trials for FA, LAD-I, PKD and Danon disease, but have not completed any clinical

trials to date.

We cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all.

A clinical trial may be delayed or halted at any stage of testing for various reasons, including:

failure of patients to enroll in the studies at the rate we expect;

ineffectiveness of our product candidates;

patients experiencing unexpected side effects or other safety concerns being raised during treatment;

changes in governmental regulations or administrative actions;

failure to conduct studies in accordance with required clinical practices;

inspection of clinical study operations or study sites by the FDA, the EMA or other regulatory authorities, resulting in a clinical hold;

insufficient financial resources;

insufficient supplies of drug product to treat patients in our ongoing and planned clinical trials;

political unrest at domestic or foreign clinical sites;

a shutdown of the U.S.

government, including the FDA;

public health crises such as pandemics and epidemics;

natural disasters at any of our clinical sites.

In addition, to the extent we seek to obtain regulatory approval for our product candidates in foreign countries, our ability to successfully initiate, enroll and complete a clinical study in any

foreign country is subject to numerous risks unique to conducting business in foreign countries, including:

difficulty in establishing or managing relationships with CROs and physicians;

different standards for the conduct of clinical trials;

absence in some countries of established groups with sufficient regulatory expertise for review of LVV and AAV gene therapy protocols;

our inability to locate qualified local partners or collaborators for such clinical trials;

the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of pharmaceutical and biotechnology products and treatment.

If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need to delay, limit or terminate planned

clinical trials, the occurrence of any of which would harm our business, financial condition, results of operations and prospects.

Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success.

We may not be able to identify, recruit and enroll

enough patients, or those with required or desired characteristics, to complete clinical trials in a timely manner.

Patient enrollment and trial completion is affected by numerous factors including:

severity of the disease under investigation;

design of the study protocol;

size of the patient population;

eligibility criteria for the study in question;

perceived risks and benefits of the product candidate under study, including as a result of adverse effects observed in similar or competing therapies;

proximity and availability of clinical study sites for prospective patients;

availability of competing therapies and clinical studies;

efforts to facilitate timely enrollment in clinical studies;

patient referral practices of physicians;

ability to monitor patients adequately during and after treatment.

In particular, each of the conditions for which we plan to evaluate our current product candidates are rare genetic diseases with limited patient pools from which to draw for clinical studies.

process of identifying and diagnosing patients may prove costly.

In some cases, potential patients may be located outside of the U.S., and immigration related issues, including government policy changes, may introduce additional delays into the

enrollment process.

Finally, the treatment process for our LVV programs requires that the cells be obtained from patients and then shipped to a transduction facility within the required timelines, and this may introduce unacceptable

shipping-related delays to the process.

We have not completed any clinical studies of our current product candidates.

Preliminary, interim or topline results in our ongoing clinical studies may not

be indicative of results obtained when these studies are completed.

Furthermore, success in early clinical studies may not be indicative of results obtained in later studies.

We have initiated our sponsored clinical trials for FA, LAD-I, PKD and DD but have not completed any clinical trials to date.

We cannot guarantee that any clinical trials will be conducted as planned

or completed on schedule, if at all.

Study designs and results from previous or ongoing studies and clinical trials are not necessarily predictive of future study or clinical trial results, and initial or interim results may not continue or be

confirmed upon completion of the study or trial.

Positive data may not continue or occur for subjects in our clinical studies or for any future subjects in our ongoing or future clinical studies and may not be repeated or observed in ongoing or

future studies involving our product candidates.

Furthermore, our product candidates may also fail to show the desired safety and efficacy in later stages of clinical development despite having successfully advanced through initial clinical

We cannot guarantee that any of these studies will ultimately be successful or that preclinical or early-stage clinical studies will support further clinical advancement or regulatory approval of our product candidates.

From time to time, we may publicly disclose interim or topline data from our preclinical studies and clinical trials, which is based on a preliminary analysis of then-available data, and the results

and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study or trial.

We also make assumptions, estimations, calculations and conclusions as part of our analyses of

data, and we may not have received or had the opportunity to fully and carefully evaluate all data.

As a result, the topline or preliminary results that we report may differ from future results of the same studies, or different conclusions or

considerations may qualify such results, once additional data have been received and fully evaluated.

Topline data also remain subject to audit and verification procedures that may result in the final data being materially different from the

preliminary data we previously published.

As a result, topline data should be viewed with caution until the final data are available.

From time to time, we may also disclose interim data from our clinical trials.

Interim data from clinical trials

that we may complete are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data become available or as patients from our clinical trials continue other treatments

for their disease.

Adverse differences between preliminary or interim data and final data could significantly harm our business prospects.

Further, others, including regulatory agencies, may not accept or agree with our assumptions, estimates, calculations, conclusions or analyses or may interpret or weigh the importance of data

differently, which could impact the value of the particular program, the approvability or commercialization of the particular product candidate or product and our company in general.

In addition, the information we choose to publicly disclose

regarding a particular study or clinical trial is based on what is typically extensive information, and you or others may not agree with what we determine is material or otherwise appropriate information to include in our disclosure.

Data obtained from preclinical and clinical activities are subject to varying interpretations, which may delay, limit or prevent regulatory approval.

addition, regulatory delays or rejections may be encountered as a result of many factors, including changes in regulatory policy during the period of product development .

Our product candidates may cause undesirable and unforeseen side effects or be perceived by the public as unsafe, which could delay or prevent their

advancement into clinical trials or regulatory approval, limit the commercial potential or result in significant negative consequences.

Gene therapy is still a relatively new approach to disease treatment and adverse side effects could develop with our product candidates.

There also is the potential risk of delayed adverse events

following exposure to gene therapy products due to persistent biologic activity of the genetic material or other components of products used to carry the genetic material.

Possible adverse side effects that could occur with treatment with gene therapy products include an immunologic reaction soon after administration which could substantially limit the effectiveness

and durability of the treatment.

If certain side effects are observed in testing of our potential product candidates, we may decide or be required to halt or delay further clinical development of our product candidates.

The FDA or other

regulatory authorities may require us to halt or delay clinical development of our product candidates for reasons unrelated to new drug-related safety events being observed.

For example, our Phase 1 clinical trial of RP-A501 for the treatment of

Danon Disease was placed on clinical hold by the FDA in May of 2021 following a thrombotic microangiopathy event believed to be due to immune-mediated complement activation.

We modified the study protocol and other supporting documents with

revised guidelines for patient selection and safety management.

The clinical hold was lifted in August 2021.

In addition to side effects caused by the product candidate, the administration process or related procedures associated with a given product candidate also can cause adverse side effects.

such adverse events occur, our clinical trials could be suspended or terminated.

Under certain circumstances, the FDA, the European Commission, the EMA or other regulatory authorities could order us to cease further development of, or deny

approval of, our product candidates for any or all targeted indications.

Moreover, if we elect or are required, to not initiate or to delay, suspend or terminate any ongoing or future clinical trial of any of our product candidates, the

commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated.

Any of these occurrences may harm our ability to develop other product

candidates, and may harm our business, financial condition and prospects significantly.

Furthermore, if undesirable side effects caused by our product candidate are identified following regulatory approval of a product candidate, such as in long-term follow-up studies, several

potentially significant negative consequences could result, including:

regulatory authorities may suspend or withdraw approvals of such product candidate;

regulatory authorities may require additional warnings on the label;

we may be required to change the way a product candidate is administered or conduct additional clinical trials;

our reputation may suffer.

Any of these occurrences may harm our business, financial condition and prospects significantly.

Risks Related to Government Regulation

Our gene therapy product candidates are based on novel technology, which makes it difficult to predict the time and cost of product candidate development and

subsequently obtaining regulatory approval.

Currently, only a few gene and cell therapy products have been approved in the United States and the European Union.

We have concentrated our R&D efforts to date on a gene therapy platform, and our future success depends on the successful development of viable gene therapy product candidates.

guarantee that we will not experience problems or delays in developing current or future product candidates or that such problems or delays will not cause unanticipated costs, or that any such development problems or delays can be resolved.

may also experience unanticipated problems or delays in developing our manufacturing capacity or transferring our manufacturing process to commercial partners, which may prevent us from completing our clinical studies or commercializing our

products on a timely or profitable basis, if at all.

In addition, the clinical study requirements of the FDA, the EMA, and other regulatory agencies and the criteria these regulators use to determine the safety and efficacy of a product candidate vary

substantially according to the type, complexity, novelty and intended use and market of the potential products.

The regulatory approval process for novel product candidates such as ours can be more expensive and take longer than for other, better

known or more extensively studied pharmaceutical or other product candidates.

Currently, only a few gene and cell therapy products have received marketing authorization in the U.S.

or the EU, including Novartis Pharmaceuticals’ Kymriah and

Zolgensma (developed by AveXis), Kite Pharma’s Yescarta, GlaxoSmithKline’s Strimvelis and Spark Therapeutics’ Luxturna.

It is therefore difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our

product candidates in the U.S., the EU or other jurisdictions.

Approvals by the EMA may not be indicative of what the FDA may require for approval.

Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approvals necessary

to bring a potential product to market could decrease our ability to generate sufficient product revenue and our business, financial condition, results of operations and prospects could be materially harmed.

Regulatory requirements governing gene therapy products have evolved and may continue to change in the future.

For example, FDA’s Center for Biologics Evaluation and Research

(“CBER”) may require us to perform additional nonclinical studies or clinical trials that may increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our gene

therapy product candidates or lead to significant post-approval limitations or restrictions.

Additionally, the FDA continues to develop its approach to assessing gene and cell therapy products.

For example, the agency has released a series of

draft and final guidance documents relating to, among other topics, various aspects of gene therapy product development, review, and approval, including aspects relating to clinical and manufacturing issues related to gene therapy products.

January 2020, FDA released a final guidance with recommendations for long-term follow-up studies of patients following human gene therapy administration due to the increased risk of undesirable and unpredictable outcomes with gene therapies that

may present as delayed adverse events.

The final guidance advises that patients treated with gene therapies that incorporate integrating vectors, such as lentiviral vectors, undergo long-term safety and efficacy follow up of fifteen years post

therapy while patients treated with gene therapies that incorporate AAV vectors undergo long-term safety and efficacy follow-up as long as five years post therapy.

We cannot be certain whether such guidance, or others that FDA may issue, will

adversely impact our gene therapy candidates or the duration or expense of any applicable regulatory development and review processes.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials

involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety committees, or IBCs, as set forth in the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH

Under the NIH Guidelines, recombinant and synthetic nucleic acids are defined as:

(i) molecules that are constructed by joining nucleic acid molecules and that can replicate in a living cell (i.e., recombinant nucleic acids);

nucleic acid molecules that are chemically or by other means synthesized or amplified, including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules (i.e., synthetic nucleic acids);

or (iii) molecules that result from the replication of those described in (i) or (ii).

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional

committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and

such review may result in some delay before initiation of a clinical trial.

While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or

synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

In addition, the EMA’s Committee for Advanced Therapies (“CAT”) and other regulatory review committees and advisory groups and any new guidelines they promulgate may lengthen the regulatory review

process, require us to perform additional studies, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our product candidates or lead to significant

post-approval limitations or restrictions.

As we advance our product candidates, we will be required to consult with these regulatory and advisory groups and comply with applicable guidelines.

If we fail to do so, we may be required to delay or

discontinue development of certain of our product candidates.

These additional processes may result in a review and approval process that is longer than we otherwise would have expected.

Delay or failure to obtain, or unexpected costs in

obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate product revenue, and our business, financial condition, results of operations and prospects would be materially harmed.

Even though we have obtained orphan designation for certain of our product candidates, we may not be able to realize the benefits of such designation, including potential

marketing exclusivity of our product candidates, if approved.

Regulatory authorities in some jurisdictions, including the United States and other major markets, may designate drugs intended to treat conditions or diseases affecting relatively small patient

populations as orphan drugs.

The FDA may designate a product candidate as an orphan drug if it is intended to treat a rare disease or condition, which is generally defined as having a patient population of fewer than 200,000 individuals in the

United States, or a patient population greater than 200,000 in the United States where there is no reasonable expectation that the cost of developing the drug will be recovered from sales in the United States.

In the European Union, the European

Commission, based on the recommendation of the EMA’s Committee for Orphan Medicinal Products grants orphan drug designation to promote the development of products that are intended for the diagnosis, prevention or treatment of a life-threatening

or chronically debilitating condition and either (i) such condition affects not more than 5 in 10,000 persons in the European Union;

or (ii) without incentives, it is unlikely that sales of the drug in the European Union would be sufficient to

justify the necessary investment in developing the drug or biologic product.

In either case, the applicant for orphan designation must also demonstrate that there exists no satisfactory method of diagnosis, prevention, or treatment of the

condition in question that has been authorized in the European Union or, if such method exists, the product must be of significant benefit compared to products available for the condition.

We have received orphan designation from the FDA and the European Commission for RP-L102 for the treatment of Fanconi Anemia, for RP-L201 for the treatment of Leukocyte Adhesion Deficiency-1, for

RP-L301 for the treatment of Pyruvate Kinase Deficiency, and FDA orphan drug designation for RP-A501 for treatment of Danon Disease and RP-401 for the treatment of Infantile Malignant Osteopetrosis.

To date, we have not requested orphan drug

designation (or the foreign equivalent) for any other product candidates, and even if we do in the future there can be no assurances that the FDA or foreign regulatory authorities will grant any of our product candidates such designation.

Additionally, the designation of any of our product candidates as an orphan product does not mean that any regulatory agency will accelerate regulatory review of, or ultimately approve, that product candidate, nor does it limit the ability of any

regulatory agency to grant orphan drug designation to product candidates of other companies that treat the same indications as our product candidates prior to our product candidates receiving exclusive marketing approval.

Generally, if a product candidate with an orphan drug designation receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of

marketing exclusivity, which precludes the FDA or foreign regulatory authorities from approving another marketing application for a product that constitutes the same drug (or “similar medicinal product” in the EEA, which is defined as a medicinal

product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication) treating the same indication for that marketing exclusivity period,

except in limited circumstances.

If another sponsor receives such approval before we do (regardless of our orphan drug designation), we will be precluded from receiving marketing approval for our product for the applicable exclusivity period.

applicable period is seven years in the United States and 10 years in the European Union.

The exclusivity period in the European Union can be reduced to six years if a product no longer meets the criteria for orphan drug designation, including if

the product is sufficiently profitable so that market exclusivity is no longer justified.

Orphan drug exclusivity may be revoked if any regulatory agency determines that the request for designation was materially defective or if the manufacturer

is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or condition.

Even if we obtain orphan drug exclusivity for a product candidate, that exclusivity may not effectively protect the product candidate from competition because different drugs can

be approved for the same condition in the United States.

Even after an orphan drug is approved, the FDA may subsequently approve another drug for the same condition if the FDA concludes that the latter drug is not the same drug or is clinically

superior in that it is shown to be safer, more effective or makes a major contribution to patient care.

The FDA may further reevaluate its regulations and policies related to orphan designation and orphan drug exclusivity.

We do not know if,

when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business.

Depending on what changes the FDA may make to its orphan drug regulations and policies, our

business could be adversely impacted.

In the European Union, marketing authorization may be granted to a similar medicinal product for the same orphan indication if:

the second applicant can establish in its application that its medicinal product, although similar to the orphan medicinal product already authorized, is safer, more effective or otherwise clinically superior;

the holder of the marketing authorization for the original orphan medicinal product consents to a second orphan medicinal product application;

the holder of the marketing authorization for the original orphan medicinal product cannot supply sufficient quantities of orphan medicinal product.

A Fast Track or regenerative medicine advanced therapy, or RMAT, designation by the FDA, or a PRIority MEdicines, or PRIME, designation by the EMA, even if

granted for any of our current or future product candidates, may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our current product candidate and any future product candidates

will receive marketing approval.

If a product candidate is intended for the treatment of a serious or life-threatening condition and the product demonstrates the potential to address unmet medical needs for this condition, the

sponsor may apply for FDA Fast Track designation for a particular indication.

We have received fast track designation for RP-A501 for Danon disease, RP-L102 for FA, RP-L201 for LAD-I and RP-L301 for PKD, and we may seek Fast Track designation for

future product candidates, but there is no assurance that the FDA will grant this status to any of our proposed product candidates.

Marketing applications filed by sponsors of products in fast-track development may qualify for priority review

under the policies and procedures offered by the FDA.

A company may request RMAT designation of its product candidate, and FDA may grant such designation if the product meets the following criteria:

(i) it is a cell therapy, therapeutic tissue

engineering product, human cell and tissue product, or any combination product using such therapies or products, with limited exceptions;

(ii) it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition;

and (iii) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such a disease or condition.

We have received RMAT designation for RP-L102 for FA and RP-L201 for LAD-I.

RMAT designation

provides potential benefits that include more frequent meetings with FDA to discuss the development plan for the product candidate, and potential eligibility for rolling review and priority review.

Products granted RMAT designation may also be

eligible for accelerated approval on the basis of a surrogate or intermediate endpoint reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites, including through expansion of

trials to additional sites.

PRIME designation is a scheme provided by the EMA to enhance support for the development of medicines that target an unmet medical need.

To qualify for PRIME designation, product candidates require

early clinical evidence that the therapy has the potential to offer a therapeutic advantage over existing treatments or benefits patients without treatment options.

We have received PRIME designation for RP-L102 for FA and RP-L201 for LAD-I.

Among the benefits of PRIME are the appointment of a rapporteur to provide continuous support and help build knowledge ahead of a marketing authorization application, early dialogue and scientific advice at key development milestones, and the

potential to qualify products for accelerated review earlier in the application process.

The FDA has broad discretion whether or not to grant Fast Track or RMAT designation, and the EMA has broad discretion whether or not to grant PRIME designation, so even if we believe a particular

product candidate is eligible for such designations, there can be no assurance that the FDA or EMA would decide to grant it.

Even if we do receive Fast Track, RMAT or PRIME designation, we may not experience a faster development process, review

or approval compared to conventional development, review, and approval timelines, and receiving a Fast Track, RMAT or PRIME designation does not change the standards for the product approval.

In addition, the FDA may withdraw Fast Track or RMAT

designation and the EMA may revoke PRIME designation if it believes that the designation is no longer supported by data from our clinical development program.

Accelerated approval by the FDA, and conditional approval by the EMA, may not lead to a faster development process or regulatory review and does not increase the

likelihood that our product candidates will receive marketing approval.

If we are not successful with this process, the development or commercialization of our product candidates for which we seek accelerated approval or conditional approval

could be delayed, abandoned or become significantly more costly .

We may seek approval of our product candidates using the FDA’s accelerated approval and the EMA’s conditional approval pathways.

While we may utilize trial designs to support accelerated approval,

such product candidates may not be subject to faster development or regulatory review timelines.

A product may be eligible for accelerated approval by the FDA if it treats a serious or life-threatening condition, generally provides a meaningful advantage over available therapies, and

demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

As a condition of accelerated approval, the FDA may impose specific obligations with defined timelines, including to perform adequate and

well-controlled post-marketing clinical trials.

These confirmatory trials must be completed with due diligence.

In addition, the FDA currently requires, unless otherwise informed by the agency, pre-approval of promotional materials for products

receiving accelerated approval, which could adversely impact the timing of the commercial launch of a product.

If the FDA or the EMA do not approve our product candidates for which we seek accelerated approval or conditional approval, but instead

require the completion of a full Phase 3 clinical trial or trials prior to the filing of marketing applications, the development and commercialization timeline of such product candidates will be delayed.

Even if we do receive accelerated approval

or conditional approval, we may not ultimately receive full approval from the regulatory agencies.

The additional data generated through post-marketing clinical trials may not confirm that the benefit-risk balance of any of our product candidates

that receive accelerated approval is positive or the burden to further complete the obligations may become too high.

In the European Union, the conditional marketing authorization is subject to an annual renewal procedure that assesses the marketing authorization holder’s compliance with the specific obligations of

the authorization.

If conditions are not complied with, the EMA may decide to extend the timeline for the existing obligations, change the scope of such obligations or add new obligations, which may require additional financial resources and

We may not be able to comply with such changes or additional obligations and may need to withdraw the marketing authorization.

The EMA may also decide not to renew the conditional marketing authorization, although such measure is rarely

applied in practice.

An analysis of reimbursement decisions for conditionally authorized medicines in the European Union has shown some delays in the timeline for reaching a positive health technology recommendation.

If this happens for any

product candidate for which we seek conditional approval, it may delay the timing and success of the commercialization of such product.

Finally, if new data obtained from fulfilment of the conditions of the conditional authorization or otherwise

show that our product’s benefits no longer outweigh its risks, the EMA can take regulatory action, such as suspending or revoking the conditional marketing authorization.

We have received rare pediatric disease designation for RP-A501 for Danon disease, RP-L102 for FA, and RP-L201 for LAD-I.

However, a marketing application for these product

candidates, if approved, may not meet the eligibility criteria for a rare pediatric disease priority review voucher.

We have received rare pediatric disease designation for RP-A501 for Danon disease, RP-L102 for FA, and RP-L201 for LAD-I.

Designation of a biological product as a product for a rare pediatric disease

does not guarantee that a BLA for such biological product will meet the eligibility criteria for a rare pediatric disease priority review voucher at the time the application is approved.

Under the Federal Food, Drug, and Cosmetic Act (“FDCA”), we

will need to request a rare pediatric disease priority review voucher in our original BLA for our product candidates for which we have received rare pediatric disease designation.

The FDA may determine that a BLA for any such product candidates,

if approved, does not meet the eligibility criteria for a priority review voucher.

The authority for the FDA to award rare pediatric disease priority review vouchers for biological products after September 30, 2024 is currently limited to biological products that receive rare

pediatric disease designation on or prior to September 30, 2024, and FDA may only award rare pediatric disease priority review vouchers through September 30, 2026.

However, it is possible the authority for FDA to award rare pediatric disease

priority review vouchers will be further extended by Congress.

Even if we successfully complete the necessary preclinical studies and clinical trials, we cannot predict when, or if, we will obtain regulatory approval to

commercialize a product candidate and the approval may be for a narrower indication than we seek.

We cannot commercialize a product candidate until the appropriate regulatory authorities have reviewed and approved the product candidate.

We have not received approval from regulatory authorities in

any jurisdiction to market any of our product candidates.

Even if our product candidates meet their safety and efficacy endpoints in clinical trials, the regulatory authorities may not complete their review processes in a timely manner, issue a

complete response letter, or ultimately, we may not be able to obtain regulatory approval.

In addition, we may experience delays or rejections if an FDA Advisory Committee recommends disapproval or restrictions on use.

In addition, we may

experience delays or rejections based upon additional government regulation from future legislation or administrative actions, or changes in regulatory authority policy during the period of product development, clinical trials and the review

Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that our data are insufficient for approval and require additional preclinical, clinical or other studies.

In addition, varying interpretations of data obtained from preclinical and clinical testing could delay, limit or prevent the receipt of marketing approval for a product candidate.

Regulatory authorities also may approve a product candidate for more limited indications than requested or they may impose significant limitations in the form of narrow indications, warnings or other

labeling changes.

These regulatory authorities may require precautions or contra-indications with respect to conditions of use or they may grant approval subject to the performance of costly post-marketing clinical trials.

Regulatory authorities

may impose restrictions and conditions on product distribution, prescribing, or dispensing in the form of a Risk Evaluation and Mitigation Strategy, or REMS, or equivalent requirement.

In addition, regulatory authorities may not approve the

labeling claims that are necessary or desirable for the successful commercialization of our product candidates.

Any of the foregoing scenarios could materially harm the commercial prospects for our product candidates and materially harm our

business, financial condition, results of operations and prospects.

Even if we obtain regulatory approval for a product candidate, we will remain subject to ongoing regulatory obligations and continued regulatory scrutiny.

Even if we obtain regulatory approval in a jurisdiction, we will remain subject to ongoing regulatory obligations and continued regulatory scrutiny.

The applicable regulatory authority may still

impose significant restrictions on the indicated uses or marketing of our product candidates or impose ongoing requirements for potentially costly post-approval studies, post-market surveillance or patient or drug restrictions once a product

candidate is approved.

Additionally, the holder of an approved BLA is obligated to monitor and report adverse events and any failure of a product to meet the specifications in the BLA.

The holder of an approved BLA must also submit new or

supplemental applications and obtain FDA approval for certain changes to the approved product, product labeling or manufacturing process.

FDA guidance advises that patients treated with some types of gene therapy undergo follow-up observations

for potential adverse events for as long as 15 years.

Advertising and promotional materials must comply with FDA rules and are subject to FDA review, in addition to other potentially applicable federal and state laws.

In addition, product manufacturers and their facilities are subject to payment of user fees and continual review and periodic inspections by the FDA and other regulatory authorities for compliance

with GMP, and current good tissue practice, as well as adherence to commitments made in the BLA.

For certain commercial prescription biological products, manufacturers and other parties involved in the supply chain must also meet chain of

distribution requirements and build electronic, interoperable systems for product tracking and tracing and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or other products that are otherwise unfit

for distribution in the United States.

If we or a regulatory agency discover previously unknown problems with a product such as adverse events of unanticipated severity or frequency, or problems with the facility where the product is

manufactured, a regulatory agency may impose restrictions on that product or the manufacturing facility, including requiring recall or withdrawal of the product from the market or suspension of manufacturing.

If we fail to comply with applicable regulatory requirements following approval of any of our product candidates, a regulatory agency may take a variety of actions, including:

issue a warning letter asserting that we are in violation of the law;

seek an injunction or impose civil or criminal penalties or monetary fines;

suspend any ongoing clinical studies;

refuse to approve a pending marketing application, such as a BLA or supplements to a BLA submitted by us;

seize products;

refuse to allow us to enter into supply contracts, including government contracts.

Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could generate negative publicity.

The occurrence of any event or

penalty described above may inhibit our ability to commercialize our product candidates and generate revenues and could harm our business, financial condition, results of operations and prospects.

In addition, the FDA’s policies, and those of comparable foreign regulatory authorities, may change and additional government regulations may be enacted that could prevent, limit or delay regulatory

approval of our product candidates.

We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative actions, either in the U.S.

If we are slow or unable to adapt to

changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval which we may have obtained and we may not achieve or sustain

profitability, which would materially harm our business, financial condition, results of operations and prospects.

We may never obtain FDA or EMA approval for any of our product candidates in the U.S.

or the EU, and even if we do, we may never obtain approval for or commercialize any of our

product candidates in any other jurisdiction, which would limit our ability to realize our full market potential.

In order to eventually market any of our product candidates in any particular jurisdiction, we must establish and comply with numerous and varying regulatory requirements regarding safety and

efficacy on a jurisdiction-by-jurisdiction basis.

Approval by the FDA in the U.S.

or the EMA in the EU, if obtained, does not ensure approval by regulatory authorities in other countries or jurisdictions.

In addition, preclinical studies and

clinical trials conducted in one country may not be accepted by regulatory authorities in other countries, and regulatory approval in one country does not guarantee regulatory approval in any other country.

Approval processes vary among countries

and can involve additional product testing and validation and additional administrative review periods.

Seeking foreign regulatory approval could result in difficulties and costs for us and require additional preclinical studies or clinical

trials which could be costly and time-consuming.

Regulatory requirements can vary widely from country to country and could delay or prevent the introduction of our products in those countries.

The foreign regulatory approval process involves

similar risks to those associated with FDA and EMA approval.

We do not have any product candidates approved for sale in any jurisdiction, including international markets, nor have we attempted to obtain such approval.

If we fail to comply with

regulatory requirements in international markets or to obtain and maintain required approvals, or if regulatory approvals in international markets are delayed, our target market will be reduced and our ability to realize the full market potential

of our products will be unrealized.

If approved, our product candidates may face competition from biosimilars approved through an abbreviated regulatory pathway.

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the ACA, includes a subtitle called the

Biologics Price Competition and Innovation Act of 2009, or BPCIA, which created an abbreviated approval pathway for biologic products that are biosimilar to or interchangeable with an FDA-licensed reference biologic product.

Under the BPCIA, an

application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA.

In addition, the approval of a biosimilar product may not be made effective by

the FDA until 12 years from the date on which the reference product was first licensed.

During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a BLA for the

competing product containing the sponsor’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity, and potency of the other company’s product.

The law is complex and is still being

interpreted and implemented by the FDA.

As a result, its ultimate impact, implementation, and meaning are subject to uncertainty.

We believe that any of our product candidates approved as a biologic product under a BLA should qualify for the 12-year period of exclusivity.

However, there is a risk that

this exclusivity could be shortened due to congressional action or otherwise, or that the FDA will not consider our investigational medicines to be reference products for competing products, potentially creating the opportunity for generic

competition sooner than anticipated.

Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity provisions, have also been the subject of recent litigation.

Moreover, the extent to which a biosimilar, once licensed, will be

substituted for any one of our reference products in a way that is similar to traditional generic substitution for non-biologic products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still

If competitors are able to obtain marketing approval for biosimilars referencing our products, our products may become subject to competition from such biosimilars, with the

attendant competitive pressure and consequences.

Healthcare legislative reform measures may have a material adverse effect on our business and results of operations.

and many foreign jurisdictions have enacted or proposed legislative and regulatory changes affecting the healthcare system that could prevent or delay marketing approval of our product

candidates or any future product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any product for which we obtain marketing approval.

Changes in regulations, statutes or the interpretation of

existing regulations could impact our business in the future by requiring, for example:

(i) changes to our manufacturing arrangements;

(ii) additions or modifications to product labeling;

(iii) the recall or discontinuation of our products;

(iv) additional record-keeping requirements.

If any such changes were to be imposed, they could adversely affect the operation of our business.

See the section entitled, “ Business — Government Regulation —

Healthcare Legislative Reform ”.

Moreover, increasing efforts by governmental and third-party payors in the United States and abroad to cap or reduce healthcare costs may cause such organizations to limit both coverage and the level

of reimbursement for newly approved products and, as a result, they may not cover or provide adequate payment for our product candidates.

There has been increasing legislative and enforcement interest in the United States with respect to

specialty drug pricing practices.

Specifically, there have been several recent U.S.

Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce

the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

We expect that additional U.S.

federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that the U.S.

Federal Government will pay for healthcare drugs and services, which could result in reduced demand for our drug candidates or

additional pricing pressures.

Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical and biological

product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain drug access and marketing cost disclosure and transparency measures, and designed to encourage importation from other countries and bulk

Legally mandated price controls on payment amounts by third-party payors or other restrictions could harm our business, financial condition, results of operations and prospects.

In addition, regional healthcare authorities and

individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.

This could reduce the ultimate demand for our

drugs or put pressure on our drug pricing, which could negatively affect our business, financial condition, results of operations and prospects.

The United Kingdom’s withdrawal from the European Union could result in increased regulatory and legal complexity, which may make it more difficult for us

to do business in Europe and impose additional challenges in securing regulatory approval of our product candidates in Europe and/or the United Kingdom.

We currently have clinical trial sites in the United Kingdom, contract laboratories in the United Kingdom conducting testing for our global clinical trials, and other collaborators and potential

collaborators in the United Kingdom and throughout Europe.

Pursuant to Article 50 of the Treaty on EU, the UK ceased being a Member State of the EU on January 31, 2020.

There was a transitional period, during which EU laws, including

pharmaceutical laws, continued to apply in the UK, however this ended on December 31, 2020.

The UK reached a trade agreement with the European Union on December 24, 2020, which became provisionally applicable on January 1, 2021 and has been

formally applicable since May 1, 2021.

Under the terms of the deal, the EU and UK have separate regulatory regimes for pharmaceutical products, although there are some provisions for mutual recognition of standards, for example with regards to

For instance, the UK is no longer covered by the centralized procedure for obtaining EU-wide marketing authorizations for medicinal products, and a separate process for authorization of medicinal products will be required in the UK,

resulting in an authorization covering the UK or Great Britain (England, Scotland and Wales) only.

At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines

Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework will continue to apply in Northern Ireland).

The regulatory regime in Great Britain therefore currently broadly aligns with EU regulations, however it

is possible that these regimes will diverge in future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.

The cumulative effects of the disruption to the regulatory framework may add considerably to the development lead time to marketing authorization and commercialization of products in the European

Union and/or the United Kingdom.

It is possible that there will be increased regulatory complexities which can disrupt the timing of our clinical trials and regulatory approvals.

In addition, changes in, and legal uncertainty with regard to,

national and international laws and regulations may present difficulties for our clinical and regulatory strategy.

In addition, as a result of Brexit, other European countries may seek to conduct referenda with respect to their continuing membership with the European Union.

possibilities and others we may not anticipate, as well as the absence of comparable precedent, it is unclear what financial, regulatory and legal implications the withdrawal of the United Kingdom from the European Union would have and how such

withdrawal would affect us, and the full extent to which our business could be adversely affected.

Risks Related to Noncompliance with Applicable Laws or Regulations

If we are successful in commercializing any product, our relationships with customers and third-party payors will be subject to applicable anti-kickback,

fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, exclusion from government healthcare programs, contractual damages, reputational harm and diminished profits and future

Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of any products for which we obtain regulatory approval.

Our arrangements with

third-party payors, healthcare providers and physicians may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we

conduct our operations, including how we research, market, sell and distribute any products for which we obtain regulatory approval.

See the section entitled, “ Business — Government Regulation — Anti-Kickback and

False Claims Laws and Other Regulatory Matters ”.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements

in the healthcare industry.

Efforts to ensure that our business arrangements with third parties, and our business generally, will comply with applicable healthcare laws and regulations will involve substantial costs.

It is possible that

governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations, agency guidance or case law involving applicable fraud and abuse or other healthcare laws and regulations.

operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant administrative, civil and criminal penalties, damages, fines, disgorgement, the exclusion

from participation in federal and state healthcare programs, individual imprisonment, reputational harm, and the curtailment or restructuring of our operations, as well as additional reporting obligations and oversight if we become subject to a

corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, any of which could adversely affect our ability to operate our business and our results of operations.

Defending against any such actions

can be costly, time-consuming and may require significant financial and personnel resources.

Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.

If any of the

physicians or other healthcare providers or entities with whom we expect to do business are found to be not in compliance with applicable laws, they may be subject to significant criminal, civil or administrative sanctions, including exclusions

from government funded healthcare programs.

If we fail to comply with applicable U.S.

and foreign privacy and data protection laws and regulations, we may be subject to liabilities

that adversely affect our business, operations and financial performance.

We may also be subject to or affected by foreign laws and regulation, including regulatory guidance, governing the collection, use, disclosure, security, transfer and storage of personal data, such

as information that we collect about patients and healthcare providers in connection with clinical trials and our other operations in the U.S.

For example, the E.U.’s General Data Protection Regulation (“GDPR”), which introduces

strict requirements for processing all personal data and imposes even more stringent requirements for certain categories of sensitive information, including health related information.

The GDPR increases the compliance burden on us, including by

mandating potentially burdensome documentation requirements and granting certain rights to individuals to control how we collect, use, disclose, retain and leverage information about them.

The processing of sensitive personal data, such as health

information, imposes heightened compliance burdens under the GDPR and is a topic of active interest among foreign regulators.

In addition, the GDPR provides for breach reporting requirements, more robust regulatory enforcement and fines of up to

20 million euros or up to 4% of annual global revenue.

While the GDPR affords some flexibility in determining how to comply with the various requirements, significant effort and expense has been, and will continue to be, invested to ensure

continuing compliance.

Moreover, the requirements under the GDPR may change periodically or may be modified by EU national law and could affect our business operations if compliance becomes substantially more costly than under current

requirements.

In addition, further to the U.K.’s exit from the EU on January 31, 2020, the GDPR ceased to apply in the U.K.

at the end of the transition period on December 31, 2020.

However, as of January 1, 2021,

the U.K.’s European Union (Withdrawal) Act 2018 incorporated the U.K.

GDPR into U.K.

GDPR and the U.K.

Data Protection Act 2018 set out the U.K.’s data protection regime, which is independent from but aligned to the EU’s data

protection regime.

Non-compliance with the U.K.

GDPR may result in monetary penalties of up to £17.5 million or 4% of worldwide revenue, whichever is higher.

Although the UK is regarded as a third country under the EU’s GDPR, the European

Commission (“EC”) has now issued a decision recognizing the UK as providing adequate protection under the EU GDPR and, therefore, transfers of personal data originating in the EU to the UK remain unrestricted.

Like the EU GDPR, the UK GDPR

restricts personal data transfers outside the UK to countries not regarded by the UK as providing adequate protection.

The UK government has confirmed that personal data transfers from the UK to the EEA remain free flowing.

To enable the transfer of personal data outside of the EEA or the UK, adequate safeguards must be implemented in compliance with European and UK data protection laws.

On June 4, 2021, the EC issued

new forms of standard contractual clauses for data transfers from controllers or processors in the EU/EEA (or otherwise subject to the GDPR) to controllers or processors established outside the EU/EEA (and not subject to the GDPR).

standard contractual clauses replace the standard contractual clauses that were adopted previously under the EU Data Protection Directive.

The UK is not subject to the EC’s new standard contractual clauses but has published a draft version of a

UK-specific transfer mechanism, which, once finalized, will enable transfers from the UK.

We will be required to implement these new safeguards when conducting restricted data transfers under the EU and UK GDPR and doing so will require

significant effort and cost.

In the United States, there are numerous privacy laws that may be applicable to our activities, and a range of enforcement agencies at both the state and federal levels that can review companies for

privacy and data security concerns based on general consumer protection laws.

New laws also are being considered or have been implemented at both the state and federal levels.

For example, the California Consumer Privacy Act of 2018, or the CCPA,

which became effective on January 1, 2020, requires companies that process information of California residents to make new disclosures to consumers about their data collection, use and sharing practices, provides Californian consumers (as defined

under the CCPA) with new individual data privacy rights, imposes new operational requirements for covered businesses, provides a private right of action for data breaches and creates a statutory damages framework.

Although there are limited

exemptions for clinical trial data under the CCPA, the CCPA and other similar laws could impact our business activities depending on how such laws are interpreted.

Additionally, effective starting on January 1, 2023, the California Privacy Rights

Act, or the CPRA, will significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information.

The CPRA also creates a new state agency that will be vested with authority to implement and

enforce the CCPA and the CPRA.

Certain states, including Colorado and Virginia, have enacted laws similar to the CCPA and many other states are considering similar legislation, and a broad range of legislative measures also have been introduced

at the federal level.

Additionally, some observers have noted that the CCPA and CPRA could mark the beginning of a trend toward more stringent privacy legislation in the U.S., which could increase our potential liability

and adversely affect our business.

Already, in the United States, we have witnessed significant developments at the state level.

For example, on March 2, 2021, Virginia enacted the Consumer Data Protection Act (the “CDPA”), and, on July 8, 2021,

Colorado’s governor signed the Colorado Privacy Act (“CPA”), into law.

The CDPA and the CPA will both become effective January 1, 2023.

While the CDPA and CPA incorporate many similar concepts of the CCPA and CPRA, there are also several key

differences in the scope, application, and enforcement of the law that will change the operational practices of regulated businesses.

The new laws will, among other things, impact how regulated businesses collect and process personal sensitive

data, conduct data protection assessments, transfer personal data to affiliates, and respond to consumer rights requests.

A number of other states have proposed new privacy laws, some of which are similar to the above discussed recently passed laws.

Such proposed legislation, if enacted, may add additional complexity,

variation in requirements, restrictions and potential legal risk, require additional investment of resources in compliance programs, impact strategies and the availability of previously useful data and could result in increased compliance costs

and/or changes in business practices and policies.

The existence of comprehensive privacy laws in different states in the country would make our compliance obligations more complex and costly and may increase the likelihood that we may be subject

to enforcement actions or otherwise incur liability for noncompliance.

Further, regulations promulgated pursuant to HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their implementing regulations, or collectively HIPAA,

imposes privacy, security and breach notification obligations on certain healthcare providers, health plans, and healthcare clearinghouses, known as covered entities, as well as their business associates that perform certain services that involve

creating, receiving, maintaining or transmitting individually identifiable health information for or on behalf of such covered entities, and their covered subcontractors.

HIPAA establishes privacy and security standards that limit the use and

disclosure of individually identifiable health information and protected health information, or PHI, and requires the implementation of administrative, physical and technological safeguards to protect the privacy of PHI and ensure the

confidentiality, integrity and availability of electronic PHI.

Most healthcare providers, including research institutions from which we obtain patient health information, are privacy and security regulations promulgated under HIPAA, as amended by

the Health Information Technology for Economic and Clinical Health Act.

We do not believe that we are currently acting as a covered entity or business associate under HIPAA and thus are not directly subject to its requirements or penalties.

However, any person may be prosecuted under HIPAA’s criminal provisions either directly or under aiding-and-abetting or conspiracy principles.

Consequently, depending on the facts and circumstances, we could face substantial criminal penalties if

we knowingly receive individually identifiable health information from a HIPAA-covered healthcare provider or research institution that has not satisfied HIPAA’s requirements for disclosure of individually identifiable health information.

The global legislative and regulatory landscape for privacy and data protection continues to evolve, and implementation standards and enforcement practices are likely to remain uncertain for the

foreseeable future.

This evolution may create uncertainty in our business, result in liability or impose additional costs on us.

The cost of compliance with these laws, regulations and standards is high and is likely to increase in the future.

It is possible that privacy laws may be interpreted and applied in a manner that is inconsistent with our practices.

Any failure or perceived failure by us to comply with federal, state, or foreign

laws or self-regulatory standards could result in negative publicity, diversion of management time and effort and proceedings against us by governmental entities or others.

In many jurisdictions, enforcement actions and consequences for

noncompliance are rising.

As we continue to expand into other foreign countries and jurisdictions, we may be subject to additional laws and regulations that may affect how we conduct business.

In addition to the risks associated with enforcement activities and potential contractual liabilities, our ongoing efforts to comply with evolving laws and regulations at the federal and state level

may be costly and require ongoing modifications to our policies, procedures and systems.

Further, any failure by our third-party collaborators, service providers, contractors or consultants to comply with applicable law, regulations or

contractual obligations related to data privacy or security could result in proceedings against us by governmental entities or others.

We may also publish privacy policies and other documentation regarding our collection, processing, use and disclosure of personal information and/or other confidential information.

endeavor to comply with our published policies and other documentation, we may at times fail to do so or may be perceived to have failed to do so.

Despite our efforts, we may not be successful in achieving compliance if our employees or vendors

fail to comply with our published policies and documentation.

Such failures can subject us to potential international, local, state and federal action if they are found to be deceptive, unfair, or misrepresentative of our actual practices.

that we have violated individuals’ privacy rights or failed to comply with data protection laws or applicable privacy notices, even if we are not found liable, could be expensive and time-consuming to defend and could result in adverse publicity

that could harm our business.

We also face a threat of consumer class actions related to these laws and the overall protection of personal information.

Even if we are not determined to have violated these laws, government investigations into

these issues typically require the expenditure of significant resources and generate negative publicity, which could harm our reputation and our business, financial condition, results of operations or prospects

We are subject to environmental, health and safety laws and regulations, and we may become exposed to liability and substantial expenses in connection with

environmental compliance or remediation activities.

Our operations, including our development, testing and manufacturing activities, are subject to numerous environmental, health and safety laws and regulations.

These laws and

regulations govern, among other things, the controlled use, handling, release and disposal of and the maintenance of a registry for, hazardous materials and biological materials, such as chemical solvents, human cells, carcinogenic compounds,

mutagenic compounds and compounds that have a toxic effect on reproduction, laboratory procedures and exposure to blood-borne pathogens.

If we fail to comply with such laws and regulations, we could be subject to fines or other sanctions.

As with other companies engaged in similar activities, we face a risk of environmental liability inherent in our activities, including liability relating to releases of or exposure to hazardous or

biological materials.

Environmental, health and safety laws and regulations are becoming more stringent.

We may be required to incur substantial expenses in connection with future environmental compliance or remediation activities, in which case,

the production efforts of our third-party manufacturers or our development efforts may be interrupted or delayed.

Risks Related to Manufacturing, Commercialization and Development of Our Product Candidates

Risks Related to Manufacturing our Product Candidates

Products intended for use in gene therapies are novel, complex and difficult to manufacture.

We could experience production problems that result in delays

in our development or commercialization programs, limit the supply of our products or otherwise harm our business.

We currently have development, manufacturing and testing agreements with third parties to manufacture supplies of our product candidates.

Several factors could cause production interruptions,

including equipment malfunctions, facility contamination, raw material shortages or contamination, natural disasters, public health crises such as pandemics and epidemics, disruption in utility services, human error or disruptions in the

operations of suppliers.

Our product candidates require processing steps that are more complex than those required for small molecule pharmaceuticals.

The facilities used by our contract manufacturers to manufacture our

product candidates must be inspected by the FDA pursuant to pre-approval inspections that will be conducted after we submit our marketing applications to the FDA.

We do not control the manufacturing process of, and will be completely dependent

on, our contract manufacturers for compliance with cGMPs in connection with the manufacture of our product candidates.

If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict

regulatory requirements of the FDA or others, they will not be able to pass regulatory inspections and/or maintain regulatory compliance for their manufacturing facilities.

In addition, we have no control over the ability of our contract

manufacturers to maintain adequate quality control, quality assurance and qualified personnel.

If the FDA or a comparable foreign regulatory authority finds deficiencies with or does not approve these facilities for the manufacture of our product

candidates or if it finds deficiencies or withdraws any such approval in the future, we may need to find alternative manufacturing facilities, which would significantly impact our ability to develop, obtain regulatory approval for or market our

product candidates, if approved.

Any problems in our manufacturing process or the facilities with which we contract could make us a less attractive collaborator for potential partners, including larger pharmaceutical

companies and academic research institutions, which could limit our access to attractive development programs.

Problems in third-party manufacturing processes or facilities also could restrict our ability to complete our clinical trials in a

timely manner or meet market demand for our products.

Additionally, should our manufacturing agreements with third parties be terminated for any reason, there may be a limited number of manufacturers who would be suitable replacements and it

could take a significant amount of time to transition the manufacturing to a replacement.

In some cases, the technical skills required to manufacture our products or product candidates may be unique or proprietary to the original manufacturer and

we may have difficulty, or there may be contractual restrictions prohibiting us from, transferring such skills to a back-up or alternate supplier, or we may be unable to transfer such skills at all.

Changes to the manufacturing process or the

transfer or setup of new manufacturing facilities could require that we conduct bridging studies before being able to proceed with either clinical or commercial manufacturing activities.

We may be unsuccessful in demonstrating the comparability

of clinical supplies which could require the conduct of additional clinical trials.

Further, the shift would likely be expensive and time-consuming, particularly since the new facility would need to comply with the necessary regulatory

requirements or may require approval before selling any products manufactured at that facility.

We are preparing our manufacturing facility for cGMP manufacturing.

We have no experience in manufacturing, and there can be no assurance that we will be able

to manufacture products.

We have historically relied on third parties to manufacture supplies of our product candidates.

We have completed a build-out of a new manufacturing facility in Cranbury, New Jersey, and are now

preparing the facility to be ready for cGMP manufacturing in 2022.

Although some of our employees have experience in the manufacturing of biopharmaceutical products from prior employment at other companies, we as a company have no prior experience in manufacturing.

In addition, government approvals will be required for us to operate a manufacturing facility and can be time-consuming to obtain, and there can be no assurance that such approval will be obtained.

As a manufacturer of pharmaceutical products, we

also will be required to demonstrate and maintain compliance with cGMP requirements related to production processes, quality control and assurance and recordkeeping.

Furthermore, establishing and maintaining manufacturing operations may require a

reallocation of other resources, particularly the time and attention of certain of our senior management as well as potentially significant capital expenditures.

Any failure or delay in the development of our manufacturing capabilities could

adversely impact the development or commercialization of our product candidates.

Our manufacturing facilities are subject to significant government regulations and approvals, which are often costly and could result in adverse consequences

to our business if we fail to comply with the regulations or maintain the approvals.

We must comply with cGMP requirements, as set out in statute, regulations and guidance.

We may encounter difficulties in achieving quality control and quality assurance and may experience shortages

in qualified personnel.

We are subject to inspections by the FDA and comparable agencies in other jurisdictions to confirm compliance with applicable regulatory requirements.

Any failure to follow cGMP or other regulatory requirements or delay,

interruption or other issues that arise in the manufacture, fill-finish, packaging, or storage of our product candidates as a result of a failure of our facilities or the facilities or operations of third parties to comply with regulatory

requirements or pass any regulatory authority inspection could significantly impair our ability to develop and commercialize our product candidates, including leading to significant delays in the availability of drug product for our clinical

trials or the termination or hold on a clinical trial, or the delay or prevention of a filing or approval of marketing applications for our product candidates.

Significant noncompliance could also result in the imposition of sanctions, including

fines, injunctions, civil penalties, failure of regulatory authorities to grant marketing approvals for our product candidates, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of products, operating

restrictions and criminal prosecutions, any of which could damage our reputation.

If we are not able to maintain regulatory compliance, we may not be permitted to market our product candidates and/or may be subject to product recalls, seizures,

injunctions, or criminal prosecution.

Risks Related to Commercialization of our Product Candidates

Our ability to successfully develop and commercialize our product candidates will substantially depend upon the availability of reimbursement for the costs

of the resulting drugs and related treatments.

In the United States and markets in other countries, patients generally rely on third-party payors to reimburse all, or part of the costs associated with their treatment.

The availability and extent

of reimbursement by governmental and private payors is essential for most patients to be able to afford expensive treatments.

Sales of our product candidates will depend substantially, both domestically and abroad, on the extent to which the

costs of our product candidates will be covered and paid by government authorities and other third-party payors, such as private health insurers and health maintenance organizations.

We cannot guarantee that reimbursement will be available for

any of our product candidates.

We have not commenced efforts to have our product candidates reimbursed by government or third-party payors.

If coverage and reimbursement are not available or are available only at limited levels, we may not be

able to successfully commercialize our products.

Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a sufficient return on our investment.

may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement.

If reimbursement is not available, or is available only at limited levels, we may not be able to successfully commercialize our product

candidates, if approved.

The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the reimbursement rate that the payor will pay for the product.

Payors may limit coverage to

specific products on an approved list, or formulary, which might not include all of the FDA-approved products for a particular indication A decision by a payor not to cover our product candidates could reduce physician utilization of our products

once approved and have a material adverse effect on our sales, results of operations and financial condition.

See the section entitled, “ Business — Government Regulation — Coverage and Reimbursement ”.

There is significant uncertainty related to the insurance coverage and reimbursement of newly approved products.

In the U.S., the principal decisions about coverage and

reimbursement for new medicines are typically made by the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S.

Department of Health and Human Services, or HHS, as CMS decides whether and to what extent a new medicine

will be covered and reimbursed under Medicare.

Private payors tend to follow the CMS to a substantial degree.

It is difficult to predict what the CMS will decide with respect to reimbursement for fundamentally novel products such as ours, as

there is no body of established practices and precedents for these new products.

Factors payors consider in determining reimbursement are based on whether the product is:

a covered benefit under its health plan;

safe, effective, and medically necessary;

appropriate for the specific patient;

cost-effective;

neither experimental nor investigational.

In recent years, numerous proposals to change the health care system in the U.S.

have been made.

These reform proposals include measures that would limit or prohibit payments for certain medical

treatments or subject the pricing of drugs to government control.

In addition, in many foreign countries, particularly the countries of the EU, the pricing of prescription drugs is subject to government control.

If our products are or become

subject to government regulation that limits or prohibits payment for our products, or that subjects the price of our products to governmental control, we may not be able to generate revenue, attain profitability or commercialize our products.

In addition, third-party payors are increasingly limiting both coverage and the level of reimbursement of new drugs.

They may also impose strict prior authorization requirements and/or refuse to

provide any coverage of uses of approved products for medical indications other than those for which the FDA has granted market approvals.

As a result, significant uncertainty exists as to whether and how much third-party payors will reimburse

patients for their use of newly approved drugs.

Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict

imports of drugs from countries where they may be sold at lower prices than in the United States.

Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging

the prices charged for medical products.

We cannot be sure that reimbursement will be available for any product candidate that we commercialize and, if reimbursement is available, the level of reimbursement.

In addition, many pharmaceutical

manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price, or ASP, and best price.

Penalties may apply in some cases when such metrics are not submitted accurately and timely.

these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs.

If we are unable to obtain adequate levels of reimbursement for our product candidates, our ability to successfully market and

sell our product candidates will be harmed.

The manner and level at which reimbursement is provided for services related to our product candidates (e.g., for administration of our product to patients) is also important to successful

commercialization of our product candidates.

Inadequate reimbursement for such services may lead to physician resistance and limit our ability to market or sell our products.

In addition, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.

The requirements governing drug pricing vary widely from country to

For example, the European Union provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products

for human use.

To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently available therapies.

State may approve a specific price for the medicinal product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

There can be no assurance that any

country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates.

Historically, products launched in the European Union do not

follow price structures of the U.S.

and generally prices tend to be significantly lower.

Even if approved, we may not successfully commercialize our product candidates.

Our gene therapy product candidates are subject to the risks of failure inherent in the development of pharmaceutical products based on new technologies, and our failure to develop safe, commercially

viable products would severely limit our ability to become profitable or to achieve significant revenues.

Even if one or more of our product candidates is approved, we may be unable to successfully commercialize our product candidates for several

reasons, including:

some or all of our product candidates may be found to be unsafe or ineffective or otherwise fail to meet applicable regulatory standards or receive necessary regulatory clearances;

our product candidates, if safe and effective, may

nonetheless not be able to be developed into commercially viable products;

it may be difficult to manufacture or market our product candidates on a scale that is necessary to ultimately deliver our products to end-users;

proprietary rights of third parties may preclude us from marketing our product candidates;

the nature of our indications as rare diseases means that the potential market size may be limited;

third parties may market superior or equivalent drugs which could adversely affect the commercial viability and success of our product candidates.

We face intense competition and rapid technological change and the possibility that our competitors may develop therapies that are more advanced or effective than ours, which may

adversely affect our financial condition and our ability to successfully commercialize our product candidates.

We are engaged in gene therapy for severe genetic and rare diseases, which is a competitive and rapidly changing field.

Although we are not currently aware of any gene therapy competitors addressing

any of the same indications as those in our pipeline, we may have competitors both in the U.S.

and internationally, including major multinational pharmaceutical companies, biotechnology companies and universities and other research institutions.

Our potential competitors may have substantially greater financial, technical and other resources, such as larger R&D staff, manufacturing capabilities and experienced marketing and manufacturing

organizations.

These competitors may succeed in developing, acquiring or licensing on an exclusive basis, products that are more effective or less costly than any product candidate that we may develop, or achieve earlier patent protection,

regulatory approval, product commercialization and market penetration than us.

Additionally, technologies developed by our competitors may render our potential product candidates uneconomical or obsolete, and we may not be successful in marketing

our product candidates against those of our competitors.

In addition, if our patent rights were to expire or be successfully challenged, we could face increased litigation with respect to the validity and/or scope of patents relating to our competitors’

The availability of our competitors’ products could limit the demand, and the price we are able to charge, for any products that we may develop and commercialize, thereby causing harm to our business, financial condition, results of

operations and prospects.

The commercial success of any of our product candidates will depend upon the degree of market acceptance by physicians, patients, third-party payors and

others in the medical community.

Ethical, social, legal and other concerns about gene therapy could result in additional regulations restricting or prohibiting our products.

Even with the requisite approvals from the FDA in the

U.S., the EMA in the EU and other regulatory authorities internationally, the commercial success of our product candidates will depend, in part, on the acceptance of physicians, patients and health care payors of gene therapy products in general,

and our product candidates in particular, as medically beneficial, cost-effective and safe.

Any product that we commercialize may not gain acceptance by physicians, patients, health care payors and others in the medical community.

products do not achieve an adequate level of acceptance, we may not generate significant product revenue and may not become profitable.

The degree of market acceptance of gene therapy products and our product candidates, if approved for

commercial sale, will depend on several factors, including:

the efficacy and safety of such product candidates as demonstrated in preclinical studies and clinical trials;

the potential and perceived advantages of product candidates over alternative treatments;

the cost of our treatment relative to alternative treatments;

the clinical indications for which the product candidate is approved by the FDA or the EMA;

patient awareness of, and willingness to seek, gene therapy;

the willingness of physicians to prescribe new therapies;

the willingness of physicians to undergo specialized training with respect to administration of our product candidates;

the willingness of the target patient population to try new therapies;

the prevalence and severity of any side effects;

product labeling or product insert requirements of the FDA, the EMA or other regulatory authorities, including any limitations or warnings contained in a product’s approved labeling;

relative convenience and ease of administration;

the strength of marketing and distribution support;

the timing of market introduction of competitive products;

publicity concerning our products or competing products and treatments;

sufficient third-party payor coverage and reimbursement.

Even if a potential product displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product will not be fully known until after it is

approved and launched and is subject to change over time if adverse long-term follow-up data become available after approval.

The failure of any of our product candidates to achieve market acceptance could materially harm our business, financial

condition, results of operations and prospects.

Risks Related to Development of our Pipeline and Research and Development Activities

We may not be successful in our efforts to expand our pipeline of additional product candidates for development.

Our business model is centered on applying our expertise in rare genetic diseases by establishing focused selection criteria to develop and advance a portfolio of gene therapy product candidates

through development into commercialization.

We may not be able to continue to identify and develop new product candidates in addition to the pipeline of product candidates that our efforts to date have resulted in.

Even if we are successful in

continuing to expand our pipeline, any potential product candidates that we identify may not be suitable for clinical development.

If we do not successfully identify, develop and commercialize product candidates, we will not be able to obtain

product revenue in future periods, which would likely result in significant harm to our financial position and results of operations.

The success of our research and development activities, clinical testing and commercialization, upon which we primarily focus, is uncertain.

Our primary focus is on our R&D activities and the clinical testing and commercialization of our product candidates, and we anticipate that we will remain principally engaged in these activities

for an indeterminate, but substantial, period.

R&D was our most significant operating expense for the year ended December 31, 2021.

R&D activities, including the conduct of clinical studies, by their nature, preclude definitive statements

as to the time required and costs involved in reaching certain objectives.

Actual R&D costs, therefore, could significantly exceed budgeted amounts and estimated time frames may require significant extension.

Cost overruns, unanticipated

regulatory delays or demands, unexpected adverse side effects or insufficient therapeutic efficacy will prevent or substantially slow our R&D effort and our business could ultimately suffer.

Risks Related to Third Parties

We rely on third parties to conduct certain aspects of our preclinical studies and clinical trials and perform other tasks for us.

these third parties do not successfully carry out their contractual duties, meet expected deadlines, or comply with regulatory requirements, we may not be able to obtain regulatory approval for or commercialize our product candidates and our

business, financial condition and results of operations could be substantially harmed.

We have relied upon and plan to continue to rely upon third parties, including CROs, medical institutions, and contract laboratories for certain aspects of our ongoing preclinical and clinical

Nevertheless, we maintain responsibility for ensuring that each of our clinical trials and preclinical studies is conducted in accordance with the applicable protocol, legal, regulatory, and scientific standards and our reliance on

these third parties does not relieve us of our regulatory responsibilities.

We and our vendors are required to comply with current requirements of GMP, good clinical practice (“GCP”), and good laboratory practice (“GLP”), which are a collection

of laws and regulations enforced by the FDA, the EMA or comparable foreign authorities for our drug candidates in clinical development.

Regulatory authorities enforce these regulations through periodic inspections of preclinical study and clinical trial sponsors, principal investigators, preclinical study and clinical trial sites,

and other contractors.

If we or any of our vendors fail to comply with applicable regulations, the data generated in our preclinical studies and clinical trials may be deemed unreliable and the FDA, the EMA or comparable foreign authorities may

require us to perform additional preclinical studies and clinical trials before approving our marketing applications.

We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of

our clinical trials comply with GCP regulations.

In addition, our clinical trials must be conducted with products produced consistent with GMP regulations.

Our failure to comply with these regulations may require us to repeat clinical trials,

which would delay the development and regulatory approval processes.

If any of our relationships with these third parties, medical institutions, clinical investigators or contract laboratories terminate, we may not be able to enter into arrangements with alternative

CROs on commercially reasonable terms, or at all.

In addition, our CROs are not our employees, and except for remedies available to us under our agreements with such CROs, we cannot control whether they devote sufficient time and resources to our

ongoing preclinical and clinical programs.

If our CROs do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the data, they obtain is

compromised due to the failure to adhere to our protocols, regulatory requirements, or for other reasons, our clinical trials may be extended, delayed or terminated and we may not be able to obtain regulatory approval for or successfully

commercialize our product candidates.

CROs may also generate higher costs than anticipated.

As a result, our business, financial condition and results of operations and the commercial prospects for our product candidates could be materially and

adversely affected, our costs could increase, and our ability to generate revenue could be delayed.

Switching or adding additional CROs, medical institutions, clinical investigators or contract laboratories involves additional cost and requires management time and focus.

In addition, there is a

natural transition period when a new CRO commences work replacing a previous CRO.

As a result, delays may occur, which can materially impact our ability to meet our desired clinical development timelines.

Though we carefully manage our

relationships with our CROs, we cannot guarantee that we will not encounter similar challenges or delays in the future or that these delays or challenges will not have a material adverse effect on our business, financial condition or results of

We expect to rely on third parties to conduct some or all aspects of our drug product manufacturing, research and preclinical and clinical testing, and these

third parties may not perform satisfactorily.

We do not expect to independently conduct all aspects of our gene therapy production, product manufacturing, research and preclinical and clinical testing.

We currently rely, and

expect to continue to rely, on third parties with respect to certain of these items.

In some cases, these third parties are academic, research or similar institutions that may not apply the same quality control protocols utilized in certain

commercial settings.

Our reliance on these third parties for R&D activities will reduce our control over these activities but will not relieve us of our responsibility to ensure compliance with all required

regulations and study protocols.

If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our studies in accordance with regulatory requirements or our stated study plans and protocols, we

will not be able to complete, or may be delayed in completing, the preclinical and clinical studies required to support future product submissions and approval of our product candidates.

Generally, these third parties may terminate their engagements with us at will upon notice.

If we need to enter into alternative arrangements, it could delay our product development activities.

We expect to rely on third-party manufacturers to manufacture supplies of certain of our product candidates, including all of the LVV product candidates.

Reliance on third-party manufacturers entails

risks to which we would not be subject if we manufactured all the product candidates ourselves, including:

the inability to negotiate manufacturing agreements with third parties under commercially reasonable terms;

reduced control as a result of using third-party manufacturers for certain aspects of manufacturing activities;

the risk that these activities are not conducted in accordance with our study plans and protocols;

termination or nonrenewal of manufacturing agreements with third parties in a manner or at a time that is costly or damaging to us;

disruptions to the operations of our third-party manufacturers or suppliers caused by conditions unrelated to our business or operations, including the bankruptcy of the manufacturer or supplier.

Any of these events could lead to clinical study delays or failure to obtain regulatory approval or impact our ability to successfully commercialize future products.

Some of these events could be the

basis for FDA action, including an injunction, recall, seizure or total or partial suspension of production.

We may not be successful in finding strategic collaborators for continuing development of certain of our product candidates or successfully commercializing

our product candidates.

We may seek to establish strategic partnerships for developing and/or commercializing certain of our product candidates due to relatively high capital costs required to develop the product

candidates, manufacturing constraints or other reasons.

We may not be successful in our efforts to establish such strategic partnerships or other alternative arrangements for our product candidates for several reasons, including because our

R&D pipeline may be insufficient, our product candidates may be deemed to be at too early of a stage of development for collaborative effort or third parties may not view our product candidates as having the requisite potential to demonstrate

efficacy or market opportunity.

In addition, we may be restricted under existing agreements from entering into future agreements with potential collaborators.

If we are unable to reach agreements with suitable licensees or collaborators on a timely basis, on acceptable terms or at all, we may have to curtail the development of a

product candidate, reduce or delay our development program, delay our potential commercialization, reduce the scope of any sales or marketing activities or increase our expenditures and undertake development or commercialization activities at our

If we elect to independently fund development or commercialization activities, we may need to obtain additional expertise and additional capital, which may not be available on acceptable terms or at all.

If we fail to enter into

collaboration arrangements and do not have sufficient funds or expertise to undertake necessary development and commercialization activities, we may not be able to further develop our product candidates and our business, financial condition,

results of operations and prospects may be materially harmed.

Our reliance on third parties requires us to share our trade secrets, which increases the possibility that a competitor will discover them or that our trade

secrets will be misappropriated or disclosed.

We rely on third parties to manufacture our product candidates and to perform quality testing, and because we collaborate with various organizations and academic institutions for the advancement of

our gene therapy platform, we must, at times, share our proprietary technology and confidential information, including trade secrets, with them.

We seek to protect our proprietary technology, in part, by entering into confidentiality agreements

and, if applicable, material transfer agreements, collaborative research agreements, consulting agreements or other similar agreements with our collaborators, advisors, employees and consultants prior to beginning research or disclosing

proprietary information.

These agreements typically limit the rights of the third parties to use or disclose our confidential information.

Despite the contractual provisions employed when working with third parties, the need to share trade

secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently incorporated into the technology of others or are disclosed or used in violation of these agreements.

that our proprietary position is based, in part, on our know‑how and trade secrets, a competitor’s discovery of our proprietary technology and confidential information or other unauthorized use or disclosure would impair our competitive position

and may have a material adverse effect on our business, financial condition, results of operations and prospects.

Despite our efforts to protect our trade secrets, our competitors may discover our trade secrets, either through breach of these agreements, independent development or publication of information

including our trade secrets by third parties.

A competitor’s discovery of our trade secrets would impair our competitive position and have an adverse impact on our business, financial condition, results of operations and prospects.

Disruptions at the FDA and other government agencies caused by funding shortages or global health concerns could hinder their ability to hire, retain or

deploy key leadership and other personnel, or otherwise prevent new or modified products from being developed, approved, or commercialized in a timely manner or at all, which could negatively impact our business.

The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, statutory, regulatory, and policy changes, the FDA’s

ability to hire and retain key personnel and accept the payment of user fees, and other events that may otherwise affect the FDA’s ability to perform routine functions.

Average review times at the agency have fluctuated in recent years as a

In addition, government funding of other government agencies that fund research and development activities is subject to the political process, which is inherently fluid and unpredictable.

Disruptions at the FDA and other agencies may

also slow the time necessary for biologics or modifications to approved biologics to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.

For example, over the last several years, including for

35 days beginning on December 22, 2018, the U.S.

government has shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical FDA employees and stop critical activities.

Additionally as of May 26, 2021, the FDA noted it is continuing to ensure timely reviews of applications for medical products during the ongoing COVID-19 pandemic in line with its user fee

performance goals;

however, the FDA may not be able to continue its current pace and approval timelines could be extended, including where a pre-approval inspection or an inspection of clinical sites is required and due to the COVID-19 pandemic

and travel restrictions the FDA is unable to complete such required inspections during the review period.

Since March 2020 when foreign and domestic inspections of facilities were largely placed on hold, the FDA has been working to resume routine

surveillance, bioresearch monitoring and pre-approval inspections on a prioritized basis.

Since April 2021, the FDA has conducted limited inspections and employed remote interactive evaluations, using risk management methods, to meet user fee

commitments and goal dates.

Ongoing travel restrictions and other uncertainties continue to impact oversight operations both domestic and abroad and it is unclear when standard operational levels will resume.

The FDA is continuing to complete

mission-critical work, prioritize other higher-tiered inspectional needs (e.g., for-cause inspections), and carry out surveillance inspections using risk-based approaches for evaluating public health.

Should FDA determine that an inspection is

necessary for approval and an inspection cannot be completed during the review cycle due to restrictions on travel, and the FDA does not determine a remote interactive evaluation to be adequate, the agency has stated that it generally intends to

issue, depending on the circumstances, a complete response letter or defer action on the application until an inspection can be completed.

During the COVID-19 public health emergency, a number of companies announced receipt of complete response

letters due to the FDA’s inability to complete required inspections for their applications.

Regulatory authorities outside the U.S.

may adopt similar restrictions or other policy measures in response to the ongoing COVID-19 pandemic and may

experience delays in their regulatory activities.

If the FDA becomes unable to continue its current level of performance, we could experience delays and setbacks for our product candidates and for any approvals we may seek which could adversely

affect our business.

Risks Related to Our Intellectual Property

Our rights to intellectual property for the development and commercialization of our product candidates are subject to the terms and conditions of licenses

granted to us by others.

We are heavily reliant upon licenses to certain patent rights and proprietary technology from third parties that are important or necessary to the development of our technology and products,

including technology related to our manufacturing process and our gene therapy product candidates.

These and other licenses may not provide exclusive rights to use such intellectual property and technology in all relevant fields of use and in all

territories in which we may wish to license our platform or develop or commercialize our technology and products in the future.

As a result, we may not be able to prevent competitors from developing and commercializing competitive products in

territories not included in our licenses.

Licenses to additional third-party technology that may be required for our licensing or development programs may not be available in the future or may not be available on

commercially reasonable terms, or at all, which could materially harm our business and financial condition.

In some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain or enforce the patents, covering technology that we license

from third parties.

If our licensors fail to maintain such patents, or lose rights to those patents or patent applications, the rights we have licensed may be reduced or eliminated and our right to develop and commercialize any of our products

that are the subject of such licensed rights could be impacted.

In addition to the foregoing, the risks associated with patent rights that we license from third parties will also apply to patent rights we may own in the future.

Furthermore, the research resulting in certain of our licensed patent rights and technology was funded by the U.S.

As a result, the government may have certain rights, or march-in rights,

to such patent rights and technology.

When new technologies are developed with government funding, the government generally obtains certain rights in any resulting patents, including a non-exclusive license authorizing the government to use the

invention for non-commercial purposes.

These rights may permit the government to disclose our confidential information to third parties and to exercise march-in rights to use or allow third parties to use our licensed technology.

The government

can exercise its march-in rights if it determines that action is necessary because we fail to achieve practical application of the government-funded technology, because action is necessary to alleviate health or safety needs, to meet requirements

of federal regulations or to give preference to U.S.

In addition, our rights in such inventions may be subject to certain requirements to manufacture products embodying such inventions in the U.S.

Any exercise by the government of such

rights could harm our competitive position, business, financial condition, results of operations and prospects.

If we are unable to obtain and maintain patent protection for products and related technology, or if the scope of the patent protection obtained is not

sufficiently broad, our competitors could develop and commercialize products and technology similar or identical to ours, and our ability to successfully commercialize our products may be harmed.

Our success depends, in large part, on our ability to obtain and maintain patent protection in the U.S.

and other countries with respect to our product candidates and our manufacturing technology.

Our licensors have sought, and we may intend to seek, to protect our proprietary position by filing patent applications in the U.S.

and abroad related to many of our novel technologies and product candidates that are important to our business.

The patent prosecution process is expensive, time-consuming and complex, and we may not be able to file, prosecute, maintain, enforce or license all necessary or desirable patent applications at a

reasonable cost or in a timely manner.

In addition, certain patents in the field of gene therapy that may have otherwise potentially provided patent protection for certain of our product candidates may expire prior to commercial launch of our

this patent expiration risk could be partially addressed by pursuing and receiving 10 years Biologics regulatory exclusivity from the FDA, which would grant protection in later years where patent expiration may not exist.

In some cases,

the work of certain academic researchers in the gene therapy field has entered the public domain, which we believe precludes our ability to obtain patent protection for certain inventions relating to such work.

It is also possible that we will

fail to identify patentable aspects of our R&D output before it is too late to obtain patent protection.

We are party to intellectual property license agreements with several entities, each of which is important to our business, and we expect to enter into additional license agreements in the future.

Our patent portfolio includes a number of patents and patent applications in-licensed pursuant to those license agreements, and those agreements impose, and we expect that future license agreements will impose various diligence, development and

commercialization timelines, milestone obligations, payments and other obligations on us.

If we or our licensors fail to comply with our obligations under these agreements, or we are subject to a bankruptcy, the licensor may have the right to

terminate the license, in which event we could lose certain rights provided by the licenses, including our ability to market products covered by the license.

The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has, in recent years, been the subject of much

As a result, the issuance, scope, validity, enforceability and commercial value of our patent rights are highly uncertain.

Pending and future patent applications may not result in patents being issued which protect our technology or

product candidates or which effectively prevent others from commercializing competitive technologies and product candidates.

Changes in either the patent laws or interpretation of the patent laws in the U.S.

and other countries may diminish the

value of our patent rights or narrow the scope of our patent protection.

While we believe our intellectual property allows us to pursue our current development programs, several companies and academic institutions are pursuing alternate approaches to gene therapy and have

built intellectual property around these approaches and methods.

For example, Institut Pasteur controls a patent family related to vector elements for lentiviral-based gene therapy.

These patents relate to an element that improves nuclear

localization.

While these patents began expiring in 2019, and will entirely expired by 2023, if our products were to launch before the fourth quarter of 2023, we may need to secure a license.

In addition, we may not be aware of all third-party

intellectual property rights potentially relating to our technology and product candidates.

Publications of discoveries in the scientific literature often lag the actual discoveries, and patent applications in the U.S.

and other jurisdictions are

typically not published until 18 months after filing or, in some cases, not at all.

Therefore, we cannot be certain that we were the first to make the inventions claimed in any owned or any licensed patents or pending patent applications, or that

we were the first to file for patent protection of such inventions.

Even if the patent applications we license or may own in the future do issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors or other

third parties from competing with us or otherwise provide us with any competitive advantage.

Our competitors or other third parties may avail themselves of safe harbor under the Drug Price Competition and Patent Term Restoration Act of 1984

(Hatch-Waxman Amendments) to conduct research and clinical trials and may be able to circumvent our patent rights by developing similar or alternative technologies or products in a non-infringing manner.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our patent rights may be challenged in the courts or patent offices in

Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated or held unenforceable, which could limit our ability to stop others from using or commercializing similar or identical

technology and products, or limit the duration of the patent protection of is technology and product candidates.

Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting

such candidates might expire before or shortly after such candidates are commercialized.

As a result, our intellectual property may not provide sufficient rights to exclude others from commercializing products similar or identical to ours.

If we breach our license agreements, it could have a material adverse effect on our commercialization efforts for our product candidates.

If we breach any of the agreements under which we license intellectual property relating to the use, development and commercialization rights to our product candidates or

technology from third parties, we could lose license rights that are important to our business.

Licensing of intellectual property is of critical importance to our business and involves complex legal, business and scientific issues.

arise between us and our licensors regarding intellectual property subject to a license agreement, including:

the scope of rights granted under the license agreement;

whether and the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the licensing agreement;

our right to sublicense patent and other intellectual property rights to third parties under collaborative development relationships;

our diligence obligations with respect to the use of the licensed technology in relation to our development and commercialization of is product candidates, and what activities satisfy those diligence obligations;

the ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors and us and our partners;

whether and the extent to which inventors are able to contest the assignment of their rights to our licensors.

If disputes over intellectual property that we have in-licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, we may be unable to successfully

develop and commercialize the affected product candidates.

In addition, if disputes arise as to ownership of licensed intellectual property, our ability to pursue or enforce the licensed patent rights may be jeopardized.

If we or our licensors

fail to adequately protect this intellectual property, our ability to commercialize our products could suffer.

If we are unable to protect the confidentiality of our trade secrets, our business and competitive position may be harmed.

In addition to the protection afforded by patents, we rely upon unpatented trade secret protection, unpatented know-how and continuing technological innovation to develop and maintain our competitive

We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our contractors, collaborators, employees and consultants.

Nonetheless, we may not be able to prevent the

unauthorized disclosure or use of our technical know-how or other trade secrets by the parties to these agreements, however, despite the existence generally of confidentiality agreements and other contractual restrictions.

Monitoring unauthorized

uses and disclosures is difficult and we do not know whether the steps we have taken to protect our proprietary technologies will be effective.

If any of the contractors, collaborators, employees and consultants who are parties to these

agreements breaches or violates the terms of any of these agreements, we may not have adequate remedies for any such breach or violation.

As a result, we could lose our trade secrets.

Enforcing a claim that a third-party illegally obtained and is

using our trade secrets, like patent litigation, is expensive and time consuming and the outcome is unpredictable.

In addition, courts outside the United States are sometimes less willing or unwilling to protect trade secrets.

Our trade secrets could otherwise become known or be independently discovered by our competitors.

Competitors could attempt to replicate some or all of the competitive advantages we derive from our

development efforts, willfully infringe our intellectual property rights, design around our protected technology or develop their own competitive technologies that fall outside of our intellectual property rights.

If any of our trade secrets were

to be lawfully obtained or independently developed by a competitor, we would have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with us.

If our trade secrets are not

adequately protected or sufficient to provide an advantage over our competitors, our competitive position could be adversely affected, as could our business.

Additionally, if the steps taken to maintain our trade secrets are deemed inadequate, we

may have insufficient recourse against third parties for misappropriating our trade secrets.

If we are unable to obtain or protect intellectual property rights related to our product candidates, we may not be able to compete effectively in our

We rely upon a combination of patents, trade secret protection and confidentiality agreements to protect the intellectual property related to our product candidates.

The strength of patents in the

biotechnology and pharmaceutical field involves complex legal and scientific questions and can be uncertain.

The patent applications that we own, or in-license may fail to result in issued patents with claims that cover our product candidates in

the United States or in other foreign countries.

There is no assurance that all of the potentially relevant prior art relating to patents and patent applications owned or in-licensed by us have been found, which can invalidate a patent or prevent

a patent from issuing from a pending patent application.

Even if patents do successfully issue and even if such patents cover our product candidates, third parties may challenge their validity, enforceability or scope, which may result in such

patents being narrowed or invalidated.

Furthermore, even if they are unchallenged, patents and patent applications that we own or in-license may not adequately protect our intellectual property, provide exclusivity for our product candidates or

prevent others from designing around our claims.

Any of these outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our business.

If the patent applications we hold or have in-licensed with respect to our programs or product candidates fail to issue, if their breadth or strength of protection is threatened,

or if they fail to provide meaningful exclusivity for our product candidates, it could dissuade companies from collaborating with us to develop product candidates, and threaten our ability to commercialize, future products.

In addition to our

existing patent application filings, we expect to continue to file additional patent applications covering our product candidates.

Further, we intend to pursue additional activities to protect the patents, trade secrets and other intellectual

property covering our product candidates.

We cannot offer any assurances about which, if any, patents will issue, the breadth of any such patent or whether any issued patents will be found invalid and unenforceable or will be threatened by third

Any successful opposition to these patents or any other patents owned by or licensed to us could deprive us of rights necessary for the successful commercialization of any product candidates that we may develop.

Further, if we or the

relevant licensor encounter delays in regulatory approvals, the period of time during which we could market a product candidate under patent protection could be reduced.

Since patent applications in the United States and most other countries are

confidential for a period of time after filing, and some remain so until issued, we cannot be certain that we or the relevant licensor were the first to file any patent application related to a product candidate.

Furthermore, if third parties

have filed such patent applications, an interference proceeding in the United States can be initiated by a third-party to determine who was the first to invent any of the subject matter covered by the patent claims of our applications.

addition, patents have a limited lifespan.

In the United States, the natural expiration of a patent is generally 20 years after it is filed.

Various extensions may be available however the life of a patent, and the protection it affords, is

Even if patents covering our product candidates are obtained, once the patent life has expired for a product, we may be open to competition from generic medications.

In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable or that we elect not to

patent, processes for which patents are difficult to enforce and any other elements of our product candidate discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents.

trade secrets can be difficult to protect.

We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors.

We also seek to

preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

While we have confidence in these individuals,

organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach.

In addition, our trade secrets may otherwise become known or be independently discovered by competitors.

Although we expect all of our employees and consultants to assign their inventions to us, and all of our employees, consultants, advisors and any third parties who have access to our proprietary

know-how, information or technology to enter into confidentiality agreements, we cannot provide any assurances that all such agreements have been duly executed or that our trade secrets and other confidential proprietary information will not be

disclosed or that competitors will not otherwise gain access to our trade secrets or independently develop substantially equivalent information and techniques.

Misappropriation or unauthorized disclosure of our trade secrets could impair our

competitive position and may have a material adverse effect on our business.

Additionally, if the steps taken to maintain our trade secrets are deemed inadequate, we may have insufficient recourse against third parties for misappropriating our

trade secret.

In addition, others may independently discover our trade secrets and proprietary information.

Further, the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States.

As a result, we may encounter significant

problems in protecting and defending our intellectual property, both in the United States and abroad.

If we are unable to prevent material disclosure of the non-patented intellectual property related to our technologies to third parties, and

there is no guarantee that we will have any such enforceable trade secret protection, it may not be able to establish or maintain a competitive advantage in our market, which could materially adversely affect our business, results of operations

and financial condition.

We may not be successful in obtaining or maintaining necessary rights to gene therapy product components and processes for our development pipeline through

acquisitions and in-licenses.

Presently we have rights to the intellectual property, through licenses from third parties and under patents that we own, to develop our gene therapy product candidates.

Because our programs may

involve additional product candidates that may require the use of proprietary rights held by third parties, the growth of our business will likely depend in part on our ability to acquire, in-license or use these proprietary rights.

our product candidates may require specific formulations to work effectively and efficiently, and these rights may be held by others.

We may be unable to acquire or in-license any compositions, methods of use, processes or other third-party

intellectual property rights from third parties that we identify.

The licensing and acquisition of third-party intellectual property rights is a competitive area, and a number of more established companies are also pursuing strategies to license

or acquire third-party intellectual property rights that we may consider attractive.

These established companies may have a competitive advantage over us due to their size, cash resources and greater clinical development and commercialization

capabilities.

For example, we sometimes collaborate with U.S.

and foreign academic institutions to accelerate our preclinical research or development under written agreements with these institutions.

these institutions provide us with an option to negotiate a license to any of the institution’s rights in technology resulting from the collaboration.

Regardless of such right of first negotiation for intellectual property, we may be unable to

negotiate a license within the specified time frame or under terms that are acceptable to it.

If we are unable to do so, the institution may offer the intellectual property rights to other parties, potentially blocking our ability to pursue our

In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us.

We also may be unable to license or acquire third-party

intellectual property rights on terms that would allow us to make an appropriate return on our investment.

If we are unable to successfully obtain rights to required third-party intellectual property rights, our business, financial condition and

prospects for growth could suffer.

Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and

other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and/or applications will be due to be paid to the U.S.

PTO and various governmental patent

agencies outside of the United States in several stages over the lifetime of the patents and/or applications.

We and, to our knowledge, our licensors have systems in place to remind us and them to pay these fees, and we and, to our knowledge, our

licensors employ outside firms and rely on our and their respective outside counsel to pay these fees due to non-U.S.

patent agencies.

PTO and various non-U.S.

governmental patent agencies require compliance with a number of procedural,

documentary, fee payment and other similar provisions during the patent application process.

We and, to our knowledge, our licensors employ reputable law firms and other professionals to help us and them comply, and in many cases, an inadvertent

lapse can be cured by payment of a late fee or by other means in accordance with the applicable rules.

However, there are situations in which non-compliance can result in abandonment or lapse of the patent or patent application, resulting in

partial or complete loss of patent rights in the relevant jurisdiction.

In such an event, our competitors might be able to enter the market and this circumstance would have a material adverse effect on our business.

Issued patents covering our product candidates could be found invalid or unenforceable if challenged in court.

If we or one of our licensing partners initiated legal proceedings against a third-party to enforce a patent covering one of our product candidates, the defendant could counterclaim that the patent

covering our product candidate is invalid and/or unenforceable.

In patent litigation in the United States, defendant counterclaims alleging invalidity and/or unenforceability are commonplace.

Grounds for a validity challenge could be an alleged

failure to meet any of several statutory requirements, including patent eligible subject matter, lack of novelty, obviousness, or non-enablement.

Grounds for an unenforceability assertion could be an allegation that someone connected with

prosecution of the patent withheld relevant information from the U.S.

PTO, or made a misleading statement, during prosecution.

Third parties may also raise similar claims before administrative bodies in the United States or abroad, even outside

the context of litigation.

Such mechanisms include re-examination, post grant review, and equivalent proceedings in foreign jurisdictions (e.g., opposition proceedings).

Such proceedings could result in revocation or amendment to our or our

licensing partners’ patents in such a way that they no longer cover our product candidates.

The outcome following legal assertions of invalidity and unenforceability is unpredictable.

With respect to the validity question, for example, we cannot

be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution.

If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and

perhaps all, of the patent protection on our product candidates.

Such a loss of patent protection would have a material adverse impact on our business.

Changes in U.S.

patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.

As is the case with other biotechnology companies, our success is heavily dependent on intellectual property, particularly patents.

Obtaining and enforcing patents in the biotechnology industry

involves both technological and legal complexity, and therefore obtaining and enforcing biotechnology patents is costly, time-consuming, and inherently uncertain.

Congress may pass patent reform legislation that is unfavorable to us.

Supreme Court has ruled on several patent cases in recent years, narrowing the scope of patent protection available in certain circumstances and weakening the rights of patent owners in

certain situations.

Depending on future actions by the U.S.

Congress, the U.S.

courts, the USPTO and the relevant law-making bodies in other countries, the laws and regulations governing patents could change in unpredictable ways that would

weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.

We may not be able to protect our intellectual property rights throughout the world.

Filing, prosecuting, and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside

the United States can be less extensive than those in the United States.

In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States.

Consequently,

we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions.

Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and further, may export otherwise infringing products to territories where we have patent protection, but enforcement

is not as strong as that in the United States.

These products may compete with our products and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions.

The legal systems of certain countries,

particularly certain developing countries, do not favor the enforcement of patents, trade secrets and other intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for us to stop the

infringement of our patents or marketing of competing products in violation of our proprietary rights generally.

Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and

attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us.

prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful.

Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a

significant commercial advantage from the intellectual property that we develop or license.

Patent terms may be inadequate to protect our competitive position on our product candidates for an adequate amount of time.

Patents have a limited lifespan.

In the United States, if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years from its earliest U.S.

non-provisional filing

Various extensions may be available, but the life of a patent, and the protection it affords, is limited.

Even if patents covering our product candidates are obtained, once the patent life has expired, we may be open to competition from

competitive products, including generics or biosimilars.

Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such

candidates are commercialized.

As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

Intellectual property rights do not necessarily address all potential threats.

The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations and may not adequately protect our business or permit us to maintain our

competitive advantage.

others may be able to make product candidates that are similar to ours but that are not covered by the claims of the patents that we own;

we, or our license partners or current or future collaborators, might not have been the first to make the inventions covered by the issued patent or pending patent applications that we license or may own in the future;

we, or our license partners or current or future collaborators, might not have been the first to file patent applications covering certain of our or their inventions;

others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our owned or in-licensed intellectual property rights;

our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to develop competitive products for sale in our major

commercial markets;

we cannot ensure that any of our patents, or any of our pending patent applications, if issued, or those of our licensors, will include claims having a scope sufficient to protect our product candidates;

we cannot ensure that any patents issued to us, or our licensors will provide a basis for an exclusive market for our commercially viable product candidates or will provide us with any competitive advantages;

we cannot ensure that our commercial activities or product candidates will not infringe upon the patents of others;

we cannot ensure that we will be able to successfully commercialize our product candidates on a substantial scale, if approved, before the relevant patents that we own, or license expire;

we may not develop additional proprietary technologies that are patentable;

the patents or intellectual property rights of others may harm our business;

we may choose not to file a patent in order to maintain certain trade secrets or know-how, and a third party may subsequently file a patent covering such intellectual property.

Should any of these events occur, they could have a material adverse effect on our business, financial condition, results of operations and prospects.

Risks Related to Claims Arising from our Intellectual Property

We may incur substantial costs as a result of litigation or other proceedings relating to patent and other intellectual property rights and we may be unable to

protect our rights to, or use, our technology.

If we choose to engage in legal action to prevent a third-party from using the inventions claimed in our patents or patents which we license, that third-party has the right to ask the court to rule

that these patents are invalid and/or should not be enforced against that third-party.

These lawsuits are expensive and would consume time and other resources even if we were successful in stopping the infringement of these patents.

there is a risk that the court will decide that these patents are not valid and that we do not have the right to stop the other party from using the inventions.

There is also the risk that, even if the validity of these patents is upheld, the

court will refuse to stop the other party on the ground that such other party’s activities do not infringe our rights to these patents.

Furthermore, a third-party may claim that we are using inventions covered by the third-party’s patent rights and may go to court to stop us from engaging in our normal operations and activities,

including making or selling our product candidates.

These lawsuits are costly and could affect our results of operations and divert the attention of managerial and technical personnel.

There is a risk that a court would decide that we are

infringing the third-party’s patents and would order us to stop the activities covered by the patents.

In addition, there is a risk that a court will order us to pay the other party damages for having violated the other party’s patents.

biotechnology industry has produced a proliferation of patents, and it is not always clear to industry participants which patents cover various types of products or methods of use.

The coverage of patents is subject to interpretation by the

courts, and the interpretation is not always uniform.

If we are sued for patent infringement, we would need to demonstrate that our products or methods of use either do not infringe the patent claims of the relevant patent and/or that the patent

claims are invalid.

Proving invalidity, in particular, is difficult since it requires a showing of clear and convincing evidence to overcome the presumption of validity enjoyed by issued patents.

Our competitors have filed, and may in the future

file, patent applications covering technology similar to ours.

Any such patent application may have priority over our in-licensed patent applications and could further require us to obtain rights to issued patents covering such technologies.

another party has filed a U.S.

patent application on inventions similar to ours, we may have to participate in an interference proceeding declared by the U.S.

Patent and Trademark Office, to determine priority of invention in the U.S.

of these proceedings could be substantial, and it is possible that such efforts would be unsuccessful, resulting in a loss of our United States patent position with respect to such inventions.

Some of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources.

any uncertainties resulting from the initiation and continuation of any litigation could have a material adverse effect on our ability to raise the funds necessary to continue our operations.

We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.

We may also be subject to claims that former employees, collaborators or other third parties have an ownership interest in our patents or other intellectual property.

We may have in the future,

ownership disputes arising, for example, from conflicting obligations of consultants or others who are involved in developing our product candidates.

Litigation may be necessary to defend against these and other claims challenging inventorship or

If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property.

Such an outcome could

have a material adverse effect on our business.

Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Third-party claims of intellectual property infringement may prevent or delay our development and commercialization efforts.

Our commercial success depends in part on avoiding infringement of the patents and proprietary rights of third parties.

There is a substantial amount of litigation, both within and outside the United

States, involving patent and other intellectual property rights in the biotechnology and pharmaceutical industries, including patent infringement lawsuits, interferences, oppositions, ex parte reexaminations, post-grant review, and inter partes review proceedings before the U.S.

Patent and Trademark Office, or U.S.

PTO, and corresponding foreign patent offices.

Numerous U.S.

and foreign issued patents and pending patent applications,

which are owned by third parties, exist in the fields in which we are pursuing development candidates.

As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our product candidates may be

subject to claims of infringement of the patent rights of third parties.

Third parties may assert that we are employing their proprietary technology without authorization.

There may be third-party patents or patent applications with claims to

materials, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our product candidates.

Because patent applications can take many years to issue, there may be currently pending patent applications

which may later result in issued patents that our product candidates may infringe.

In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents.

If any third-party patents were

held by a court of competent jurisdiction to cover the manufacturing process of any of our product candidates, any molecules formed during the manufacturing process or any final product itself, the holders of any such patents may be able to block

our ability to commercialize such product candidate unless we obtained a license under the applicable patents, or until such patents expire.

Similarly, if any third-party patents were held by a court of competent jurisdiction to cover aspects of

our formulations, processes for manufacture or methods of use, including combination therapy, the holders of any such patents may be able to block our ability to develop and commercialize the applicable product candidate unless we obtained a

license or until such patent expires.

In either case, such a license may not be available on commercially reasonable terms or at all.

Parties making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize one or more of our product candidates.

Defense of these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from our business.

In the event of a successful claim of infringement against us, we may

have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign our infringing products, or obtain one or more licenses from third parties, which may be impossible or require

substantial time and monetary expenditure.

Risks Related to Personnel and Expansion of our Company

Risks Related to our Personnel

Our business could suffer if it loses the services of, or fails to attract, key personnel.

We are highly dependent upon the efforts of our senior management, including our Chief Executive Officer, Gaurav Shah, MD;

our Chief Medical Officer and Head of Clinical Development, Jonathan

Schwartz, MD;

our President and Chief Operating Officer, Kinnari Patel, PharmD, MBA;

and our Chief Financial Officer, Carlos Garcia-Parada.

The loss of the services of these individuals and other members of our senior management could delay or

prevent the achievement of research, development, marketing, or product commercialization objectives.

Our employment arrangements with the key personnel are “at-will.” We do not maintain any “key-man” insurance policies on any of the key

employees nor do we intend to obtain such insurance.

In addition, due to the specialized scientific nature of our business, we are highly dependent upon our ability to attract and retain qualified scientific and technical personnel and

There is intense competition among major pharmaceutical and chemical companies, specialized biotechnology firms and universities and other research institutions for qualified personnel in the areas of our operations, and we may be

unsuccessful in attracting and retaining these personnel.

Our employees, principal investigators, consultants, and commercial partners may engage in misconduct or other improper activities, including non-compliance

with regulatory standards and requirements and insider trading.

We are exposed to the risk of fraud or other misconduct by our employees, consultants, and commercial partners.

Misconduct by these parties could include intentional failures to comply with the

regulations of the FDA and non-U.S.

regulators, provide accurate information to the FDA and non-U.S.

regulators, comply with healthcare fraud and abuse laws and regulations in the U.S.

and abroad, report financial information or data accurately

or disclose unauthorized activities to us.

In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other

abusive practices.

These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements.

Such misconduct could also

involve the improper use of information obtained during clinical studies, which could result in regulatory sanctions and cause serious harm to our reputation or could cause regulatory agencies not to approve our product candidates.

We have a code

of business ethics and conduct applicable to all employees, but it is not always possible to identify and deter employee or third-party misconduct, and the precautions we take to detect and prevent this activity may not be effective in

controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations.

If any such actions are instituted against us,

and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

We may be subject to claims that our employees, consultants, or independent contractors have wrongfully used or disclosed confidential information of third

parties or that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.

We employ individuals who were previously employed at universities or other biotechnology or pharmaceutical companies, including our competitors or potential competitors.

Although we endeavor to

ensure that our employees, consultants, and independent contractors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or our employees, consultants or independent contractors

have inadvertently or otherwise used or disclosed intellectual property, including trade secrets or other proprietary information, of any of our employees’ former employers or other third parties.

Litigation may be necessary to defend against

these claims.

If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel, which could adversely impact our business.

Even if we are successful in defending

against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Risks Related to Our Expansion and Growth Plans

We may need to expand our organization and may experience difficulties in managing this growth, which could disrupt our operations.

As our business activities expand, we may expand our full-time employee base and hire more consultants and contractors.

Our management may need to divert a disproportionate amount of its attention

away from day-to-day activities and devote a substantial amount of time to managing these growth activities.

We may not be able to effectively manage the expansion of our operations, which may result in weaknesses in our infrastructure,

operational setbacks, loss of business opportunities, loss of employees and reduced productivity among remaining employees.

Our expected growth could require significant capital expenditures and may divert financial resources from other projects,

such as the development of additional product candidates.

If our management is unable to effectively manage our growth, our expenses may increase more than expected our ability to generate and/or grow revenues could be reduced and we may not be

able to implement our business strategy.

Given our commercial relationships outside of the United States, in particular in the European Union, a variety of risks associated with international

operations could harm our business.

We engage in various commercial relationships outside the U.S., and we may commercialize our product candidates outside of the U.S.

In many foreign countries, it is common for others to engage in

business practices that are prohibited by U.S.

laws and regulations applicable to us, including the Foreign Corrupt Practices Act.

Although we may implement policies and procedures specifically designed to comply with these laws and policies,

there can be no assurance that our employees, contractors, and agents will comply with these laws and policies.

If we are unable to successfully manage the challenges of international expansion and operations, our business and operating results

could be harmed.

We may be, and to the extent we commercialize our product candidates outside the United States, expect to be subject to various risks associated with operating internationally, including:

different regulatory requirements for approval of drugs and biologics in foreign countries;

reduced protection for intellectual property rights;

unexpected changes in tariffs, trade barriers and regulatory requirements;

economic weakness, including inflation, or political instability in particular foreign economies and markets;

compliance with tax, employment, immigration, and labor laws for employees living or traveling abroad;

foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to doing business in another country;

workforce uncertainty in countries where labor unrest is more common than in the United States;

shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad;

business interruptions resulting from geopolitical actions, including war and terrorism or natural disasters including earthquakes, typhoons, floods and fires, public health crises such as pandemics and epidemics, or from economic or

political instability;

compliance with foreign laws, regulations, standards, and regulatory guidance governing the collection, use, disclosure, retention, security and transfer of personal data, including the European Union General Data Privacy Regulation

greater difficulty with enforcing our contracts in jurisdictions outside of the United States.

These and related risks could materially harm our business, financial condition, results of operations and prospects.

Future acquisitions of businesses or products, formations of strategic alliances or joint ventures with third parties could disrupt our business and harm our

financial condition and operating results.

We may acquire additional businesses or products, form strategic alliances or create joint ventures with third parties that we believe will complement or augment our existing business.

If we acquire

businesses with promising markets or technologies, we may not be able to realize the benefit of acquiring such businesses if we are unable to successfully integrate them with our existing operations and company culture.

We may encounter numerous

difficulties in developing, manufacturing and marketing any new products resulting from a strategic alliance or acquisition that delay or prevent us from realizing their expected benefits or enhancing our business.

We cannot assure you that,

following any such acquisition, we will achieve the expected synergies to justify the transaction.

The risks we face in connection with any anticipated business or product acquisitions, include:

diversion of management time and focus from operating our business to addressing acquisition integration challenges;

coordination of R&D efforts;

retention of key employees from any acquired company;

changes in relationships with strategic partners as a result of any product acquisitions or strategic positioning resulting from the acquisition;

cultural challenges associated with integrating employees from any acquired company into our organization or managing a strategic alliance or joint venture;

the need to implement or improve controls, procedures, and policies at any acquired business that prior to the acquisition may have lacked sufficiently effective controls, procedures and policies;

liability for activities of any acquired company before the acquisition, including intellectual property infringement claims, violation of laws, commercial disputes, tax liabilities, and other known liabilities;

unanticipated write-offs or charges;

litigation or other claims in connection with any acquired company, including claims from terminated employees, customers, former stockholders or other third parties

Our failure to address these risks or other problems encountered in connection with our past or future acquisitions or strategic alliances could cause us to fail to realize the anticipated benefits

of these transactions, cause us to incur unanticipated liabilities and harm the business generally.

There is also a risk that future acquisitions will result in the incurrence of debt, contingent liabilities, amortization expenses or incremental

operating expenses, any of which could harm our financial condition or operating results.

Risks Related to Ownership of our Common Stock

Future sales of our common stock in the public market could cause the market price of our common stock to drop significantly, even if our business is

performing well.

Sales of a substantial number of shares of our common stock in the public market could occur at any time.

These sales, or the perception or the perception that such sales may occur, could reduce the

market price of our common stock.

Our outstanding shares of common stock may be freely sold in the public market at any time to the extent permitted by Rules 144 and 701 under the Securities Act of 1933, as amended (the “Securities Act”), or to

the extent such shares have already been registered under the Securities Act and are held by non-affiliates of ours.

In addition, certain of our employees, executive officers, directors and affiliated stockholders have entered or may enter into

Rule 10b5-1 plans providing for sales of shares of our common stock from time to time.

Under a Rule 10b5-1 plan, a broker executes trades pursuant to parameters established by the employee, director or officer when entering into the plan, without

further direction from the employee, officer, director or affiliated stockholder.

A Rule 10b5-1 plan may be amended or terminated in some circumstances.

Our employees, executive officers, directors and affiliated stockholders also may buy or sell

additional shares outside of a Rule 10b5-1 plan when they are not in possession of material, nonpublic information.

In addition, in the future, we may issue additional shares of common stock or other equity or debt securities convertible into

common stock in connection with a financing, acquisition, litigation settlement, employee arrangements or otherwise.

Any such issuance could result in substantial dilution to our existing stockholders and could cause our stock price to decline.

If securities analysts do not publish research or reports about our business or if they publish negative evaluations of our stock, the price of our stock

could decline.

The trading market for our common stock relies, in part, on the research and reports that industry or financial analysts publish about us or our business.

Although we have obtained analyst coverage,

if one or more of the analysts covering our business downgrade their evaluations of our stock, the price of our stock could decline.

If one or more of these analysts cease to cover our stock or fail to regularly publish reports on us, we could

lose visibility in the market for our stock, which in turn could cause our stock price to decline.

The price of our common stock may be volatile and fluctuate substantially, which could result in substantial losses for our stockholders.

Our stock price is likely to be volatile.

The stock market in general, and the market for biopharmaceutical companies in particular, has experienced extreme volatility that has often been unrelated

to the operating performance of particular companies.

As a result of this volatility, our stockholders may not be able to sell their shares of common stock at or above the price they paid for their shares.

The market price for our common stock

may be influenced by many factors, including:

results of clinical trials of our product candidates or those of our competitors;

the success of competitive products or technologies;

commencement or termination of collaborations;

regulatory or legal developments in the United States and other countries;

developments or disputes concerning patent applications, issued patents or other proprietary rights;

the recruitment or departure of key personnel;

the level of expenses related to any of our product candidates or clinical development programs;

the results of our efforts to discover, develop, acquire or in-license additional product candidates;

actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;

negative publicity around gene therapy in general, or our product candidates;

variations in our financial results or those of companies that are perceived to be similar to us;

changes in the structure of healthcare payment systems;

market conditions in the pharmaceutical and biotechnology sectors;

general economic, industry and market conditions.

If our quarterly operating results fall below the expectations of investors or securities analysts, the price of our common stock could decline substantially.

Furthermore, any quarterly fluctuations

in our operating results may, in turn, cause the price of our stock to fluctuate substantially.

We believe that quarterly comparisons of our financial results are not necessarily meaningful and should not be relied upon as an indication of our

future performance.

In the past, following periods of volatility in the market price of a company’s securities, securities class-action litigation often has been instituted against that company.

Such litigation, if

instituted against us, could cause us to incur substantial costs to defend such claims and divert management’s attention and resources, which could seriously harm our business, financial condition, results of operations and prospects.

RTW Investments, LP, our largest stockholder, may have the ability to significantly influence all matters submitted to stockholders for approval.

RTW Investments, LP (“RTW”), in the aggregate, beneficially owns approximately 25.2% of our outstanding shares of common stock.

This concentration of voting power gives RTW the power to significantly

influence all matters submitted to our stockholders for approval, as well as our management and affairs.

For example, RTW could significantly influence the election of directors and approval of any merger, consolidation or sale of all or

substantially all of our assets.

In addition, this may prevent or discourage unsolicited acquisition proposals or offers for our capital stock that you may believe are in your best interest as one of our stockholders.

Because we do not anticipate paying any cash dividends on our capital stock in the foreseeable future, capital appreciation, if any, will be stockholders’

sole source of gain.

We have never declared or paid cash dividends on our capital stock.

We currently intend to retain all future earnings, if any, to finance the growth and development of our business.

In addition, the

terms of any future debt agreements may preclude us from paying dividends.

As a result, capital appreciation, if any, of our common stock will be stockholders’ sole source of gain for the foreseeable future.

Other Risks Related to Our Business

As of December 31, 2020, we were no longer an “emerging growth company,” as defined in the JOBS Act.

or a “smaller reporting company” as defined in the

Exchange Act and were a “large accelerated filer” which subjects us to increased disclosure and compliance requirements.

As a large accelerated filer, we are subject to certain disclosure and compliance requirements that apply to other public companies but did not historically apply to us due to our prior status as an

emerging growth company.

These requirements include, but are not limited to:

the requirement that our independent registered public accounting firm attest to the effectiveness of our internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act of 2002;

compliance with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and

the financial statements;

the requirement that we provide full and more detailed disclosures regarding executive compensation;

the requirement that we hold a non-binding advisory vote on executive compensation and obtain stockholder approval of any golden parachute payments not previously approved.

We expect that continued compliance with the requirements of being a large accelerated filer may increase our legal and financial compliance costs and cause management and other personnel to divert

attention from operational and other business matters to devote substantial time to public company reporting requirements.

In addition, if we are not able to comply with changing requirements in a timely manner, the market price of our stock

could decline and we could be subject to sanctions or investigations by the stock exchange on which our common stock is listed, the SEC, or other regulatory authorities, which would require additional financial and management resources.

If we fail to maintain proper and effective internal control over financial reporting, our ability to produce accurate and timely financial statements could

be impaired, which could harm our operating results, investors’ views of us and, as a result, the value of our common stock.

As a public company, we are required to maintain internal control over financial reporting and to report any material weaknesses in such internal control.

Beginning in 2020, we will be required to

furnish a report by management on the effectiveness of our internal control over financial reporting pursuant to Section 404 of the Sarbanes-Oxley Act (“Section 404”).

Pursuant to Section 404 our independent registered public accounting firm will

be required to attest to the effectiveness of our internal control over financial reporting.

Preparing such attestation report and the cost of compliance with reporting requirements may increase our expenses and require significant management

Investors may find our common stock less attractive because of the additional compliance costs.

If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and our

stock price may be more volatile.

The rules governing the standards that must be met for management and our independent registered public accounting firm to assess our internal control over financial reporting are complex and require

significant documentation, testing, and possible remediation.

In connection with our and our independent registered public accounting firm’s evaluations of our internal control over financial reporting, we may need to upgrade systems, including

information technology, implement additional financial and management controls, reporting systems, and procedures, and hire additional accounting and finance staff.

Any failure to implement required new or improved controls, or difficulties encountered in their implementation, could cause us to fail to meet our reporting obligations.

In addition, any testing by

us or our independent registered public accounting firm conducted in connection with Section 404 may reveal deficiencies in our internal control over financial reporting that are deemed to be material weaknesses or that may require prospective or

retroactive changes to our financial statements or identify other areas for further attention or improvement.

Inferior internal controls could also cause investors to lose confidence in our reported financial information, which could have a

negative effect on the trading price of our common stock.

Internal control deficiencies could also result in a restatement of our financial results in the future.

We could become subject to stockholder or other third-party litigation, as well as

investigations by the SEC, the New York Stock Exchange, or other regulatory authorities, which could require additional financial and management resources and could result in fines, trading suspensions, payment of damages or other remedies.

Further, any delay in compliance with the auditor attestation provisions of Section 404 could subject us to a variety of administrative sanctions, including ineligibility for short-form resale registration, action by the SEC and the suspension or

delisting of our common stock, which could reduce the trading price of our common stock and could harm our business.

Provisions in our corporate charter documents and under Delaware law could make an acquisition of us, which may be beneficial to our stockholders, more

difficult and may prevent attempts by our stockholders to replace or remove our current management.

Provisions in our certificate of incorporation and our bylaws may discourage, delay or prevent a merger, acquisition or other change in control of our company that stockholders may consider

favorable, including transactions in which you might otherwise receive a premium for your shares.

These provisions could also limit the price that investors might be willing to pay in the future for shares of our common stock, thereby depressing

the market price of our common stock.

In addition, because our Board of Directors is responsible for appointing the members of our management team, these provisions may frustrate or prevent any attempts by our stockholders to replace or remove

our current management by making it more difficult for stockholders to replace members of our Board of Directors.

Among other things, these provisions:

permit only the Board of Directors to establish the number of directors;

require super-majority voting to amend some provisions in our restated certificate of incorporation and restated bylaws;

prohibit stockholder action by written consent, which requires all stockholder actions to be taken at a meeting of our stockholders;

establish advance notice requirements for nominations for election to our board or for proposing matters that can be acted upon by stockholders at annual stockholder meetings.

Moreover, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which prohibits a person who owns in excess of 15% of our outstanding voting stock from merging or

combining with us for a period of three years after the date of the transaction in which the person acquired in excess of 15% of our outstanding voting stock, unless the merger or combination is approved in a prescribed manner.

provisions of our charter documents or Delaware law could, under certain circumstances, depress the market price of our common stock.

Our internal computer systems, or those of our third-party collaborators or other contractors, may fail or suffer security breaches, which could result in a

material disruption of our development programs.

Our internal computer systems and those of our current and any future collaborators and other consultants and contractors are vulnerable to damage from computer viruses, unauthorized access,

cyberattacks, data breaches, natural disasters, terrorism, war and telecommunication and electrical failures.

While we have not experienced any such material system failure, accident, attack or security breach to date, if such an event were to

occur and cause interruptions in our operations, it could result in a material disruption of our development programs and our business operations, whether due to a loss of our trade secrets or other proprietary information or other similar

For example, the loss of clinical trial data from completed or future clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data.

To the extent that

any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be harmed, and

the further development and commercialization of our product candidates could be delayed.

The increasing use of social media platforms presents new risks and challenges.

Social media is increasingly being used to communicate about our clinical development programs and the diseases our product candidates are being developed to treat.

We intend to utilize appropriate

social media in connection with our commercialization efforts following approval of our product candidates.

Social media practices in the biopharmaceutical industry continue to evolve and regulations relating to such use are not always clear.

This evolution creates uncertainty and risk of noncompliance with regulations applicable to our business.

For example, patients may use social media channels to report an alleged adverse event.

When such disclosures occur, there is a risk that we

fail to monitor and comply with applicable adverse event reporting obligations, or we may not be able to defend our business or the public’s legitimate interests in the face of the political and market pressures generated by social media due to

restrictions on what we may say about our investigational products.

There is also a risk of inappropriate disclosure of sensitive information or negative or inaccurate posts or comments about us on any social networking website, or a risk that a

post on a social networking website by any of our employees may be construed as inappropriate promotion.

If any of these events were to occur or we otherwise fail to comply with applicable regulations, we could incur liability, face regulatory

actions, or incur other harm to our business.

Unresolved SEC Comments

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business