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Item 1. Business

2023-03-06 compared with 2022-03-03 · 323 added, 493 removed, 548 unchanged (60% of the section changed)

We are a clinical stage genetic medicines company focused on developing transformative therapies for central nervous system, or CNS, disorders with limited or no approved treatment options.

Our vision is to finally fulfill the promise of gene therapy by developing groundbreaking therapies that transform the lives of patients with CNS diseases.

Our vision is to fulfill the promise of gene therapy by developing groundbreaking therapies that transform the lives of patients with CNS diseases.

The field of genetic medicine is rapidly expanding and we believe we have a differentiated approach to developing treatments for CNS disorders that enables us to select and advance product candidates with a higher probability of technical and regulatory success.

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We also leverage our close working relationship with Penn’s Orphan Disease Center, or ODC, to develop historical and prospective comparable natural history patient profiles for comparison to participants in interventional trials.

Through this collaboration we have assembled a deep portfolio of genetic medicine product candidates, for which we retain global rights, including our three clinical product candidates:

PBGM01 for the treatment of GM1 gangliosidosis, or GM1 , PBFT02 for the treatment of frontotemporal dementia, or FTD, and PBKR03 for the treatment of Krabbe disease.

We have six programs in the research stage:

PBML04 for metachromatic leukodystrophy, or MLD, PBAL05 for amyotrophic lateral sclerosis, or ALS, PBCM06 for Charcot-Marie-Tooth Type 2A, or CMT2A, and unnamed programs for Canavan disease, Parkinson’s disease and Huntington’s disease.

We also have exploratory research programs for Alzheimer’s disease, or AD, and Temporal Lobe Epilepsy, or TLE.

Through this collaboration we have assembled a strong portfolio of genetic medicine product candidates, for which we retain global rights, including our two lead clinical product candidates:

PBGM01 for the treatment of GM1 gangliosidosis, or GM1 , and PBFT02 for the treatment of frontotemporal dementia, or FTD;

and two clinical stage product candidates for which, in order to reduce operating expenses, we have stopped further clinical development and are exploring strategic alternatives:

PBKR03 for the treatment of Krabbe disease and PBML04 for metachromatic leukodystrophy, or MLD.

We have two programs in the research stage:

PBAL05 for amyotrophic lateral sclerosis, or ALS, and an unnamed program for Huntington’s disease.

We also have an exploratory research program for Temporal Lobe Epilepsy, or TLE.

We founded Passage Bio with the intent to build a differentiated CNS genetic medicines company delivering transformative therapies to patients by combining our team’s experience in rare and neurological disease development, manufacturing and commercialization with the pioneering research expertise of GTP in gene therapy.

We are purposefully focusing on rare, monogenic CNS disorders for which we believe our genetic medicine approach provides distinct technical advantages based on decades of research by GTP.

We are purposefully focusing on rare CNS disorders for which we believe our genetic medicine approach provides distinct technical advantages based on decades of research by GTP.

GTP conducts rigorous preclinical studies to identify promising product candidates.

Our collaboration provides us with access to cutting edge capabilities and innovation in the field of genetic medicine research, including in capsid engineering and next-generation capsid libraries, vector engineering, transgene design and gene therapy modalities, animal disease models and related studies for lead-optimization of product candidates.

Our collaboration provides us with access to cutting edge capabilities and innovation in the field of genetic medicine research, including capsid engineering and next-generation capsid libraries, vector engineering, transgene design and gene therapy modalities, animal disease models and related studies for lead-optimization of product candidates.

Further, we believe our team’s deep clinical development experience in rare and neurological diseases will enable well planned clinical trials with the potential for efficient advancement to regulatory approval.

In addition, we are engaging with key opinion leaders, practitioners and patient advocacy groups in the field of rare, monogenic CNS disorders that provide strategic input and help inform our clinical development activities.

In addition, we are engaging with key opinion leaders, practitioners and patient advocacy groups in the field of rare CNS disorders who provide strategic input and help inform our clinical development activities.

We believe that our ability to execute on the above tenets provides us with product candidates that have an improved profile for clinical development and an enhanced probability of success.

We are focused on developing and commercializing disease-modifying therapies that can have a transformative impact on patients’ lives.

Utilizing our rigorous selection process, we have assembled a deep portfolio of product candidates for rare, monogenic CNS disorders.

Utilizing our rigorous selection process, we have assembled a strong portfolio of product candidates for rare, monogenic CNS disorders.

Our first product candidate, PBGM01, utilizes a next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GLB1 gene encoding lysosomal beta-galactosidase, or β-gal, for GM1.

Our second product candidate, PBFT02, utilizes an AAV1 capsid to deliver to the brain a functional GRN gene encoding progranulin, or PGRN, for FTD caused by progranulin deficiency, or FTD-GRN.

Our third product candidate, PBKR03, utilizes a next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional gene encoding the hydrolytic enzyme galactosylceramidase, or GALC , for Krabbe disease.

There are currently no approved disease-modifying therapies for these diseases.

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Our research collaboration with GTP provides us with access to one of the premier research institutions in the world for the discovery and preclinical development of genetic medicine product candidates and exclusive rights to product candidates for certain CNS disorders.

As part of this collaboration, we have exclusive rights to all

discovery work and IND-enabling research for product candidates in up to seventeen CNS indications that we select.

In addition to our three clinical product candidates, we have six ongoing research programs and eight remaining options available to us to license additional programs from GTP until May 2026.

We also have exploratory research programs with GTP in non-rare, non-monogenic, or large, CNS indications, initially focused on AD and TLE, which can be expanded to other large, CNS diseases upon mutual agreement with GTP.

As part of this collaboration, we have exclusive rights to all discovery work and IND-enabling research for product candidates in the CNS indications that we select.

addition to our two lead clinical product candidates, we have two clinical product candidates for which, in order to reduce operating expenses, we have stopped further clinical development and are exploring strategic alternatives, two ongoing research programs, and eight remaining options available to us to license additional programs from GTP until August 2026.

We also have an exploratory research program with GTP in non-rare, non-monogenic, or large, CNS indications, currently focused on TLE, which can be expanded to other large, CNS diseases upon mutual agreement with GTP.

Further, we have exclusive rights, subject to certain limitations, to technologies resulting from the discovery program for our products developed with GTP, such as novel capsids, toxicity reduction technologies, delivery, and formulation.

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Wilson, one of our scientific founders, is recognized as a world leader in research and development in the fields of genetic medicines and rare disease.

Wilson’s continuing relationship with our company and involvement in both academic research and clinical drug development allows us to gain early insight into emerging technologies that informs our business strategy.

Wilson’s continuing relationship with our company helps guide our clinical and research programs.

We have assembled a team whose members have extensive experience in successfully developing, manufacturing and commercializing genetic medicine and rare disease products.

We have assembled a deep portfolio of genetic medicine product candidates for rare, monogenic CNS disorders characterized by high unmet medical needs.

We intend to further expand our portfolio with genetic medicine product candidates for rare, monogenic and large CNS disorders, as well as other treatment approaches as technology advances in the field.

We have assembled a strong portfolio of genetic medicine product candidates for rare, monogenic CNS disorders characterized by high unmet medical needs.

We intend to further expand our portfolio with genetic medicine product candidates for other CNS disorders, as well as other treatment approaches as technology advances in the field.

Our development programs consist of:

*8 additional CNS pipeline license options remain;

3 license options were previously exercised, and rights were subsequently returned to the University of Pennsylvania.

† Program includes ongoing natural history study of infantile and juvenile GM1 gangliosidosis patients

PBGM01 for the treatment of GM1

We are currently developing PBGM01, which utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GLB1 gene encoding β-gal for infantile GM1.

Infantile GM1 is the most common and severe form of GM1, in which patients have mutations in the GLB1 gene that produce little or no residual β-gal enzyme activity.

β-gal is an enzyme that catalyzes the first step in the natural degradation of GM1 ganglioside.

β-gal is an enzyme that catalyzes the first step in the natural degradation of GM1 ganglioside as well as other glycan substrates.

Reduced β-gal activity results in the accumulation of toxic levels of GM1 ganglioside in neurons throughout the brain, causing rapidly progressive neurodegeneration, with a life expectancy of two to ten years.

Currently, there are no disease-modifying therapies approved for the treatment of GM1.

Early onset infantile GM1 is characterized by onset in

the first 6 months of life, while late onset infantile GM1 is characterized by onset between 6 and 24 months.

Early onset infantile GM1 is characterized by onset in the first 6 months of life, while late onset infantile GM1 is characterized by onset between 6 and 24 months.

We believe PBGM01 could provide patients with significantly improved outcomes.

In preclinical studies we observed meaningful transgene expression in both the CNS and in peripheral organs affected in GM1.

preclinical studies we observed meaningful transgene expression in both the CNS and in peripheral organs affected in GM1.

We are conducting clinical trials using an ICM method of administration, which involves an injection at the craniocervical junction.

We have an active IND, or Investigational New Drug application, from the U.S.

We have an active Investigational New Drug application, or IND, from the U.S.

Food and Drug Administration, or FDA, and approved clinical trial authorizations, or CTAs, in multiple countries for PBGM01, and we are actively proceeding with our Imagine-1 Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBGM01 in patients with a diagnosis of early and late infantile GM1.

In March 2021, we dosed the first patient in our Imagine-1 Trial.

In the fourth quarter of 2021, we reported initial safety and 30-day biomarker data from the initial cohort of two early onset GM1 patients treated with the low dose of PBGM01.

We also reported interim safety data for the initial cohort that showed PBGM01 was well tolerated with no series adverse events and no evidence of dorsal root ganglion toxicity.

In February 2022, we reported meaningful developmental improvement in assessments, utilizing the Bayley III and Vineland II scales, performed by trained healthcare providers and caregivers, respectively, for both patients in the initial cohort.

Additionally, in February 2022, we reported that we dosed our first patients in Cohort 2, for late onset infantile with high dose PBGM01, and Cohort 3, for early onset infantile GM1 with low dose PBGM01, with initial biomarker and safety data expected to be reported in the second half of 2022.

We have completed dosing of the initial four cohorts in our Imagine-1 Trial.

This includes a total of eight patients, as follows:

Cohort 1 for late infantile GM1 treated with low dose PBGM01, Cohort 2 for late infantile GM1 treated with high dose PBGM01, Cohort 3 for early infantile GM1 treated with low dose PBGM01, and Cohort 4 for early infantile GM1 treated with high dose PBGM01.

In December 2022 and February 2023, we reported interim safety and biomarker data for the first three cohorts of our Imagine-1 trial.

The safety data showed that PBGM01 was well tolerated with no serious adverse events and no evidence of dorsal root ganglion toxicity or complications related to the ICM injection.

We observed a dose-dependent increase in β-gal activity in the cerebral spinal fluid, or CSF, coupled with a dose-dependent decrease in CSF levels of GM1 ganglioside.

We also reported meaningful improvement in a subset of patients across developmental areas in assessments utilizing the Vineland II and Bayley III scales, performed by caregivers and trained healthcare providers, respectively.

The data suggests that stage of disease may be a determinant in treatment outcomes.

We expect to report initial safety and biomarker data from patients in Cohort 4 in the middle of 2023.

A key objective of the initial phase of the Imagine-1 trial is to determine the optimal dose for the confirmatory phase of the study.

Based on the favorable safety profile of PBGM01 observed to date, the observed dose-response in key biomarkers, such as CSF b -gal activity and GM1 ganglioside levels, and that our preclinical studies showed no safety signals at doses higher than currently being evaluated in the ongoing clinical trial, we plan to treat additional patients in the Imagine-1 trial at higher doses of PBMG01 than the doses of PBGM01 administered to date in Cohorts 1 to 4.

Following regulatory review, we expect to dose the first patient at a higher dose of PBGM01 in the second half of 2023.

The FDA has granted Orphan Drug Designation, or ODD, Rare Pediatric Disease Designation, or RPDD, and Fast Track Designation, to PBGM01 for the treatment of GM1.

The European Commission has granted Orphan designation for PBGM01.

The European Commission has granted Orphan designation and Advanced Therapy Medicinal Product, or ATMP, designation for PBGM01.

PBFT02 for the treatment of FTD-GRN

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Based on findings in preclinical studies, we believe that PBFT02 may provide FTD-GRN patients with significantly improved outcomes.

We selected the AAV1 capsid and ICM administration for PBFT02 because this approach led to extensive and robust expression of human PGRN throughout the brain and spinal cord of NHPs, and due to the higher PGRN levels in CSF using AAV1 as compared with other serotypes tested.

ICM administration of AAV1 to NHPs resulted in CSF levels of human PGRN in excess of 50-fold higher than those in healthy human subjects’ CSF, and in excess of 5-fold higher than levels achieved in NHPs with AAVhu68 or AAV5.

We selected the AAV1 capsid and ICM administration for PBFT02 because this approach led to extensive and robust expression of human PGRN throughout the brain and spinal cord of non-human primates, or NHPs, and due to the higher PGRN levels in CSF using AAV1 as compared with other serotypes tested.

ICM administration of AAV1 to NHPs resulted in supraphysiologic CSF levels of human PGRN compared to levels in healthy human subjects’ CSF, and in excess of levels achieved in NHPs with AAVhu68 or AAV5.

We have an active IND from the FDA and approved CTAs in multiple countries for PBFT02, which allows us to proceed with our upliFT-D Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBFT02 in patients with a diagnosis of early symptomatic FTD-GRN.

We expect to dose the first patient in our initial cohort of our upliFT-D Trial in early 2022.

In August 2022, we dosed the first patient in our upliFT-D trial.

We expect to report initial safety and biomarker data from patients in Cohort 1 in the second half of 2023.

The FDA has granted ODD and Fast Track Designation to PBFT02 for the treatment of FTD-GRN and the European Commission granted Orphan designation for PBFT02.

PBKR03 for the treatment of Krabbe disease

We are currently developing PBKR03, which utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GALC gene encoding the hydrolytic enzyme galactosylceramidase for Krabbe disease.

Krabbe disease is an autosomal recessive lysosomal storage disease caused by mutations in the GALC gene, which provides instructions for making an enzyme called galactosylceramidase, which breaks down certain fats,

including galactosylceramide and psychosine.

Other Clinical Product Candidates

We have two clinical product candidates, PBKR03 and PBML04, for which, in order to reduce operating expenses, we have stopped further clinical development and are exploring strategic alternatives for these assets.

PBKR03 utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional GALC gene encoding the hydrolytic enzyme galactosylceramidase to treat Krabbe disease.

This results in the accumulation of galactolipids such as psychosine, resulting in widespread death of myelin-producing cells in the CNS and in the peripheral nervous system, or PNS.

Without myelin, nerves in the brain and other parts of the body cannot transmit signals properly, leading to the signs and symptoms of Krabbe disease.

We believe PBKR03 may provide patients with significantly improved outcomes.

In preclinical models, we have observed meaningful transduction of both the CNS and other critical peripheral organs for Krabbe disease patients using our ICM method of administration in combination with our next-generation AAVhu68 capsid.

We have an active IND from the FDA and approved CTAs in multiple countries for PBKR03, which allows us to proceed with our GALax-C Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBKR03 in patients with a diagnosis of early infantile Krabbe disease.

We expect to dose the first patient in our initial cohort of our GALax-C Trial in early 2022.

The FDA has granted ODD, RPDD, and Fast Track Designation to PKBR03, and the European Commission granted Orphan designation for PBKR03.

We have an active IND from the FDA and approved CTAs in multiple countries for PBKR03 to support our GALax-C Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBKR03 in patients with a diagnosis of infantile Krabbe disease.

In March 2022, we dosed the first patient in our GALax-C Trial.

In November 2022, we announced plans to stop further clinical development of PBKR03 in order to reduce operating expenses, and are exploring strategic alternatives for this asset.

PBML04 utilizes a proprietary, next-generation AAVhu68 capsid to deliver to the brain and peripheral tissues a functional arylsulfatase A gene, or ARSA , encoding the ARSA enzyme to treat Metachromatic Leukodystrophy, or MLD.

MLD is a rare, autosomal recessive lysosomal storage disease caused by mutations in the ARSA gene, resulting in little or no functional activity of the ARSA enzyme, which is essential for the degradation of sphingolipid cerebroside-3-sulfate, or sulfatide.

When the ARSA enzyme is lacking, sulfatides accumulate in lysosomal storage deposits in microglia, oligodendrocytes, and Schwann cells, leading to widespread demyelination.

Our preclinical data in ARSA -/- mice and in NHPs support the ability of PBML04 administration into CSF to result in dose-dependent increases in brain and CSF levels of functional human ARSA enzyme, leading to improved biochemical, histopathological, behavioral, survival endpoints, and with no safety or toxicity signs up to the highest tested dose in NHPs.

Preclinical findings were presented by GTP in 2021.

In April 2022, we submitted an IND for PBML04 to support clinical development in MLD.

On May 20, 2022, the FDA cleared our IND application for PBML04, which supports PBML04-001, an international, multi-center, open-label, single-arm clinical trial of PBML04 in patients with a diagnosis of late onset infantile MLD.

In November 2022, we announced plans to stop further clinical development of PBML04 in order to reduce operating expenses, and are exploring strategic alternatives for this asset.

Research Programs

We have six programs in preclinical research stages under our license agreement with Penn:

PBML04 for MLD, PBAL05 for ALS, PBCM06 for CMT2A and unnamed programs for Canavan disease, Parkinson’s disease and Huntington’s disease.

PBML04 is in preclinical development for MLD, which is caused by mutations in the ARSA gene.

We have two programs in preclinical research stages under our license agreement with Penn:

PBAL05 for ALS and, an unnamed program for Huntington’s disease.

PBAL05 is targeting patients with ALS who have a gain-of-function mutation in the C9orf72 gene.

PBCM06 is in development for CMT2A, which is caused by a mutation in the MFN2 gene.

Our unnamed programs comprise of:

a program to treat patients with an inherited form of Parkinson’s disease with PRKN mutations;

a program for the treatment of Canavan’s disease, which is caused by mutations in the aspartyoacylase, or ASPA , gene;

and a program for the treatment of Huntington’s disease, a repeat expansion disorder.

Beyond this portfolio, through our research collaboration with GTP, we also have the option to license programs for eight additional new indications in CNS diseases along with rights and licenses to new gene therapy technologies developed by Penn, such as novel capsids, toxicity reduction technologies and delivery and formulation.

We also have exploratory research programs with GTP for large indications, initially focused on AD and TLE, which can be expanded to other large CNS diseases upon mutual agreement with GTP.

Our unnamed program is focused on the treatment of Huntington’s disease, a repeat expansion disorder.

Beyond this portfolio, through our research collaboration with GTP, we also have the option to license programs for eight additional new indications in CNS diseases along with certain rights and licenses to new gene therapy technologies developed by Penn, such as novel capsids, toxicity reduction technologies and delivery and formulation.

We also have an exploratory research program with GTP for larger non-monogenic indications, currently focused on TLE, which can be expanded to other large CNS diseases upon mutual agreement with GTP.

We are a genetic medicines company focused on developing transformative therapies for CNS disorders with limited or no approved treatment options.

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To achieve our vision, we have assembled a world-class team whose members have decades of collective experience in genetic medicines and rare disease drug development and commercialization.

We leverage this experience, along with the decades of experience of Dr.

Wilson, as well as the transformative potential of genetic medicine technology to develop treatments that improve outcomes for patients with serious, life-threatening CNS diseases.

We leverage this experience, to develop treatments that improve outcomes for patients with serious, life-threatening CNS diseases.

Patients are considered every step of the way, in every decision we make.

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• Focus on underserved indications for which we can have a transformative impact on patients’ lives.

We believe that genetic medicine has the potential to have a transformative impact on CNS disorders, and on patients’ lives, by providing them with a treatment for life-threatening diseases with limited or no approved disease-modifying treatments.

• Rapidly advance our clinical product candidates through clinical development and commercialization.

We leverage our collaboration with GTP, as well as our internal capabilities, to

select optimal product candidates for each indication based on extensive preclinical data, including animal data and disease-specific animal models and biomarkers, thus enhancing the probability of clinical success of our product candidates.

We leverage our collaboration with GTP, as well as our internal capabilities, to select optimal product candidates for each indication based on extensive preclinical data, including animal data and disease-specific animal models and biomarkers, thus enhancing the probability of clinical success of our product candidates.

Our goal is to select candidates that have the potential to address high unmet clinical needs and have transformative therapeutic effects for patients.

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Through our collaboration with GTP, we are continuing to develop additional genetic medicine product candidates targeting life-threatening CNS disorders.

Beyond our three clinical product candidates, we have six additional products advancing through the research stage.

We have two lead clinical product candidates, two clinical product candidates for which we have stopped further clinical development in order to reduce operating expenses and are exploring strategic alternatives for these assets, and three additional programs advancing through the research or discovery stage.

We also have the option to license eight additional CNS indications from GTP until May 2026.

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Our relationship with Penn’s ODC, which is currently performing a natural history study for GM1 that we are funding, represents an example of our strategy, and has been helping us to engage effectively with patients.

We have a collaboration with Invitae to facilitate genetic testing and support early identification of GM1 and Krabbe disease through Invitae’s Detect Lysosomal Storage Disorders, as well as provide clinical trial information to physicians and patients, and have partnered with InformedDNA to offer free genetic counseling and testing for adults who have been diagnosed with FTD.

We have a collaboration with Invitae to facilitate genetic testing and support early identification of GM1 through Invitae’s Detect Lysosomal Storage Disorders, as well as provide clinical trial information to physicians and patients, and have partnered with InformedDNA to offer free genetic counseling and testing for adults who have been diagnosed with FTD.

• Continue to develop proprietary manufacturing capabilities.

We believe the quality, reliability and scalability of our genetic medicine manufacturing techniques and know-how will be a critical advantage to our long-term success.

We currently have access to a state-of-the-art purpose-fit manufacturing suite through Catalent Maryland, a unit of Catalent Biologics, Inc., or Catalent.

We expect this facility will be capable of producing supplies of our product candidates sufficient to conduct our clinical trials and potentially for initial commercial launch of our clinical product candidates, if approved.

Catalent will also provide packaging, labeling and distribution services, including its FastChain® demand led supply offering, which we believe is well suited to studies of advanced therapy medicinal products.

We have invested in our own laboratory, which is initially focused on state-of-the-art analytical capabilities, assay development and validation, and clinical product testing to support both viral vector manufacturing and clinical development.

We also expect to open a pilot plant manufacturing suite to provide scale-up capabilities in support of our product pipeline and future development plans by the end of 2022.

We will continue to invest in developing our manufacturing capabilities and plan to establish our own manufacturing facility for long-term commercial supplies.

We have established robust in-house analytical and process development operations to support ongoing and future manufacturing operations.

We have also advanced our manufacturing and testing technology platforms;

our in-house laboratory is equipped with state-of-the-art analytical capabilities, capable of assay development and validation, clinical product testing, and process and product development to support viral vector manufacturing.

We also have the internal manufacturing

and quality expertise to oversee external manufacturing and supply chain operations provided by third party strategic relationships, such as Catalent Maryland, a unit of Catalent Biologics, Inc, or Catalent.

We also have access to a manufacturing suite through Catalent where we have successfully produced GMP material for our clinical programs.

This facility is capable of producing sufficient supplies to conduct our planned clinical trials and, supply initial commercial launch of our current clinical product candidates, if approved.

• Selectively enter into new discovery relationships with premier research institutions and expand our existing collaboration.

We will continue to foster our well-established relationship with Penn, and potentially enter into new collaborations to build our pipeline.

We will continue to foster our well-established relationship with Penn, and potentially enter into new collaborations to build or advance our pipeline.

We will look to nurture our genetic medicine technology capabilities by keeping abreast of advances in next-generation capsid development, promoter selection, transgene design, gene silencing and gene editing, which will help us to engineer optimal product profiles to address life-threating CNS disorders characterized by high unmet medical needs.

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Currently, there are estimated to be over 10,000 diseases caused by a genetic abnormality in a single gene.

These are also known as monogenic

These are also known as monogenic diseases.

Based on research commissioned by us, we believe there are at least 790 rare monogenic CNS diseases, with few currently approved disease modifying treatments for any rare monogenic CNS diseases.

In addition, gene therapy can also be applied to correct biological pathways that are not necessarily inherited or associated with a defective gene.

In addition, gene therapy can also be applied to correct biological pathways that are not necessarily inherited or associated with one defective gene.

This approach aims to reduce the expression of pathological proteins or increase the production of corrective biological targets.

This is the basis for the programs that target non-hereditary conditions such as sporadic AD and TLE.

This is the basis for the programs that target non-hereditary conditions such as TLE.

The development of molecular therapeutics to modulate human gene expression and correct disease-causing genetic defects had its advent several decades ago, and with advances in science and a deeper understanding of human genetics it has expanded to include a broader range of genetic medicines with the potential to modulate gene expression through additional molecular mechanisms.

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These disorders are generally life-threatening to patients.

There is a significant need for genetic medicines that can target these disorders.

There is a significant need for genetic

medicines that can target these disorders.

Our initial programs focus on rare, monogenic CNS disorders because they offer a compelling opportunity for the effective application of genetic medicines.

In the year ended December 31, 2021, we exercised options under the Penn Agreement to include Canavan disease and Huntington's disease to our portfolio, and also amended the Penn Agreement to broaden the scope under the Penn Agreement to include large CNS disorders, and entered into exploratory research programs to identify gene targets and develop therapeutic AAVs for large CNS disorders, initially TLE and AD.

The field of genetic medicine is rapidly expanding and we believe we have developed a differentiated approach to developing treatments for CNS disorders that allows us to select and advance product candidates with a higher probability of technical and regulatory success.

Our gene therapy product candidates use an AAV, a small, non-pathogenic virus that is genetically engineered to function as a delivery vehicle, or vector.

Our gene therapy product candidates use AAV, a small, non-pathogenic virus that is genetically engineered to function as a delivery vehicle, or vector.

In our current clinical programs, the AAV is administered to a patient to introduce a healthy copy of a mutated gene, or the transgene, to the cells in a process referred to as transduction.

Our current approaches use AAVs to deliver either a (i) replacement non-mutant transgene, or (ii) a combination of a microRNA, known as miRNA, and replacement of a non-mutant transgene.

Our current approaches use AAVs to deliver either a (i) replacement non-mutant transgene, or (ii) a combination of a microRNA, known as miRNA, to reduce expression of a mutant transgene, and a replacement non-mutant transgene.

The components of an AAV gene therapy vector include the therapeutic gene that makes up the DNA payload, or the transgene, the outer viral shell that encloses the DNA payload, or the capsid, and any promotors added to the vector to boost expression of the transgene.

The AAV is often described by the serotype, or strain, of the vector.

The core tenets of our approach include a rigorous process for selecting product candidates, mitigation

of early development risk through relationships with leading researchers and academic institutions, and mitigation of clinical development risk through deep relationships with patient advocacy groups, key opinion leaders and practitioners.

The core tenets of our approach include a rigorous process for selecting product candidates, mitigation of early development risk through relationships with leading researchers and academic institutions, and mitigation of clinical development risk through deep relationships with patient advocacy groups, key opinion leaders and practitioners.

Together, these relationships allow us to directly benefit from decades of collective experience, the latest technologies and contemporary perspectives from patients and their experiences.

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The optimal route of administration for CNS treatments should also leverage the immuno-privileged aspects of the CNS to reduce the potential effects of neutralizing antibodies, or NAbs, on AAV capsids, which are often faced by gene therapy product candidates.

We will evaluate preclinical studies and other data to decide the preferred route of administration on a program-by-program basis.

For our three clinical product candidates, we believe that ICM administration is the optimal route of administration as compared to other potential delivery mechanisms due to its diffuse delivery distribution, potential for improved biodistribution to the brain and spinal cord and transduction, and lower expected toxicity.

We evaluate preclinical studies and other data to decide the preferred route of administration on a program-by-program basis.

For our existing clinical product candidates, we believe that ICM administration is the optimal route of administration as compared to other potential delivery mechanisms due to its diffuse delivery distribution, potential for improved biodistribution to the brain and spinal cord and transduction, and lower expected toxicity.

Administration through ICM can also reduce the potential impact of NAbs as compared with intravenous administration.

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• Cross-correction:

Our three clinical product candidates exploit the cross-correction mechanism by which secreted gene product from transduced cells is taken up by non-transduced neurons.

Our existing clinical product candidates exploit the cross-correction mechanism by which secreted gene product from transduced cells is taken up by non-transduced neurons.

We believe this cross-correction mechanism can help overcome the limits of vector biodistribution and CNS transduction inefficiency that are characteristic of other genetic medicine approaches, and ultimately drive clinical benefit.

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Our strategic research collaboration with GTP provides us with access until August 2026 to one of the premier gene therapy research institutes in the world for the discovery and preclinical development of gene therapy product candidates and exclusive rights to certain CNS disorders, including next-generation AAV capsid technology and vector engineering, and state-of-the art preclinical animal studies, including NHP models.

currently employs approximately 300 staff with cutting edge expertise and capabilities in gene therapy research and preclinical development.

Through GTP’s staff, we have access to cutting edge expertise and capabilities in gene therapy research and preclinical development.

Our collaboration with GTP allows us to choose programs that have been or will be validated through extensive testing in preclinical disease models, and once selected, to collaborate with GTP on further preclinical optimization of our product candidate, such as vector choice, transgene construct and route of administration.

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We leverage our close working relationship with Penn’s ODC to develop historical and prospective external data for each disease for use in building comparable patient profiles of participants in interventional trials.

In addition, we believe Penn’s ODC’s close ties to leading clinical centers for rare, monogenic CNS disorders will improve our ability to identify potential patients for trial enrollment, and enhance patient retention and data quality.

Penn’s ODC is currently performing a natural history study for GM1 funded by us.

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The disease rapidly progresses, with a life expectancy of less than two years for early infantile GM1 and five to ten years for late infantile GM1.

GM1 is caused by recessive mutations in the GLB1 gene, which encodes lysosomal acid β-gal, an enzyme that catalyzes the first step in the natural degradation of GM1 ganglioside.

GM1 is caused by recessive mutations in the GLB1 gene, which encodes lysosomal acid β-gal, an enzyme that catalyzes the first step in the natural degradation of GM1 ganglioside as well as other glycan substrates.

Reduced β-gal activity results in the accumulation of toxic levels of GM1 ganglioside in neurons throughout the brain, causing rapidly progressing neurodegeneration.

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There are known biomarkers in GM1 that are measurable and available to assist in drug development.

o β -gal activity.

Reduced β-gal activity is a hallmark of GM1 and treatment with PBGM01 is expected to restore this activity.

To this end, β-gal activity is being measured in CSF and blood.

o Pharmacodynamic biomarkers .

In our preclinical studies, biomarkers including β-gal activity and hexosaminidase, or HEX, activity showed treatment-related effects in PBGM01-treated GLB1 knockout mice.

CSF collected at the time of necropsy showed β-gal activity exceeding that of disease-free heterozygous control mice.

β-gal activity in the brains of PBGM01-treated GLB1 knockout mice was similar to activity in normal control mice.

Peripheral organs, including the heart, lungs, liver and spleen, also exhibited elevated β-gal activity in PBGM01-treated mice.

Reduced β-gal activity results in the accumulation of GM1 ganglioside and other glycan substrates in neurons throughout the brain.

These substrates may be reduced following treatment with PBGM01 and are being measured in CSF, blood, and urine.

o Disease progression biomarkers.

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• Preclinical validation:

We used the GLB1 knockout mouse disease model showing clinical, biologic and histological manifestations of GM1 in preclinical studies.

We used the GLB1 knockout mouse disease model showing clinical, biological and histological manifestations of GM1 in preclinical studies.

In these studies, we observed a robust dose-related improvement in both neurological status, enzyme activity, histologic lysosomal storage pathology and survival following treatment with PBGM01.

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We expect treatment-related efficacy to be measurable sooner after treatment in this more rapidly progressing form of GM1.

Patients with onset forms of GM1 later than infantile, which we define as an onset later than 24 months, are caused by less severe reductions of β-gal enzyme activity, generally demonstrate slower progression and more variable clinical courses, likely requiring larger and longer clinical trials and a broader control group.

Patients with onset forms of GM1 later than infantile, which we define as an onset later than 24 months, are caused by less severe reductions of β-gal enzyme activity and generally demonstrate slower progression and more variable clinical courses, likely requiring larger and longer clinical trials and a broader control group.

If our initial clinical trials in infantile GM1 are successful, we intend to explore expansion of the indication with trials in later onset forms of GM1.

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We believe gene replacement with PBGM01 and consequent wide brain distribution and uptake of the β-gal enzyme has the potential to greatly reduce the accumulation of GM1 gangliosides, reversing neuronal toxicity, thereby restoring developmental potential and improving the quality of life for treated patients.

We will evaluate

this clinically by assessing the prevention of further developmental regression and restoration of developmental trajectories, as measured by developmental milestones using accepted clinical scales, observer-reported outcomes and video recordings.

We will evaluate this clinically by assessing the prevention of further developmental regression and restoration of developmental trajectories, as measured by developmental milestones using accepted clinical scales and observer-reported outcomes.

Preclinical studies

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Intracerebroventricular, or ICV, injection of PBGM01 in GLB1-/- mice resulted in persistent dose-dependent elevations in β-gal activity in the brain, CSF, serum, and in peripheral organs.

Increased β-gal activity was associated with phenotypic and histopathological benefits in the GLB1-/- mice including the resolution of pre-existing brain lysosomal storage lesions as assessed by lysosomal associated membrane protein 1, or LAMP-1, immunohistochemistry, improved neurological phenotypes in assays of clinical deficits and animals’ gait, and increased survival.

Increased β-gal activity was associated with increased phenotypic and histopathological benefits in the GLB1-/- mice including the resolution of pre-existing brain lysosomal storage lesions as assessed by lysosomal associated membrane protein 1, or LAMP-1, immunohistochemistry, improved neurological phenotypes in assays of clinical deficits and animals’ gait, and increased survival.

Preclinical findings were published by GTP in 2020.

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A 120-day good laboratory practice, or GLP, compliant toxicology study conducted in NHPs assessed the safety, tolerability, biodistribution and excretion profile of PBGM01 following ICM administration of vehicle or one of three dose levels of PBGM01.

There were no blood or CSF abnormalities related to PBGM01 administration except for asymptomatic, mild, and transient increases in CSF leukocytes in the majority of animals.

PBGM01 was well-tolerated at all doses evaluated and no adverse effects were detected on body weight or clinical, neurological, or behavioral signs.

Vector distributed to the CSF and high levels of gene transfer were detected in the brain, spinal cord and dorsal root ganglia, or DRG.

PBGM01 vector distributed to the CSF and high levels of gene transfer were detected in the brain, spinal cord and dorsal root ganglia, or DRG.

The quantity of vector genomes detected in CNS tissues was generally dose-dependent.

PBGM01 also reached high levels in peripheral blood and liver.

Measurement of transgene expression by β-gal activity in CSF and serum was limited in NHPs by the nature of the assay, which could not distinguish between human and endogenous rhesus β-gal.

β-gal activity in the CSF and serum was detectable in animals from all dose groups 14 days after PBGM01 administration.

In the CSF, animals administered the two higher doses displayed dose-dependent increases in β-gal activity to approximately two-fold and four-fold higher than the levels in vehicle-treated controls, respectively.

There were no blood or CSF abnormalities related to PBGM01 administration except for asymptomatic, mild, and transient increases in CSF leukocytes in the majority of animals from all dose groups.

PBGM01 was well-tolerated at all doses evaluated and no adverse effects were detected on body weight or clinical, neurological, or behavioral signs.

PBGM01 vector DNA was detectable in urine and feces five days post-administration and was undetectable within 60 days.

Measurement of transgene expression by β-gal enzyme activity in CSF and serum of NHPs was limited by the nature of the assay, which could not distinguish human β-gal enzyme versus endogenous rhesus enzyme.

Rapid loss of transgene product activity after Day 14, which was likely due to an antibody response to the human transgene product, was an additional limitation.

Despite these caveats β-gal activity in the CSF and serum was detectable in animals from all dose groups 14 days after administration of PBGM01.

In the CSF, animals receiving the two higher doses displayed β-gal activity levels that were approximately two- and four-times higher than vehicle-treated control levels.

Pre-existing NAbs to the vector capsid were detected in the serum of some animals and did not appear to influence gene transfer to the brain and spinal cord, or transgene product levels in the CSF.

This observation supports the potential to achieve therapeutic activity in the CNS in infantile and late infantile patients with GM1 regardless of NAb status.

Pre-existing NAbs to the vector capsid correlated with reduced gene transfer in the liver, however.

PBGM01 administration resulted in asymptomatic degeneration of the DRG and the trigeminal ganglia, or TRG, sensory neurons and their associated central and peripheral axons.

The severity of these lesions was typically minimal to mild.

These findings were not clearly dose-dependent, although there was a trend of more severe lesions in the mid-dose and high dose cohorts.

DRG and TRG lesions were less severe at Day 120 than Day 60, indicating they were not progressive.

Two animals that exhibited the most severe axon loss and fibrosis of median nerves at necropsy on day 120 also exhibited impairments in nerve conduction in terms of reduced sensory nerve action potential, or SNAP, amplitudes in the median nerve.

Reductions in SNAP amplitudes were evident by Day 28 with no subsequent progression.

This observation was consistent with the findings of a retrospective analysis of DRG pathology in NHPs after AAV administration conducted by GTP.

In an analysis of five preclinical studies, increased severity of axonopathy and fibrosis correlated with reduced SNAP amplitudes.

In keeping with the findings of the retrospective analysis, the PBGM01 -induced SNAP changes and sensory neuron degeneration were not associated with any clinical or neurological abnormalities in any animals up to 120 days post-dose .

In summary, based on our preclinical studies we believe that CSF delivery of PBGM01 has the potential to sufficiently increase b-gal levels in both the CNS and in peripheral tissues to overcome intracellular b-gal deficiency in GM1.

In response to a potential AAV platform risk reported in NHPs we assayed DRG and TRG toxicity after PBGM01 administration.

Mild and transient degeneration of DRGs, TRGs, and associated sensory nerve axonopathy were observed in all dose groups;

however, these findings were not linked with any clinical or neurological abnormalities in any animals up to 120 days post-dose.

In summary, based on our preclinical studies, we believe that CSF delivery of PBGM01 has the potential to sufficiently increase β-gal levels in both the CNS and in peripheral tissues to overcome intracellular β-gal deficiency in GM1.

Clinical development

Our clinical development plan is to start with trials in infantile GM1, and if successful, explore expansion of the indication with trials in later onset forms of GM1.

We initiated patient dosing in a multi-center, open-label, single-arm Phase 1/2 clinical trial of PBGM01 in patients with a diagnosis of early and late infantile GM1 in March 2021.

The study includes both early and late infantile patients in separate, smaller cohorts.

We plan to enroll a total of four cohorts of two patients each, with separate dose-escalation cohorts for late onset infantile GM1 patients , defined as onset prior to 24 months in age and after 6 months in age, and early onset infantile GM1 , defined as onset prior to 6 months of age .

We initiated patient dosing in our Imagine-1 trial, a multi-center, open-label, single-arm Phase 1/2 clinical trial of PBGM01 in patients with a diagnosis of early and late infantile GM1 in March 2021.

Primary endpoints include safety and efficacy.

Efficacy is being evaluated by the assessment of developmental milestones using accepted clinical scales and observer-reported outcomes.

Secondary outcomes include serum and CSF β-gal enzyme activity, GM1 ganglioside levels, and disease progression endpoints including evaluations using electroencephalogram, or EEG, and MRI.

The study enrolled both early and late infantile patients in separate, smaller cohorts.

Part 1 of the study includes a total of four cohorts of two patients each, with separate dose-escalation cohorts for late onset infantile GM1 patients , defined as onset prior to 24 months in age and after 6 months in age, and early onset infantile GM1 , defined as onset prior to 6 months of age .

The study is assessing an initial low dose (3.3x10˄10 genome copies/gm brain weight) that exceeds the minimum effective dose, or MED, as determined in our preclinical studies, and a 3-fold greater high dose (1.1x10˄11 genome copies/gm brain weight).

The first cohort includes patients diagnosed with late infantile GM1 .

Cohorts 1 and 2 enrolled patients diagnosed with late infantile GM1 and treated them with low dose and high dose PBGM01, respectively, while Cohorts 3 and 4 enrolled patients diagnosed with early infantile GM1 and treated them with low dose and high dose PBGM01, respectively.

All patients are treated with an abbreviated course of low dose steroids.

To better understand the clinical significance of the peripheral nerve findings in NHPs, we implemented clinical monitoring in our Imagine-1 trial, consisting of both nerve conduction studies and neurological exams focused on sensory and peripheral nerve function .

There is a 60-day interval between all subjects dosed within a cohort to allow review of biomarker and safety data before dosing the next subject.

Clinical development results

We completed enrollment of the first cohort of two patients with late infantile GM1 receiving the initial low dose of PBGM01 in the second half of 2021 and reported interim safety and biomarker data in December 2021 .

The interim assessment included safety and biomarker results covering six months for patient 1 and 60 days for patient 2.

PBGM01 was well tolerated, with a positive safety profile, no serious adverse events, or SAEs, no complications related to ICM administration and no evidence of DRG toxicity.

β-gal activity in CSF and serum increased in both patients.

For patient 1, enzyme activity at 30 days was 1.5-fold over baseline and the increase was maintained at six months.

For patient 2, enzyme activity at 30 days was 4.8-fold over baseline.

In serum, enzyme activity for patient 1 was slightly above baseline at 30 days, 1.7-fold over baseline at three months, and maintained at six months.

Serum enzyme activity for patient 2 at 30 days was 1.2-fold over baseline.

CSF and serum β-gal activity for both patients rose above the enzyme concentrations documented in untreated infantile and juvenile GM1 participants in the ODC’s natural history study.

Large differences were observed in GM1 gangliosides in CSF at baseline, with patient 2, who was more severely affected, showing baseline values four times higher than patient 1.

In patient 1, CSF levels of GM1 ganglioside increased approximately 85 percent at 30 days and remained stable at that level at six months.

In patient 2, levels decreased approximately 46 percent at 30 days.

GM1 Cohort 1 interim data

Following the completion of this first cohort and review of safety outcomes, the Independent Data Monitoring Committee, or IDMC, recommended continuing the study with the recruitment for both the high dose late infantile GM1 and the initial dose early infantile GM1 cohorts.

The first patient in each of those two cohorts was dosed in early 2022 and we anticipate reporting initial data from these cohorts in the second half of 2022.

Upon completion of the initial low dose of the early infantile cohort, a high dose cohort is planned to be enrolled in that patient population.

Following these dose-escalation cohorts, each patient population will be enrolled into a confirmatory cohort.

Following the dose-escalation cohorts, each patient population will be enrolled into a confirmatory cohort.

Patients will be evaluated over two years for safety and efficacy, followed by an additional 36 months of long-term follow up.

We expect that pre-specified primary endpoints will include safety and efficacy.

Efficacy will be evaluated by the assessment of developmental milestones using accepted clinical scales, observer-reported outcomes and video recordings.

Secondary outcomes will include serum and CSF β-gal enzyme activity and disease progression endpoints including evaluations using EEG and MRI.

In February 2022, we reported meaningful developmental improvement in assessments, utilizing the Vineland-II and Bayley-III scales, for both patients in the initial cohort, as outlined below.

These validated scales for assessing gross motor, fine motor, language and social development have been used previously in natural history studies.

The Vineland-II determines developmental milestones through structured interviews with caregivers, while the Bayley-III assesses developmental milestones through direct observation of skills by a trained healthcare professional.

Both assessments demonstrated progressive gains across all developmental areas which is not typical for children with GM1 late infantile.

Notably, patient 2, more severely affected at baseline than patient 1, was also documented to have regained previously lost motor and language developmental milestones.

Interim Clinical Results:

Vineland-II and Bayley-III:

Interim Clinical Results:

Clinical development results

We completed dosing of the initial four cohorts in our Imagine-1 trial in November 2022.

In December 2022 and February 2023, we reported interim safety and biomarker data for the first three cohorts of the trial.

The results from the interim assessment are shown below and include clinical data from the first three cohorts with follow-up from three to eighteen months based on data as of December 2022.

PBGM01 was well tolerated, with a positive safety profile, no serious adverse events, or SAEs, and all treatment-related adverse events, or AEs, were mild to moderate in severity.

There were no clinically significant changes in liver function requiring intervention and no evidence of peripheral nerve toxicity as measured by nerve conduction studies and neurological exam.

There was also a favorable immunological profile with no evidence of an immune response requiring changes to the immunosuppression regimen.

As anticipated, moderate levels of Nabs developed to capsid in blood and low levels of NAbs to capsid were also detected in CSF.

No antibodies were detected to the transgene product in either the CSF or serum.

There were also no complications related to the ICM administration.

The six patients enrolled in Cohorts 1 to 3 ranged from 6 to 31 months of age at the time of PBGM01 administration.

Across the first three cohorts, PBGM01 administration resulted in a dose-dependent increase in CSF β-gal activity with the high dose resulting in a 3.6-5.2x increase in CSF β-gal activity relative to baseline, well above levels observed in the Natural History Study being conducted by the University of Pennsylvania ODC.

In patient 1, who was observed with the longest follow-up, increased CSF β-gal activity was sustained for 12 months.

Sustained β-gal enzyme expression was also observed in blood.

GM1 Cohorts 1-3 Interim CSF b -gal Enzyme Activity

NHS patient value range based on preliminary data from University of Pennsylvania’s ODC Natural History Study (NHS) (NCT04041102);

Value range (0.3-1.81 nmol/mL/3hr, or nanomole per milliliter per 3 hours)

To assess pharmacodynamic activity in the CNS associated with b -gal activity, GM1 gangliosides levels were measured in the CSF.

GM1 gangliosides are hypothesized to mediate CNS manifestation of disease.

PBGM01 administration resulted in a dose-dependent decrease in CSF GM1 ganglioside levels for patients in the high dose cohort, showing decreases of up to 75% at six months.

GM1 ganglioside levels in the CSF were unchanged following the administration for patients in the low dose cohort.

Clinical assessments include the Bayley III and Vineland II scales, performed by trained healthcare providers and the patients caregivers, respectively.

The scales assess the developmental age of the child across a broad range of clinical parameters.

The patients treated with PBGM01 exhibited a broad range of developmental age at baseline, as assessed with the Bayley III, as well a wide range of developmental delay, which is determined by the patients chronological age minus their developmental age.

Two patients, patients 1 and 5, exhibited developmental delay of 2 and 5.5 months, respectively, which we have characterized as mild-to-moderate delay.

The remaining patients exhibited developmental delay ranging from 12 to 24 months, which we have characterized as marked delay.

Following treatment with PBGM01, we observed that patients with a lower developmental delay at dosing experienced a better clinical response to treatment, regardless of dosage level.

On both the Bayley III and the Vineland II, the two patients with mild-to-moderate developmental delay at baseline show improvement in their developmental age over time, which contrasts with the plateau and subsequent regression generally expected based on the natural history of the disease.

The remaining patients with more marked developmental delay show stabilization or limited improvement.

Based on this data, we believe that milder developmental delay at the time of dosing may be a determinant in treatment outcomes.

Cohorts 1 – 3 Interim Clinical Results:

Vineland-II and Bayley-III

Depending on the results from the dose escalation cohorts we plan to obtain input from regulatory agencies on the requirements to submit for regulatory approval for commercialization in the United States and internationally.

*The Vineland-II is caretaker-assessed.

**The Bayley-III is based on direct observation by a neurodevelopmental specialist.

Treatment effects on brain volume and white matter integrity are being assessed using a MRI severity score, a novel scoring metric, for GM1 patients based on baseline and follow-up brain MRI scans.

The MRI severity score is based on cerebral and cerebellar atrophy, abnormalities in white matter, and signal abnormalities in the basal ganglia and hippocampi, where higher scores indicate more structural damage.

In a natural history study with six late infantile GM1 patients, the MRI severity score increased in the majority of patients over the follow up period of six months to four years, implying progression of structural damage.

In contrast, PBGM01 administration was associated with stabilization of the MRI severity score over the follow up period of six to twelve months.

While the PBGM01 data is for a shorter period of time than the natural history study data, we believe the initial trend observed, if continued, may be an important indicator of biological activity.

Cohorts 1 – 3 Interim MRI Results:

MRI Severity Score

Initial biomarker and safety data from Cohort 4 are expected to be reported in the middle of 2023.

A key objective of the initial phase of the Imagine-1 trial is to determine the optimal dose for the confirmatory phase of the study.

Based on the favorable safety profile of PBGM01 to date, the observed dose-response in key biomarkers, such as CSF b -gal activity and GM1 ganglioside levels, and that our preclinical studies showed no safety signals at doses higher than currently being evaluated in the ongoing clinical trial, we plan to treat additional patients in the Imagine-1 trial at higher doses of PBGM01 than the doses of PBGM01 administered to date in cohorts 1 to 4.

Following regulatory review, we expect to dose the first patient at a higher dose of PBGM01 in the second half of 2023.

Based on the available data in the Imagine-1 trial to date, we believe that patients with more limited developmental delay at the time of enrollment may have better outcomes.

As we consider our pivotal trial design and potential modifications to the ongoing trial, we are revising inclusion criteria to maximize the benefit-risk profile of PBGM01.

As our clinical data matures, we are planning for continued interactions with regulatory authorities to align on design of the confirmatory study and appropriate pathway to submission of a Biologics License Application, or BLA, and regulatory approval for commercialization in the United States and internationally.

Natural History Data

We are currently funding a GM1 natural history study being conducted by Penn’s ODC to collect prospective data on clinical disease progression in infantile and juvenile GM1.

This data will be used to construct natural history patient profiles for comparison to the profiles of treated participants in our planned Phase 1/2 clinical trial.

Regulatory Designations and Clinical Trial Approvals

We have an active IND from the FDA and approved CTAs in multiple countries for PBGM01, and we are actively proceeding with our Imagine-1 Trial, an international, multi-center, open-label, single-arm Phase 1/2 clinical trial of PBGM01 in patients with a diagnosis of early and late infantile GM1.

The FDA has granted Orphan Drug Designation, or ODD, Rare Pediatric Disease Designation, or RPDD, and Fast Track Designation, to PBGM01 for the treatment of GM1.

The European Commission has granted Orphan designation for PBGM01.

Through our manufacturing partners, we have manufactured the PBGM01 clinical supply and have established a clinical supply chain to support global clinical trials.

This data, supplemented with data from retrospective studies, will be used to construct natural history patient profiles for comparison to the profiles of treated participants in our planned Phase 1/2 clinical trial.

Regulatory Designations

The FDA has granted ODD, RPDD, and Fast Track Designation to PBGM01 for the treatment of GM1.

The European Commission has granted Orphan designation and Advanced Therapy Medicinal Product, or ATMP, designation for PBGM01.

Clinical Supply

Through our manufacturing partners, we have manufactured the PBGM01 clinical supply and have established a clinical supply chain to support our ongoing clinical trial activities.

Overview of FTD-GRN

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• Cross-correction:

Following treatment with PBFT02, we believe overexpressing PGRN in a subset of cells in the CNS could provide a source of secreted protein that could be taken up by surrounding cells, resulting in the potential for cross-correction and broad restoration of neuronal lysosomal function across the entire brain.

Following treatment with PBFT02, overexpressing PGRN in a subset of cells in the CNS could provide a source of secreted protein that could be taken up by surrounding cells, resulting in the potential for cross-correction and broad restoration of neuronal lysosomal function across the entire brain.

• Biomarkers:

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• Preclinical Validation:

In our preclinical studies in GRN knockout mice, or GRN -/- mice, ICV administration of PBFT02 resulted in increased levels of PGRN in the CNS and CSF, with resolution of lysosomal storage lesions.

In our preclinical studies in GRN knockout mice, or GRN -/- mice, ICV administration of PBFT02 resulted in increased levels of PGRN in the CNS and CSF, with resolution of lysosomal storage pathology.

ICM administration in NHPs, which do not have the disease phenotype, resulted in robust increases in PGRN levels in CNS and CSF.

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The goal of this vector and delivery approach is to provide higher than normal levels of PGRN to the CNS to overcome the progranulin deficiency in GRN mutation carriers, who have been observed to have reduced CSF PGRN levels ranging from 30% to 50% of the PGRN levels observed in normal, mutation non-carriers.

We selected the AAV1 capsid and ICM administration route due to the widespread and robust expression of the human PGRN transgene observed throughout the brain and spinal cord in NHP studies, and because levels of human PGRN in the CSF exceeded those measured in healthy human CSF (greater than 50 times), and those in NHPs that received AAV5 or AAVhu68 serotypes (greater than 5 times).

We selected the AAV1 capsid and ICM administration route due to the widespread and robust expression of the human PGRN transgene observed throughout the brain and spinal cord in NHP studies.

Following AAV1 administration in NHP levels of human PGRN in the CSF achieved supraphysiologic levels compared to those measured in healthy human CSF and exceeded PGRN levels observed in NHPs that received AAV5 or AAVhu68 serotypes by greater than 5 times.

Preclinical studies

PBFT02 was selected as our development candidate based on initial proof-of-concept studies utilizing AAVhu68 and follow-up studies comparing multiple vector constructs for ability to elevate PGRN.

The initial proof-of-concept studies using an AAVhu68.hGRN construct in GRN knockout (GRN -/-) mice showed PGRN elevations and improved lysosomal function after vector doses that elevated CSF PGRN to approximately 10-fold over levels in healthy human controls and decreased deposits of lipofuscin, an electron dense marker of lysosomal dysfunction, broadly across the brain.

The AAV1 capsid was selected for PBFT02 following a study that evaluated the expression of human PGRN protein in the CSF of adult NHPs after ICM administration of four different vector constructs.

PBFT02 was selected as our development candidate following a study in adult NHPs which evaluated the expression of human PGRN protein in the CSF after ICM administration of four different vector constructs.

The AAV1 vector construct produced supraphysiological levels of PGRN and greater than 5 times higher than the other vectors tested, as shown below.

ICM AAV1 did not strongly transduce the liver or significantly elevate levels of circulating PGRN, which may reduce the potential for unknown peripheral effects of PGRN.

Proof of concept findings were published by GTP in 2020.

The comparison of AAVs in NHPs is shown in the figure below.

NHPs received a single ICM administration of commensurate doses of AAV1, AAV5, or AAVhu68 expressing the human GRN transgene with a CAG promoter (n=2/group).

A second tested AAVhu68 vector, or v2, utilized a different GRN coding sequence and a UBC promoter.

We found that the production of PGRN protein in the CSF rapidly exceeded levels found in healthy human control samples (“normal” line) in all AAV- treated NHPs .

AAV1 produced 50 times normal and greater than 5-10 times all other vectors tested.

Comparison of Vector Serotypes:

Production of Human PGRN-protein in CSF of NHPs following ICM-AAV administration.

Lower limit of quantitation, or LLOQ;

Healthy human control level, or Normal

We believe PBFT02 has the potential to provide supra-physiological levels of progranulin available to neurons broadly throughout the brain, restoring lysosomal function and thereby slowing or stopping the progression of FTD pathogenesis.

Further, ICM AAV1 did not strongly transduce the liver or significantly elevate levels of circulating PGRN, which may reduce the potential for unknown peripheral effects of PGRN.

The efficacy of the AAV1 vector was assayed in GRN -/- mice.

PBFT02 was administered via ICV delivery to adult mice at an age when lipofuscin deposition, lysosomal enzyme abnormalities, and neuroinflammation were present in brain regions involved in FTD-GRN pathophysiology including the frontal cortex, hippocampus, and thalamus.

This stage of disease progression was selected to be consistent with the developmental stage of the intended patient population of young to middle-aged adult.

Dose-dependent increases in human PGRN expression in the CSF following PBFT02 administration led to the correction of histopathologic and enzymatic changes in the mice.

Benefits included a reduction in the accumulation of lipofuscin, reduced neuroinflammation, and elevated lysosomal hexosaminidase activity in key brain regions.

The efficacy of the AAV1 vector was assayed in a dose-ranging study in GRN -/- mice.

PBFT02 was administered via ICV delivery to adult mice at an age when lipofuscin deposition (a marker of lysosomal dysfunction), lysosomal enzyme abnormalities, and neuroinflammation were present in brain regions involved in FTD-GRN pathophysiology.

Human PGRN expression in the CSF increased in a dose-dependent manner following PBFT02 administration.

Transgene expression led to improvements in histopathologic and enzymatic changes in key brain regions in the mice, including a reduction in the accumulation of lipofuscin and reduced neuroinflammation (as shown in below figure), and elevated lysosomal hexosaminidase activity.

NHP Toxicology Study

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Vector distributed to the CSF and high levels of gene transfer were detected in the brain, spinal cord and DRG at Day 90.

The quantity of vector genomes detected in CNS tissues was generally dose-dependent.

PBFT02 also reached significant concentrations in the peripheral blood, liver and spleen.

PBFT02 vector DNA was detectable in urine and feces 5 days post-administration and was undetectable within 60 days.

Human PGRN was detectable in CSF and serum in all animals by 7 to 14 days after PBFT02 administration, peaking between Days 14 to 28, and was generally dose dependent.

Expression declined in all PBFT02-treated animals by Day 60, correlating with the appearance of antibodies against the human transgene product, which are

not expected to develop in haploinsufficient patients with FTD-GRN.

ICM PBFT02 administration to NHPs resulted in approximately 15-times higher PGRN levels in CSF than in CSF from healthy humans, while the low dose of PBFT02 resulted in approximately 7-times higher PGRN levels.

Pre-existing NAbs to the vector capsid were detected in the serum of 2 of 9 AAV-treated animals at baseline but did not appear to influence gene transfer to the brain and spinal cord, although their presence correlated with reduced hepatic gene transfer.

We believe that these data support the possibility of achieving supraphysiological PGRN levels in the CNS of FTD patients following ICM administration of PBFT02.

PBFT02 resulted in asymptomatic degeneration of DRG and TRG sensory neurons (8 of 9 AAV-treated animals), along with their associated central and peripheral axons (9 of 9 animals) at Day 90 post-administration.

The severity of these lesions was typically minimal to mild, with a trend to more severe lesions in the mid-dose and high-dose groups.

One PBFT02-treated animal exhibited a peripheral nerve conduction impairment in the median nerve, as detected by bilateral reductions in SNAP amplitudes on Day 28 and Day 90, that appeared to be treatment related as severe axon loss and endoneurial fibrosis were detected at necropsy.

PBFT02-induced SNAP changes and sensory neuron degeneration were not associated with any clinical or neurological abnormalities in animals up to 90 days post-dose.

In summary, based on our preclinical studies we believe that CSF delivery of PBFT02 has the potential to sufficiently increase extracellular PGRN levels in the CNS to overcome intracellular PGRN deficiency, without greatly increasing peripheral PGRN levels.

Human PGRN was detectable in CSF and serum in all animals by 7 to 14 days after PBFT02 administration, peaking between Days 14 to 28.

Responses were generally dose dependent and resulted in supraphysiologic PGRN levels after the 2 highest doses.

Expression declined by Day 60, correlating with the appearance of antibodies against the human transgene product, which are not expected to develop in haploinsufficient patients with FTD-GRN.

Mild to minimal grade transient degeneration of DRGs and TRGs, and associated sensory nerve axonopathy, were observed in all PBFT02 dose groups.

These histopathologic observations were not linked with any clinical or neurological abnormalities in any animals up to 90 days’ post-dose.

One PBFT02-treated animal exhibited a peripheral nerve conduction impairment in the median nerve, as detected by bilateral reductions in sensory nerve action potential, or SNAP, amplitudes on Day 28 and Day 90, that appeared to be treatment related as severe axon loss and endoneurial fibrosis were detected at necropsy.

PBFT02-induced SNAP changes and sensory neuron degeneration were not associated with any clinical or neurological abnormalities in any animals up to 90 days post-dose.

In summary, our preclinical studies demonstrated that CSF delivery of PBFT02 has the potential to safely increase extracellular PGRN levels in the CNS up to supraphysiologic levels and has the potential to improve histopathologic and enzymatic changes in key brain regions associated with FTD.

Clinical development

Our clinical development plan is to treat FTD-GRN with a single dose of PBFT02 via ICM administration, with our initial clinical trial focused on early symptomatic FTD patients who have the GRN mutation.

We expect to dose the first patient in our initial cohort of our upliFT-D Trial in early 2022.

This trial is expected to be a two-cohort dose-escalation trial, with three subjects per cohort, and with a potential for a third higher-dose cohort, if considered necessary based on the results of the first two cohorts .

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The primary endpoint of the trial is to assess safety and tolerability over 60 months.

To better understand the clinical significance of the peripheral nerve findings in NHPs, we implemented clinical monitoring in our uplift-D interventional trial, consisting of both nerve conduction studies and neurological exams focused on sensory and peripheral nerve function.

Secondary endpoints are to assess change from baseline to 24 months on biomarkers, including CSF and plasma progranulin levels, biomarkers of neurodegeneration and disease progression, and on clinical outcomes as measured by the Clinical Dementia Rating, or CDR, for improving evaluation of patients with frontotemporal lobar degeneration, or FTLD, or CDR ® , plus NACC FTLD, and other neurocognitive assessments.

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Feedback was also obtained from other regulatory agencies outside the United States.

In August 2022, we dosed the first patient in our upliFT-D trial.

We expect to report initial safety and biomarker data from patients in Cohort 1 in the second half of 2023.

Depending on the results from the initial cohorts, we plan to obtain input from regulatory agencies on the requirements to submit for regulatory approval for commercialization in the United States and internationally.

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The FDA has granted ODD and Fast Track Designation to PBFT02 for the treatment of FTD-GRN and the European Commission granted Orphan designation for PBFT02.

Through our manufacturing partners, we have manufactured the PBFT02 clinical supply to support clinical trial initiation.

Krabbe disease—PBKR03

Overview of Krabbe disease

Krabbe disease is a rare and often life-threatening lysosomal storage disease that presents early in the patient’s life, resulting in progressive damage to both the brain and PNS.

Infants may present with extreme irritability and excessive crying, feeding difficulties, fisted hands, poor head control, stiffness and arching.

The early infantile form of Krabbe disease typically manifests before six months of age and is the most severe form, accounting for 60% to 70% of Krabbe disease diagnoses.

In these patients the disease course is highly predictable and rapidly progresses to include loss of acquired milestones, staring episodes, apnea, peripheral neuropathy, severe weakness, unresponsiveness to stimuli, seizures, blindness, deafness and death by two years of age.

Late infantile patients present symptoms that are similar to those of early infantile Krabbe disease, with a median survival of approximately five years from onset of symptoms.

Late infantile Krabbe disease is defined by onset between seven to twelve months of age.

It comprises approximately 10% to 30% of cases and exhibits greater variability in clinical presentation.

The myelin-producing cells in the CNS and PNS are particularly sensitive to the accumulation of psychosine, resulting in widespread death of these cell populations.

Without myelin, nerves in both the brain and other parts of the body cannot transmit signals properly, leading to the signs and symptoms of Krabbe disease.

There are currently limited treatment options for patients with Krabbe disease.

While human stem cell transplant, or HSCT, has become standard of care in many centers in the US for early infantile Krabbe patients who are pre-symptomatic or who have mild symptoms, it has limited use outside the US and is a treatment with limitations.

Most HSCT-treated children still have progressive gross motor delays ranging from mild spasticity to inability to walk independently, and limited use of their upper extremities.

There is also a narrow window of treatment and a donor must be identified.

When performed after the onset of overt symptoms in these patients, HSCT provides only minimal neurologic improvement and does not substantially improve survival.

Currently, ten states conduct mandatory screening for Krabbe disease and an additional four states passed legislation to include Krabbe disease in mandatory screening, but such screening has not yet been added.

We engaged a third-party data analytics firm to conduct an analysis of screening data from six states with screening history available to our third-party data analytics firm and based on this evaluation of screening data, we believe the incidence of Krabbe disease to be approximately 2.6 in 100,000 births.

Program Selection

We chose infantile Krabbe disease as one of our initial lead programs because we believe we can develop product candidates with a higher probability of technical and regulatory success.

The indication presents cross-correction, biomarker data and preclinical validation that are supportive of advancing treatments for Krabbe disease into the clinic.

• Cross-Correction:

Following treatment with PBKR03, newly synthesized galactosylceramidase is expected to be secreted by transduced cells and provide a source of secreted protein that could be taken up by surrounding cells, resulting in the potential for cross-correction and broad CNS and PNS enzyme replacement.

• Biomarkers:

There are known biomarkers in Krabbe disease that are measurable and available to assist in drug development.

o Pharmacodynamic biomarkers.

GALC activity has been shown to be reduced in patients with Krabbe disease and can be measured in CSF and plasma.

Psychosine levels are also measurable and elevated in patients with Krabbe disease.

We will measure these biomarkers in CSF and plasma to assess the efficiency of transduction and restoration of GALC activity by PBKR03.

o Disease progression biomarkers.

We will leverage a number of neuroimaging, electrophysiological and fluid biomarkers to assess treatment effects on disease progression, including CNS myelination as measured by diffusion-tensor MRI, nerve conduction velocity, or NCV, to assess peripheral nerve myelin and conduction, and visual and brain stem-evoked potentials to assess CNS myelination and conduction.

• Preclinical validation:

In preclinical studies in a mouse model of Krabbe disease, CSF delivery of PBKR03 resulted in GALC expression levels in the CNS that rescued motor function and improved survival.

CSF delivery in mice also reduced peripheral nerve demyelination and globoid cell infiltration.

Our Product Candidate

We are developing PBKR03 to treat infantile Krabbe disease, the most common and severe form of Krabbe disease.

PBKR03 utilizes a next-generation AAVhu68 capsid to deliver DNA encoding the GALC enzyme to a patient’s cells.

PBKR03 will be administered as a single dose by ICM administration into the CSF.

The AAVhu68 capsid and ICM route of administration were selected for PBKR03 due to observations in preclinical studies of robust transduction of targeted cells in the brain, and in DRG sensory neurons and spinal cord lower motor neurons.

Consequently, we believe that ICM PBKR03 has the potential to improve both the CNS pathologies and the significant peripheral neuropathies observed in many Krabbe disease patients.

Preclinical studies

Our Krabbe clinical program for PBKR03 is supported by robust pre-clinical proof of concept and pharmacology data in a naturally occurring GALC mutant mouse line, or Twitcher mice, in dogs with spontaneous GALC mutations, and in wildtype NHPs.

Preclinical data were presented by GTP in 2020 to the American Society of Gene & Cell Therapy’s, or ASGCT, 24th Annual Meeting and by us in 2021 at the 3rd Annual Gene Therapy for Neurological Disorders Congress.

To assess dose-dependent effects of PBKR03 in Twitcher mice, vector was administered via ICV delivery at the age of onset of peripheral demyelination.

PBKR03 dose-dependently improved histopathological, biochemical, and clinical disease signs.

The outcomes included increased GALC activity in the brain, serum, and in peripheral organs, which was associated with a significant reduction in histopathological markers of peripheral nerve damage including demyelination and globoid cell infiltration.

Related functional improvements included reductions in clinical symptoms as assessed by scores of neurological decline and improvements in motor balance, coordination, and activity.

PBKR03 administration to Twitcher mice also prevented the onset of lymphopenia, which often accompanies autonomic axon degeneration and significantly extended survival.

A preclinical study in Krabbe-affected dogs, or Krabbe dogs, evaluated treatment with an AAVhu68 vector containing a codon-optimized canine GALC cDNA, or vehicle, administered directly to the CSF using ICM administration.

Krabbe dogs express naturally occurring autosomal recessive mutations in the GALC gene that result in residual enzymatic activity close to 0%, which is similar to GALC activity levels observed in patients with the infantile form of Krabbe disease.

Four Krabbe dogs received a single ICM administration of PBKR03 at two to three weeks of age, while two age-matched Krabbe dogs and one wildtype dog received vehicle by the same route and served as controls.

AAV administration led to significant improvements in outcome measures in the Krabbe dogs.

The two vehicle-treated Krabbe dogs reached the study’s pre-defined humane endpoint of severe hind limb weakness and inability to stand and walk on Study Day 35 or Day 66, consistent with the rapidly progressing natural history of the disease.

In contrast, all of the four PBKR03-treated dogs maintained normal motor function for the duration of the study, and none reached the pre-defined humane endpoint associated with hindlimb weakness.

Two of the AAV-treated

dogs were euthanized at the scheduled necropsy timepoint of 28 weeks, and the remaining two were euthanized at 39 and 82 weeks of age, respectively.

One treated dog was euthanized following a suspected seizure at 39 weeks.

Prior to seizure, the animal exhibited normal phenotype including normal motor function.

Another of the AAV-treated dogs was euthanized at 82 weeks of age due to body weight loss following recurrent vomiting and regurgitation.

AAV-treatment elevated CSF GALC enzyme activity to above baseline levels by 28 days post-treatment in all dogs and maintained activity above that in vehicle-treated wildtype dog levels for the duration of the study, including up to 82 weeks in the longest-lived animal.

The pathological impact of GALC elevations was assessed by measuring the accumulation of the GALC substrate psychosine in CSF.

In the absence of GALC in Krabbe disease the cytotoxic substrate psychosine accumulates in the nervous system affecting oligodendrocytes and Schwann cells, leading to progressive demyelination.

Psychosine was undetectable in the CSF of vehicle-treated wildtype dogs from Day 0 through Day 180 post treatment.

In the vehicle-treated Krabbe dogs, while psychosine was undetectable in the CSF at baseline (Day 0), levels were elevated in both animals by Day 28 and increased further prior to their humane endpoints.

Elevations in psychosine correlated with the onset and progression of neurological symptoms in the vehicle-treated Krabbe dogs.

In contrast, psychosine was undetectable at most time points for all four AAV-treated Krabbe dogs.

In the histological analysis, both vehicle-treated Krabbe dogs showed demyelination and globoid cell infiltration in the brain, spinal cord and peripheral nerves at post-mortem.

In contrast, all four AAV-treated Krabbe dogs showed no evidence of demyelination or globoid cell infiltration in the spinal cord, and reduced levels of each in the brain and in peripheral nerves.

AAV treatment also resulted in functional improvements in the Krabbe dogs.

In vehicle-treated Krabbe dogs, NCV in sensory and motor nerves was markedly impaired at the earliest assessment age of 6 weeks.

In contrast, in AAV-treated dogs, NCVs were similar to those in the wildtype control dog for the duration of the study, assessed up to 81 weeks of age in the longest-surviving dog.

Since hearing loss is common during Krabbe disease progression, animals’ hearing thresholds were evaluated by the Brainstem Auditory Evoked Response, or BAER, test.

One vehicle-treated Krabbe dog had a severe hearing impairment by 6 weeks of age with no determinable hearing threshold (> 90 dB), while the other vehicle-treated Krabbe dog was not hearing-impaired with a threshold similar to that in the wildtype dog.

All the treated Krabbe dogs had hearing thresholds similar to the vehicle-treated wildtype dog for the duration of the study, up to 81 weeks of age in the oldest dog.

In clinical pathology assessments, three AAV-treated Krabbe dogs presented with a mild and transient lymphocytosis two weeks post-injection.

This finding was considered possibly treatment-related as it was not observed in the vehicle-treated Krabbe or wildtype animals.

It was not considered adverse due to the low grade of elevation and its transient nature.

No vector-related modifications of coagulation parameters or serum clinical chemistry were detected.

Two AAV-treated Krabbe dogs presented transient mild CSF mononuclear pleocytosis 4 weeks post-injection.

This finding was vector-related and was not considered adverse as it resolved by 10 weeks post-injection and was not accompanied by any neurological signs.

NHP Toxicology Study

A 180-day GLP compliant toxicology study conducted in NHPs assessed the safety, tolerability, biodistribution and excretion profile of PBKR03 following ICM administration at three dose levels.

There were no blood or CSF abnormalities related to PBKR03 administration except for asymptomatic, mild, and transient increases in CSF leukocytes in the majority of animals .

PBKR03 was well-tolerated at all doses evaluated and no adverse effects were detected on body weight or clinical, neurological, or behavioral signs.

PBKR03 vector DNA was detectable in urine and feces 5 days post-administration, and was undetectable in urine within 60 days and in feces within 90 days in the majority of animals.

Human GALC expression, as measured by enzyme activity, was evaluated in CNS tissues and major organs of the AAV-treated NHPs, however detection was limited by the inability of the assay to distinguish between human and rhesus GALC activity and the high endogenous activity in NHPs.

Measurements were feasible in NHP CSF and serum, however, due to substantially lower endogenous GALC activities.

GALC activity was elevated in CSF and serum by 7 days after PBKR03 administration.

After the two higher doses, animals had CSF GALC activities

about 2-times higher than vehicle-treated animals.

In serum, GALC activity was increased approximately 2-times (low dose) to 6.6-times (high dose) over activity in vehicle-treated animals.

A rapid decline in serum GALC activity was observed after Day 14, which correlated with the onset of anti-human GALC antibody expression around Days 14 to 21.

The presence of pre-existing NAbs to the vector capsid in the serum of 11 of 18 AAV-treated animals did not appear to impact GALC activity in the serum or CSF, supporting the potential to achieve therapeutic transgene expression in Krabbe patients regardless of NAb status.

PBKR03 administration resulted in asymptomatic degeneration of primarily DRG sensory neurons along with their associated central and peripheral axons by Day 90 post-administration.

The severity of the lesions was typically minimal to mild, with a trend to more severe lesions in the mid-dose and high-dose groups.

DRG lesions did not progress between Day 90 and Day 180.

One animal in the high dose group exhibited a unilateral nerve conduction impairment in a median nerve, as detected by reduced SNAP amplitude on Day 28 and Day 90, that appeared to be treatment related as median nerve axonopathy and endoneurial fibrosis were detected at necropsy.

PBKR03-induced SNAP changes and sensory nerve degeneration were not associated with any clinical or neurological abnormalities in any animals up to 180 days post-dose.

In summary, based on our preclinical studies we believe that CSF delivery of PBKR03 has the potential to sufficiently increase GALC levels in both the CNS and in peripheral tissues to overcome intracellular GALC deficiency in Krabbe disease.

Clinical development

Our clinical development plan is to start with trials in early infantile Krabbe disease, and if successful, consider further exploration of expansion of the indication with trials in later onset forms of Krabbe disease.

We expect to dose the first patient in our initial cohort of our GALax-C Trial in early 2022.

We believe that gene replacement with PBKR03 has the potential to have meaningful clinical benefit to Krabbe patients by significantly reducing neuronal demyelination and damage in both the CNS and PNS that results from the accumulation of galactolipids, such as galactocerebroside and psychosine.

We will measure clinical benefit by assessing developmental using accepted clinical scales, observer-reported outcomes and video recordings.

We intend this trial to have two independent dose escalation cohorts (three subjects per dose) based on age at enrolment:

dosing initially in subjects > 4 and < 9 months of age, with dose escalation and initiation of dosing in subjects > 1 and < 4 months of age gated by safety in cohort 1.

Planned starting doses for each cohort will exceed the MED in the twitcher mouse model, starting with an initial low dose of 1.5 x 10˄11 GC/g estimated brain weight with planned escalation to a high dose of 5.0 x 10˄11 GC/g estimated brain weight , followed by a third confirmatory cohort using a dose selected on the basis of results from previous cohorts .

The primary endpoint of the trial is to assess safety and tolerability over 60 months.

Secondary endpoints are to assess change from baseline to 24 months on biomarkers, including CSF and plasma GALC activity and psychosine, and biomarkers of disease progression, and on clinical outcomes, as assessed using by the Bayley Scale of Infant and Toddler Development, and other developmental scales.

Interim analyses are planned for certain biomarkers starting at one month post dosing.

All subjects will be evaluated over two years for safety and efficacy, followed by an additional 36 months of long-term follow up.

In collaboration with Penn’s ODC, we are also currently planning to develop comparator data sets for our Krabbe clinical trial.

Clinical understanding of Krabbe disease has been summarized in several case studies and natural history studies.

Based on the results from this Phase 1/2 trial, we plan to obtain input from regulatory agencies on the requirements to submit for regulatory approval for commercialization in the United States and internationally.

Regulatory Designations and Clinical Trial Approvals

The FDA has granted ODD, RPDD, and Fast Track Designation to PKBR03, and the European Commission granted Orphan designation for PBKR03.

Through our manufacturing partners, we have manufactured PBKR03 clinical supply to support clinical trial initiation.

Trigeminal Ganglia and Dorsal Root Ganglia Toxicity

The primary finding of the NHP toxicology studies for each of PBGM01, PBFT02 and PBKR03 was TRG and DRG toxicity with consequent peripheral and spinal cord axonopathy.

These findings have been previously reported as an AAV platform risk based on NHP studies in which minimal to mild DRG toxicity was observed within 14 to 30 days after dosing, without clinical manifestations.

Chronic studies examining DRG toxicity have revealed no increase in severity and no clinical manifestations at four to six months or up to four years after administration.

Similarly, no clinical manifestations were observed in any animals on detailed neurological examinations or daily observations in the PBGM01 and PBFT02 toxicology studies.

We believe the asymptomatic sensory neuron findings observed in NHPs treated with AAV vectors via the ICM administration route likely represent a universal DRG pathology in NHPs administered AAV gene therapy.

Published data have shown that the administration of AAV vectors to NHPs via the blood or CSF can lead to damage of dorsal root ganglia and their associated axons.

Similar findings were observed following IV administration of an engineered variant of AAV9.

More recently, a meta-analysis of 33 non-clinical studies in 256 NHPs evaluated the severity of DRG pathology for five different capsids, five different promoters, and 20 different transgenes including an AAV9 vector expressing antibodies 170 days after ICM administration, while also comparing different ROAs, doses, time courses, study conduct, animal age, and sex.

This meta-analysis showed that mostly minimal to moderate asymptomatic DRG pathology characterized by mononuclear cell infiltrates, neuronal degeneration, and secondary axonopathy of central and peripheral axons were observed for all capsids and promoters tested, including 83% of NHPs administered AAV intrathecally and 32% of NHPs administered AAV intravenously.

DRG pathology was absent prior to 14 days post administration, was similar from 1-5 months post-injection, and was less severe after 6 months.

The transgene appeared to have the greatest impact on the severity of the sensory neuron pathology, suggesting that transgene overexpression drives the early events leading to neuronal degeneration.

Higher AAV doses correlated with increased severity.

Infant and juvenile NHPs appeared to exhibit less severe pathology compared to adult NHPs.

Animal sex and vector purification method had no impact.

Sensory nerve conduction studies detected abnormalities in a minority of animals correlating with a greater severity of peripheral nerve axonopathy.

For most studies, it was not possible to identify a no-observed-adverse-effect-level above the MED.

To date, the NHP studies examining DRG toxicity have revealed no clinical manifestations at four to six months or up to four years after administration.

To better understand the clinical significance of these findings, we plan to implement clinical monitoring in our GM1, FTD and Krabbe disease interventional trials, consisting of both nerve conduction studies and neurological exams focused on sensory and peripheral nerve function.

GTP has recently published data on certain technology regarding microRNA-mediated inhibition of transgene expression reduces DRG toxicity by AAV vectors.

We plan to work with GTP to evaluate the appropriateness of incorporating this technology into our research programs, but do not expect to incorporate this early-stage technology into our current three clinical programs for GM1, FTD or Krabbe.

We have access to this technology as part of our collaboration with GTP, whereby we have access to novel capsids, toxicity reduction technologies and delivery and formulation improvements.

Overview of MLD – PBML04

MLD is a monogenic autosomal recessive sphingolipid storage disease caused by mutations in the ARSA gene encoding the lysosomal enzyme arylsulfatase A, or ARSA.

Reduced ARSA activity leads to the progressive build-up of toxic sulfatides in neurons and glia in the central and peripheral nervous systems.

Neuronal cell death ensues with subsequent loss of motor and cognitive function, which is more severe and progresses faster in patients with early disease.

We are targeting infantile-onset MLD, which is characterized by progressive muscle weakness, rigidity and gait abnormalities, developmental delays, and is typically fatal by 5 years of age.

Estimations of worldwide prevalence of infantile-onset MLD vary within the range of 1 in 40,000 to 1 in 160,000 live births.

Our Product Candidate

We are developing PBML04, an AAVhu68 capsid expressing codon-optimized human ARSA , for ICM administration to increase the expression of ARSA in the CNS and periphery.

We expect to submit an IND application in mid-2022.

Preclinical Studies

PBML04 preclinical preliminary efficacy studies utilized a novel mouse strain developed using CRISPR/Cas9 gene deletion, by GTP in conjunction with Jackson Labs, which was presented at the 2021 ASGCT conference.

ARSA -/- mice develop a phenotype that recapitulates aspects of MLD from 9-10 months of age, including clinical deficits such as weight, balance, coordination, and gait deficiencies, sulfatide accumulation in central and peripheral neurons, lysosomal abnormalities, and increased neuro-inflammation.

In a preclinical study PBML04 treatment restored depleted ARSA activity in the brain and periphery.

In a 15 month-long study comparing three doses of PBML04 administered via ICV, functional improvements were shown in ARSA -/-, mice including significant improvements in an assessment of clinical motor performance and health, or the Neuroscore assay.

Further, while only 5 out of 10 of vehicle-treated ARSA -/- mice survived to the study endpoint 15 months post-treatment, all 30 PBML04-treated mice, which represents 10 per dose group, survived at the study end.

We are in the process of completing analysis on additional endpoints.

ARSA-/- Mouse Neuroscore

As shown in the figure below, four to five-month-old ARSA -/- mice or wildtype control mice were enrolled and scored on five parameters of clinical health and performance at baseline and at monthly intervals thereafter for 15 months.

The groups approximated to baseline age of five months for graphing.

The Neuroscore assay reflected the cumulative extent of impairment, generated by summing deficit scores of none to severe in five different parameters, including, posture, tremor, hind-limb clasping, gait and mobility, and grooming.

Maximum possible cumulative score was 17.

On Day 0 mice received PBML04 at one of three doses, which were low, medium, or high, or a vehicle control (n = 10 per group).

Data points show mean Neuroscores with standard error of the mean.

Wildtype mice showed little decline in Neuroscore assay up to 20 months of age, while vehicle-treated ARSA-/- mice showed a progressive decline over the 15-month study.

Onset and rate of decline in cumulative score was delayed and less severe in PBML04-treated ARSA-/- mice, and high dose-treated mice showed the least decline.

*** p < 0.001, statistically significant difference compared with vehicle-treated ARSA -/- mice (mixed effect model).

Abbreviations:

KO, ARSA -/- knockout mouse;

WT, wildtype mouse;

LD, low dose;

MD, mid dose;

HD, high dose.

Clinical Supply

Through our manufacturing partners, we have manufactured the PBFT02 clinical supply to support ongoing clinical trial activities.

Other Research Programs

We have five additional programs in candidate selection or discovery stages of preclinical research, in collaboration with GTP.

These include PBAL05 for ALS, PBCM06 for CMT2A, and our unnamed programs for Canavan disease, Parkinson’s disease and Huntington’s disease.

We have two additional programs in candidate selection or discovery stages of preclinical research, in collaboration with GTP.

These include PBAL05 for ALS and our unnamed program for Huntington’s disease.

Overview of C9orf72 ALS - PBAL05

C9orf72-mediated Amyotrophic Lateral Sclerosis, or C9orf72 ALS, is an adult-onset, rapidly progressing neurodegenerative disease characterized by dysfunction and death of upper and lower motor neurons leading to progressive weakness, loss of motor function, and death typically within three to five years of disease onset.

Most cases of ALS are sporadic with an unknown etiology, but approximately 10% of patients have autosomal dominantly inherited forms.

Most cases of ALS are sporadic with an unknown etiology, but approximately 10% of patients have autosomal

dominantly inherited forms.

We are focusing on C9orf72-mediated ALS, since mutations in the C9orf72 gene are the most common mutation found in ALS patients including both familial (approximately 40% of familial ALS cases) and sporadic ALS cases (approximately 8% of sporadic ALS patients carry C9orf72 mutations), accounting for approximately 11% of all ALS cases.

In 2020, prevalence of C9orf72 mutations were estimated to affect approximately 5,000 ALS patients worldwide.

In 2021, the total number of prevalent C9orf72 ALS cases was estimated to be approximately 4,500 worldwide.

In these cases, the disease is caused by a hexanucleotide repeat expansion in the first intron of C9orf72.

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Our approach is to use a single AAV vector to deliver a miRNA and a codon-optimized miRNA-resistant C9orf72 transgene combination, to both deplete normal and mutant mRNA within cells with the miRNA and to replace with functional wildtype human transgene.

Preclinical pilot data showed that AAV-C9miRNA normalized elevated

toxic poly(GP) dipeptide repeat protein levels in mouse brains with a mutation in the C9-ALS gene.

This program is currently at the discovery stage.

Overview of CMT2A - PBCM06

CMT2A is a sensory and motor neuropathy caused by mutations in the gene encoding the mitochondrial protein mitofusin-2, or MFN2.

MFN2 is a GTPase that localizes to the outer mitochondrial membrane where it regulates mitochondrial fusion and mitochondrial binding to membranes of the endoplasmic reticulum.

CMT2A may present in childhood or adulthood, with progressive distal limb weakness, muscle atrophy, and loss of sensation.

Clinically, the classic form of CMT2A is characterized by physical weakness, foot deformities, difficulty in walking, and areflexia.

After early childhood onset, however, loss of ambulation by adulthood is common.

The worldwide prevalence is estimated to be approximately 1 in 100,000.

Our approach is to use a single AAV vector to deliver a miRNA and a codon-optimized miRNA-resistant MFN2 transgene combination, to both deplete normal and mutant mRNA within cells with the miRNA and to replace with a functional wildtype human transgene.

Preclinical pilot data identified lead construct that ameliorates distal limb weakness (grip strength) after ICV delivery in mice with a mutation in the MFN2 gene.

This program is currently at the discovery stage.

Unnamed Research Programs

With GTP we have three additional discovery stage preclinical programs, to develop genetic medicines for rare neurodegenerative disorders.

One, initiated in 2021, is a pediatric program to treat children with the inherited leukodystrophy Canavan's disease.

The other two programs address adult populations, one targeting a familial form of Parkinson's disease, and the other, which was also initiated in 2021, to treat Huntington's disease.

Programs are currently in discovery stages.

Unnamed Research Program

With GTP we have one additional specified research program, to develop a genetic medicine to treat Huntington’s disease.

This program, initiated in 2021, is currently in the discovery stage.

Beyond this portfolio, through our research collaboration with GTP, we also have the option to license programs for eight additional indications.

Exploratory Research Programs

We also have an exploratory research program with GTP with the goal to develop genetic medicines for non-rare CNS disorders, initially focused on AD and treatment-resistant TLE, which can be expanded to other large CNS diseases upon mutual agreement with GTP.

Exploratory Research Program

We have an exploratory research program with GTP with the goal of developing genetic medicines for non-rare CNS disorders.

The program is currently focused on treatment-resistant TLE, and can be expanded to other large CNS diseases upon mutual agreement with GTP.

Manufacturing

Gene therapy manufacturing is a critical factor in the successful development and commercialization of novel genetic medicines, and to that end, we have established a relationship with Catalent, a contract development and manufacturing organization, or CDMO, for our initial manufacturing needs.

Our gene therapy manufacturing strategy utilizes a production platform approach with HEK293 mammalian cells as the substrate, triple plasmid transient transfection and single-use fixed-bed iCELLis® bioreactor system for the manufacture of our AAV product candidates.

Gene therapy manufacturing is a critical factor in the successful development and commercialization of novel genetic medicines, and to that end, we have established internal CMC capabilities to support our vector manufacturing and production platform and we have a relationship with Catalent, a contract development and manufacturing organization, or CDMO, for our initial manufacturing needs.

We utilize a production platform approach with HEK293 mammalian cells as the substrate, triple plasmid transient transfection and single-use fixed-bed iCELLis® bioreactor system for the manufacture of our AAV product candidates.

We are using a well-characterized production platform that has been used for both commercial and clinical AAV products and product candidates.

We believe our approach will enable rapid development, control of product quality and regulatory compliance.

Catalent has extensive experience with the iCELLis® bioreactor platform and HEK293 transient transfection gene therapy manufacturing.

As part of our research collaboration with GTP, we have access to broad and deep early-stage process science capabilities and experience to enable technology transfer of scalable processes to our CDMO, and state-of-the art analytical capabilities for product quality testing and analytical characterization.

We have invested significantly in our internal laboratory capabilities and infrastructure to support the manufacturing of our clinical product candidates.

Our in-house laboratory is equipped with state-of-the-art analytical and process development capabilities to support and enhance our viral vector manufacturing platform.

We have developed the internal technical and scientific capability along with the manufacturing and quality expertise to develop, transfer, and oversee vector production systems externally at commercial scale.

We believe our capabilities provide a core strategic advantage and position us to be a leading drug development company to address CNS disorders.

GTP currently provides us with the preclinical and toxicology research-grade vector supplies, while Catalent provides us with the cGMP AAV clinical supplies for our clinical trials.

The production process for GM1, Krabbe, FTD and MLD has been scaled up to GMP standards at Catalent’s facility and clinical materials for these candidates have been or are being manufactured.

We have a collaboration agreement with Catalent, or the Collaboration Agreement, that gives us access to a dedicated manufacturing suite .

We initiated cGMP manufacturing in the dedicated suite, giving us the ability to

meet production requirements for our current clinical product candidates through clinical studies and early commercialization.

We believe that our platform manufacturing approach along with the dedicated manufacturing capabilities and capacity provide a core strategic advantage and positions us to be a leading drug development company to address CNS disorders.

We also have a development services and clinical supply agreement, or the Manufacturing and Supply Agreement, with Catalent to secure clinical scale manufacturing capacity for batches of active pharmaceutical ingredients for our gene therapy product candidates.

We entered into a lease to support chemistry, manufacturing and controls laboratory operations for our gene therapy programs, which commenced in March 2021 in Princeton West Innovation Campus.

The production process for our two lead clinical stage product candidates, PBGM01 and PBFT02, and for the two clinical stage product candidates for which we have stopped clinical development, PBKR03 and PBML04, has been scaled up to GMP standards at Catalent’s facility.

Clinical materials for these candidates have been manufactured.

We have a collaboration agreement with Catalent, or the Collaboration Agreement, that gives us access to a cGMP manufacturing suite .

Access to cGMP manufacturing capacity gives us the ability to meet production requirements for our current clinical product candidates supporting current and future clinical trials.

We also have a development services and clinical supply agreement, or the Manufacturing and Supply Agreement, with Catalent to support clinical scale manufacturing for our gene therapy product candidates.

We entered into a lease to support chemistry, manufacturing and controls laboratory operations for our gene therapy programs, which commenced in March 2021, in the Princeton West Innovation Campus.

In 2021, we completed our build out of this new laboratory that is initially focused on state-of-the-art analytical capabilities, assay development and validation, and clinical product testing to support both viral vector manufacturing and clinical development.

Since then, we have been able to internalize all major CMC laboratory capabilities, including process development, which will enable late-stage development and commercialization of our gene therapies.

We have advanced our manufacturing platform which can be leveraged across our clinical and pre-clinical pipeline through standardization of our manufacturing and analytical technologies.

We believe that our manufacturing capabilities provide us with the advantages of better control of drug development timelines, improved control of vector supply for a portfolio of clinical assets and improved control of product quality through the improvements of the manufacturing platform.

We also expect to open a pilot plant manufacturing suite at the Princeton West Innovation Campus to provide scale-up capabilities in support of our product pipeline and future development plans by the end of 2022.

We will continue to invest in developing our manufacturing capabilities and plan to establish our own manufacturing facility for long-term commercial supplies.

We also anticipate that we will continue to make significant investments to further optimize our manufacturing capabilities and platforms to produce high-quality, cost-effective AAV vectors and we will continue to make investments in process and analytical sciences, internally or with third parties, to evaluate and develop manufacturing process improvements that may increase the productivity and efficiency of our manufacturing platform processes.

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We may also face competition from large and specialty pharmaceutical and biotechnology companies, academic research institutions, government agencies and public and private research institutions with genetic medicine and other therapeutic approaches.

We consider our most direct competitors with respect to PBGM01 for the treatment of GM1 to be Sio Gene Therapies, Inc., or Sio, and Lysogene, S.A, or Lysogene.

Sio is conducting its clinical trial for an IV gene therapy treatment for early and late infantile/juvenile GM1 and reported data from ten patients in October 2021.

Lysogene, as of February 2022, reported having dosed three patients and enrolled a fourth patient in the safety cohort, after which Lysosgene will initiate treatment of twelve patients in the efficacy confirmatory cohort of its Phase 1/2 clinical trial for a gene therapy treatment administered via intracisternal magna for early and late infantile GM1.

We consider our most direct competitors with respect to PBGM01 for the treatment of GM1 to be Lysogene, S.A, or Lysogene, which is developing a gene therapy treatment administered via intracisternal magna for early and late infantile GM1.

As of February 2022, Lysogene reported having dosed three patients and enrolled a fourth patient in the safety cohort.

The National Institutes of Health is conducting a clinical trial for an IV gene therapy treatment for early and late infantile/juvenile GM1 and reported data from ten patients in October 2021.

There are also preclinical enzyme replacement therapies in preclinical development.

We consider our most direct competitors with respect to PBFT02 for the treatment of FTD-GRN to be Alector, Inc.

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(now part of Eli Lilly & Co), which has initiated a Phase 1/2 clinical trial for a gene therapy treatment for FTD-GRN, and is expected to continue enrolling through 2023.

Several other companies, including Applied Genetic Technologies Corporation, Orchard Therapeutics plc, AcuraStem Inc.

and Shape Therapeutics Inc., are conducting preclinical research using gene therapy approaches to treat FTD-GRN patients.

Several other companies, including AviadoBio Ltd, Applied Genetic Technologies Corporation (recently acquired by Syncona Limited), and Orchard Therapeutics plc, are conducting preclinical research using gene therapy approaches to treat FTD-GRN patients.

AviadoBio Ltd has reported the planned initiation of a phase 1/2 trial in 2023.

Denali Therapeutics Inc.

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We are also aware of other therapeutic approaches in preclinical development that may target FTD-GRN patients.

We consider our most direct competitor with respect to PBKR03 to be Forge Biologics Inc., which has an active clinical trial evaluating a Krabbe gene therapy candidate that combines bone marrow transplant and gene therapy.

In addition, Neurogene Inc.

has a gene therapy in pre-clinical development for Krabbe.

We are also aware of other therapeutic approaches in preclinical development and an ongoing natural history study being conducted by the Children’s Hospital of Pittsburgh and certain academic studies for Krabbe disease.

Many of our potential competitors, alone or with their strategic partners, have substantially greater financial, technical and other resources than we do, such as larger research and development, clinical, marketing and manufacturing organizations.

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Competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market, if ever.

Additionally, new or advanced technologies developed by our competitors may render our current or future product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors.

Additionally, new or advanced technologies

developed by our competitors may render our current or future product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors.

License Agreement

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We have a research, collaboration and licensing agreement, as amended, or the Penn Agreement, with Penn, for research and development collaborations and exclusive license rights to patents for certain products and technologies.

Under the Penn Agreement, we have the obligation to fund certain research relating to the preclinical development of selected rare, monogenic products in research programs as well as the new exploratory research program in non-rare and/or non-monogenic, or large, CNS indications, initially AD and TLE.

Under the Penn Agreement, we have the obligation to fund certain research relating to the preclinical development of selected products in research programs as well as the new exploratory research program in non-rare and/or non-monogenic, or large, CNS indications, initially TLE.

We also fund discovery research conducted by Penn through August 2026 and will receive exclusive rights, subject to certain limitations, to technologies resulting from the discovery program for products developed with GTP, such as novel capsids, toxicity reduction technologies and delivery and formulation improvements.

Our discovery research funding commitment is $5.0 million annually, paid in quarterly increments of $1.3 million through June 30, 2026.

Under the Penn Agreement, we have eight remaining options available to us to commence additional licensed programs for CNS indications until May 2026.

If we were to exercise any of these remaining options, we would owe Penn a non-refundable upfront fee of $1.0 million, with $0.5 million per product indication paid immediately and another $0.5 million fee owed upon achievement of a further developmental milestone.

The Penn Agreement requires that we make payments of up to (i) $16.5 million per product candidate for rare, monogenic disorders in the aggregate and (ii) $39.0 million per product candidate in the aggregate arising from the exploratory program for large CNS indications, initially AD and TLE and such other mutually agreed upon large CNS indications.

Our discovery research funding commitment is $5.0 million a year for five years, with quarterly payments of $1.3 million through June 2026.

Under the Penn Agreement we have eight remaining options available to us to commence additional licensed programs for CNS indications until August 2026.

If we were to exercise any of these remaining options, we would owe Penn a non-refundable aggregate fee of $1.0 million, with $0.5 million per product indication paid immediately and another $0.5 million fee owed upon a further developmental milestone.

The Penn Agreement requires that we make payments of up to (i) $16.5 million per product candidate for rare, monogenic disorders in aggregate and (ii) $39.0 million per product candidate in the aggregate arising from the exploratory program for large CNS indications, currently TLE and such other mutually agreed upon large CNS indications.

Each payment will be due upon the achievement of specific development milestone events by such licensed product for a first indication, reduced development milestone payments for the second and third indications and no development milestone payments for subsequent indications.

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At any time after August 2026, we may terminate the agreement in its entirety, or for a licensed product, for convenience upon 90 days’ prior written notice to Penn.

Penn may terminate the agreement on an indication-by-indication basis if we fail to meet any diligence event and fail to timely cure such breach, or the

agreement in its entirety if we fail to pay the research funding, fail to comply with applicable laws, grant a security interest in any of the licensed patent rights, fail to achieve certain financing obligations, or make certain challenges to the licensed patent rights.

Penn may terminate the agreement on an indication-by-indication basis if we fail to meet any diligence event and fail to timely cure such breach, or the agreement in its entirety if we fail to pay the research funding, fail to comply with applicable laws, grant a security interest in any of the licensed patent rights, fail to achieve certain financing obligations, or make certain challenges to the licensed patent rights.

Either party may terminate the agreement for the other party’s insolvency or material breach that is not cured within a specified period of time.

We entered into an amendment, or the Amendment, to the Penn Agreement, on August 3, 2021.

Under the Amendment, we expanded the scope of the collaboration to include certain non-rare and/or non-monogenic, or large, CNS indications, initially AD and TLE and such other mutually agreed upon large CNS indications;

included an exploratory research collaboration to identify targets and early product candidates in such large CNS indications;

and extended the term to August 3, 2026 by which product candidates for CNS indications may be selected for the entire agreement.

The exploratory research program is focused on discovering targets and novel gene therapy candidates for large CNS diseases, initially focused on AD and TLE, and that can be expanded to other large CNS diseases upon mutual agreement.

The initial term of the exploratory research program is 3 years, which term can be extended by mutual agreement.

In addition, we will pay Penn a tiered transaction fee ranging from 1-2% of the net proceeds upon certain change of control events.

The Penn Agreement includes an exploratory research collaboration to identify targets and early product candidates in such large CNS indications.

The exploratory research program is focused on discovering targets and novel gene therapy candidates for large CNS diseases, currently focused on TLE, and that can be expanded to other large CNS diseases upon mutual agreement.

The initial term of the exploratory research program is 3 years, or until August 2024, which term can be extended by mutual agreement.

During such term we will have an exclusive right of first negotiation to include additional targets to the exploratory research program in the agreed upon large CNS indications.

Under the exploratory research program, we will have the right to further develop and commercialize any gene therapy product candidates specific for those selected targets within AD and TLE (and any future large CNS indications that are mutually agreed upon) that arise from the exploratory research programs on substantially the same terms of the current Penn Agreement.

The election of any option to any such product candidates will count against our remaining eight options and will trigger the aggregate $1.0 million option fee.

As a result, we now will fund discovery research through August 3, 2026, and will now have until August 3, 2026 to exercise our remaining eight options.

We made an upfront payment of $5.0 million;

will reimburse Penn for expenses incurred in the exploratory research program;

and will pay Penn a tiered transaction fee ranging from 1-2% of the net proceeds upon certain change of control events.

Under the exploratory research program, we will have the right to further develop and commercialize any gene therapy product candidates specific for those selected targets within TLE (and any future large CNS indications that are mutually agreed upon) that arise from the exploratory research programs on

substantially the same terms of the current Penn Agreement.

In November 2022, we agreed with GTP to not continue further advancement of our exploratory research program in AD.

Penn will notify us of any patented manufacturing methods developed by GTP during the specified research term, and we have the option to obtain a non-exclusive license under those patent rights controlled by Penn for our licensed products.

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Additionally, we intend to rely on regulatory protection afforded through rare drug designations, data exclusivity and market exclusivity as well as patent term extensions, where available.

Currently, our patent protection consists of patent applications that we have in-licensed from Penn under the Penn Agreement for our product candidates in our licensed indications.

Currently, our patent protection consists of patent applications that we have in-licensed from Penn under the Penn Agreement for our product candidates in our licensed indications and a patent application that we filed and solely own related to a process for manufacturing our products.

The in-licensed patent applications are directed to new AAV capsids and certain defined variants, to recombinant AAV viruses, or rAAVs, capable of delivering certain genes into human cells to treat monogenic diseases of the CNS, to methods of treating those monogenic diseases with rAAV, as well as certain aspects of our manufacturing capabilities and related technologies.

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• two patent families with claims directed to an rAAV containing a coding sequence of human β-gal for use in treating GM1.

The first patent family includes pending applications in twenty-three jurisdictions, including the U.S., Argentina, Brazil, Canada, China, Europe, Israel, India, Japan, and Korea.

The first patent family includes pending applications in fourteen jurisdictions, including the U.S., Argentina, Brazil, Canada, China, Europe, Israel, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on September 30, 2039, absent any term adjustments or extensions.

The second patent family includes applications pending in Argentina, Pakistan, and Taiwan and a pending Patent Cooperation Treaty, or PCT, application.

Based on the PCT filing, national and regional patent applications may be filed in the United States and over 150 foreign jurisdictions.

Any patents that may issue from applications in this family are expected to expire on February 1, 2041;

• two patent families with claims directed to rAAV for use in treating Krabbe.

The first patent family includes pending applications in twenty-one jurisdictions, including the U.S., Argentina Brazil, Canada, China, Europe, Israel, India, Japan, and Korea.

The second patent family includes applications pending in sixteen jurisdictions, including the U.S., Argentina, Brazil, Canada, China, Europe, Israel, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on February 1, 2041, absent any term adjustments or extensions;

The second patent family includes applications pending in Argentina, Pakistan, and Taiwan and a pending PCT application.

Any patents that may issue from applications in this family are expected to expire in May 11, 2041;

• two patent families with claims directed to rAAV for use in treating FTD.

The first patent family includes applications pending in twenty one jurisdictions, including the US, Argentina Brazil, Canada, China, Europe, Israel, India, Japan, and Korea.

The first patent family includes applications pending in fifteen jurisdictions, including the US, Argentina Brazil, Canada, China, Europe, Israel, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on February 21, 2040, absent any term adjustments or extensions.

The second patent family includes applications in Argentina and Taiwan and a pending PCT application.

Any patents that may issue from applications in this family are expected to expire in August 2041;

• two patent families with claims directed to rAAV for use in treating MLD.

The first patent family includes applications pending in twenty four jurisdictions, including the US, Argentina Brazil, Canada, China, Europe, Israel, India, Japan, and Korea.

Any patents that may issue from applications in this family are expected to expire on May 4, 2040.

The second patent family includes one pending unpublished U.S.

provisional patent application.

Any patents that may issue from applications in this family are expected to expire in January 2043, absent any term adjustments or extensions ;

Any patents that may issue from applications in this family are expected to expire on August 26, 2041;

• one patent family with claims directed to rAAV for use in treating ALS.

The patent family includes one pending unpublished U.S.

provisional patent application.

Any patents that may issue from applications in this family are expected to expire in January 2043, absent any term adjustments or extensions.

The patent family includes applications pending in Argentina and Taiwan and a pending PCT application.

Any patents that may issue from applications in this family are expected to expire on January 10, 2043, absent any term adjustments or extensions.

We also have options under the Penn Agreement to add additional intellectual property to our existing license, as described in the section “License Agreement”.

To date, we have exercised an option with respect to Charcot-Marie Tooth disease, or CMT, Canavan disease, Parkinson’s disease, and Huntington’s disease .

At present, there are two patent families directed to these newly licensed indications:

• two patent families with claims directed to rAAV for use in treating CMT.

The first patent family includes a pending PCT application and applications pending in Argentina and Taiwan.

Any patents that may issue from applications in this family are expected to expire in July 13, 2041, absent any term

adjustments and extensions.

The second patent family includes two pending unpublished U.S.

provisional patent applications.

Any patents that may issue from applications in this family are expected to expire in September 2042.

The term of individual patents may vary based on the countries in which they are obtained.

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Government Regulation and Product Approval

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products.

The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

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The Federal Food, Drug, and Cosmetic Act, or the FDC Act, and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.

Biological products used for the prevention, treatment, or cure of a disease or condition of a human being are subject to regulation under the FDC Act, except the section of the FDC Act which governs the approval of New Drug Applications, or NDAs.

Biological products, such as gene therapy products, are approved for marketing under provisions of the Public Health Service Act, or PHSA, via a Biologics License Application, or BLA.

Biological products used for the prevention, treatment, or cure of a disease or

condition of a human being are subject to regulation under the FDC Act, except the section of the FDC Act which governs the approval of New Drug Applications, or NDAs.

Biological products, such as gene therapy products, are approved for marketing under provisions of the Public Health Service Act, or PHSA, via a BLA.

However, the application process and requirements for approval of BLAs are very similar to those for NDAs.

Failure to comply with applicable U.S.

requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to approve pending NDAs or BLAs,

warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.

requirements may subject a company to a variety of administrative or judicial sanctions, such as clinical hold, FDA refusal to file NDA/BLAs and to approve pending NDAs or BLAs, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties, and criminal prosecution.

Biological product development for a new product or certain changes to an approved product in the United States typically involves preclinical laboratory and animal tests, the submission to the FDA of an IND which must become effective before clinical testing may commence, and adequate and well-controlled clinical trials to establish the safety and effectiveness of the drug for each indication for which FDA approval is sought.

Satisfaction of FDA pre-market approval requirements typically takes many years and the actual time required may vary substantially based upon the type, complexity, and novelty of the product or disease.

Preclinical tests include laboratory evaluation of product chemistry, formulation, and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy of the product.

Preclinical tests include laboratory evaluation of product chemistry, formulation, and toxicity, as well as animal studies to assess the characteristics and potential safety and efficacy of the product.

The conduct of the preclinical tests must comply with federal regulations and requirements, including Good Laboratory Practices.

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Phase 2 usually involves trials in a limited patient population to determine the effectiveness of the drug or biologic for a particular indication, determine optimal dose and regimen, and to identify common adverse effects and safety risks.

If a compound demonstrates evidence of effectiveness and an acceptable safety profile in Phase 2 evaluations, Phase 3 trials are undertaken to obtain additional information about clinical effects and confirm efficacy and safety in a larger number of patients, typically at geographically dispersed clinical trial sites, to permit the FDA to evaluate the overall benefit-risk relationship of the drug or biologic and to provide adequate information for the labeling of the product.

If a compound demonstrates evidence of effectiveness and an acceptable safety profile in Phase 2 evaluations, generally Phase 3 trials are undertaken to obtain additional information about clinical effects and confirm efficacy and safety in a larger number of patients, typically at geographically dispersed clinical trial sites, to permit the FDA to evaluate the overall benefit-risk relationship of the drug or biologic and to provide adequate information for the labeling of the product.

In most cases, the FDA requires two adequate and well-controlled Phase 3 clinical trials to demonstrate the safety and efficacy of the drug or biologic.

In rare instances, including instances of gene therapies intended for rare diseases, a single Phase 3 trial may be sufficient when either (1) the trial is a large, multicenter trial demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible or (2) the single trial is supported by other confirmatory evidence.

In addition, the manufacturer of an investigational drug in a Phase 2 or Phase 3 clinical trial for a serious or life-threatening disease is required to make available, such as by posting on its website, its policy on evaluating and responding to requests for expanded access to such investigational drug.

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FDA approval of the BLA is required before marketing and distribution of the product may begin in the United States.

The BLA must include the results of all preclinical, clinical, and other testing and a compilation of data relating to the product’s pharmacology, chemistry, manufacture, and controls.

The BLA must include the results of preclinical, clinical, and other testing and a compilation of data relating to the product’s pharmacology, chemistry, manufacture, and controls.

The cost of preparing and submitting a BLA is substantial.

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Changes to some of the conditions established in an approved BLA, including changes in indications, product 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.

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.

Additional Standard for Gene Therapy Products

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in general, the disease must affect fewer than 200,000 such individuals in the U.S.;

the NDA or BLA must be deemed eligible for priority review;

the NDA or BLA must be deemed

eligible for priority review;

the NDA or BLA must not seek approval for a different adult indication (i.e., for a different disease/condition);

the product must not contain an active ingredient that has been previously approved by the FDA;

and the NDA or BLA must rely on clinical data derived from studies examining a pediatric

population such that the approved product can be adequately labeled for the pediatric population.

and the NDA or BLA must rely on clinical data derived from studies examining a pediatric population such that the approved product can be adequately labeled for the pediatric population.

Before NDA or BLA approval, the FDA may designate a product in development as a product for a rare pediatric disease.

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The FDA will attempt to direct additional resources to the evaluation of an application designated for priority review in an effort to facilitate the review.

Breakthrough Therapy Designation

The FDA is also required to expedite the development and review of biological products that are intended to treat a serious or life-threatening disease or condition where preliminary clinical evidence indicates that the biologic product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

The sponsor of a new biologic product candidate may request that the FDA designate the candidate for a specific indication as a Breakthrough Therapy concurrent with, or after, the filing of the IND for the biologic product candidate.

The FDA must determine if the biological product qualifies for Breakthrough Therapy designation within 60 days of receipt of the sponsor’s request.

Regenerative Medicine Advanced Therapy (RMAT) Designation

The RMAT designation is an expedited program for the advancement and approval of regenerative medicine therapies that are intended to treat, modify, reverse, or cure a serious condition and where preliminary clinical evidence indicates the potential to address unmet medical needs for life-threatening diseases or conditions.

Similar to Breakthrough Therapy designation, the RMAT allows companies developing regenerative medicine therapies to work earlier, more closely, and frequently with the FDA, and RMAT-designated products may be eligible for priority review and accelerated approval.

Regenerative medicine therapies include cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the PHS Act and Title 21 of the Code

of Federal Regulations Part 1271.

The FDA confirmed that gene therapies, including genetically modified cells, that lead to a sustained effect on cells or tissues may meet the definition of a regenerative medicine therapy.

For product candidates that have received a RMAT designation, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of patients placed in ineffective control regimens.

The timing of a sponsor’s request for designation and FDA response are the same as for the Breakthrough Therapy designation program.

Disclosure of Clinical Trial Information

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The FDA may grant full or partial waivers, or deferrals, for submission of data.

Unless otherwise required by regulation, PREA does not apply to any biological product with orphan product designation except a product with a new active ingredient that is a molecularly targeted cancer product intended for the treatment of an adult cancer and directed at a molecular target determined by FDA to be substantially relevant to the growth or progression of a pediatric cancer.

Unless otherwise required by regulation, PREA does not apply to any biological product with

orphan product designation except a product with a new active ingredient that is a molecularly targeted cancer product intended for the treatment of an adult cancer and directed at a molecular target determined by FDA to be substantially relevant to the growth or progression of a pediatric cancer.

Additional Controls for Biologics

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Biosimilarity sufficient to reference a prior FDA-approved product requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.

Biosimilarity must be shown through analytical trials, animal trials, and a clinical trial or trials, unless the Secretary of Health and Human Services waives a required element.

A biosimilar product may be deemed

interchangeable with a previously approved product if it meets the higher hurdle of demonstrating 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.

Biosimilarity must be shown through analytical trials, animal studies, and a clinical trial or trials, unless the Secretary of Health and Human Services waives a required element.

A biosimilar product may be deemed interchangeable with a previously approved product if it meets the higher hurdle of demonstrating 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.

The first biosimilar product was approved by the FDA in 2015, and the first interchangeable product was approved in 2021.

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Once a BLA is approved, a product will be subject to certain post-approval requirements.

For instance, the FDA closely regulates the post-approval marketing and promotion of biologics, including standards and regulations for direct-to-consumer advertising, off-label promotion, industry-sponsored scientific and educational activities and promotional activities involving the Internet.

promotional activities involving the Internet.

Biologics may be marketed only for the approved indications and in accordance with the provisions of the approved labeling.

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The term remuneration has been interpreted broadly to include anything of value.

The Anti- Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and

prescribers, purchasers, and/or formulary managers on the other.

The Anti- Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and/or formulary managers on the other.

There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.

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The civil monetary penalties statute imposes penalties against any person or entity who, among other things, is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.

Federal false claims laws, including the federal civil False Claims Act, prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false claim for payment to, or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.

federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.

As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand” for money or property presented to the U.S.

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Among other things, HITECH made HIPAA’s security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.

HITECH also created four new tiers of civil

monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

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Some states also impose requirements on manufacturers and distributors to establish the pedigree of product in the chain of distribution, including some states that require manufacturers and others to adopt new technology capable of tracking and tracing product as it moves through the distribution chain.

In addition, several states have enacted legislation requiring pharmaceutical and biotechnology companies to establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical and biotechnology companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.

In addition, several states have enacted legislation requiring pharmaceutical and biotechnology companies to

establish marketing compliance programs, file periodic reports with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities, and/or register their sales representatives, as well as to prohibit pharmacies and other healthcare entities from providing certain physician prescribing data to pharmaceutical and biotechnology companies for use in sales and marketing, and to prohibit certain other sales and marketing practices.

Certain local jurisdictions also require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures.

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government rebate programs and additional downward pressure on pharmaceutical product prices.

On September 9, 2021, the Biden administration published a wide-ranging list of policy proposals, most of which would need to be carried out by Congress, to reduce drug prices and drug payment.

The HHS plan includes, among other reform measures, proposals to lower prescription drug prices, including allowing Medicare to negotiate prices and disincentivizing price increases, and to support market changes that strengthen supply chains, promote biosimilars and generic drugs, and increase price transparency.

Many similar proposals, including the plans to give Medicare Part D authority to negotiate drug prices, require drug manufacturers to pay rebates on drugs whose prices increase greater than the rate of inflation, and cap out-of-pocket costs, have already been included in policy statements and legislation currently being considered by Congress.

It is unclear to what extent these and other statutory, regulatory, and administrative initiatives will be enacted and implemented.

Healthcare reform proposals recently culminated in the enactment of the Inflation Reduction Act, or IRA, which will eliminate, beginning in 2025, the coverage gap under Medicare Part D by significantly lowering the enrollee maximum out-of-pocket cost and requiring manufacturers to subsidize, through a newly established manufacturer discount program, 10% of Part D enrollees’ prescription costs for brand drugs below the out-of-pocket maximum, and 20% once the out-of-pocket maximum has been reached.

The IRA will also allow HHS to negotiate the selling price of certain drugs and biologics that CMS reimburses under Medicare Part B and Part D (excluding drugs and biologics that are designated and approved for only one rare disease or condition), although only high-expenditure single-source biologics that have been approved for at least 11 years (7 years for drugs) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.

The negotiated prices, which will first become effective in 2026, will be capped at a statutory ceiling price.

Beginning in October 2022 for Medicare Part D and January 2023 for Medicare Part B, the IRA will also penalize drug manufacturers that increase prices of Medicare Part D and Part B drugs at a rate greater than the rate of inflation.

It is unclear to what extent other statutory, regulatory, and administrative initiatives will be enacted and implemented in the future.

Employees and Human Capital Resources

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None of our employees are represented by a labor union or covered by collective bargaining agreements, and we believe our relationship with our employees is good.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards and cash-based performance bonus awards.

Our Mission and Our Employees

At Passage Bio, our mission is to discover and develop transformative therapies for CNS disorders with limited or no approved treatment options, while also building strong relationships with the communities we serve.

We embrace collaboration, discipline and efficiency, while welcoming fresh ideas and stimulating personal development.

We align our core values with our mission statement, which is outlined below:

● Put patients first

o We place the health and safety of our patients at the center of every decision we make

o We value the voice of our patient communities;

we listen and we learn

o We are driven to improve patients’ lives;

they are relying on us

● Committ to Excellence

o We apply leading-edge science and technology to develop gene therapies for our patients

o We strive to be the best in everything we do

o We embrace diversity and inclusion as essential to the success of our company

o We have an unrelenting focus on quality

● Make and impact

o We act with a sense of urgency;

patients are waiting

o We are nimble and adaptable in driving toward our goals

o We approach every day with courage and tenacity

● Act with integrity

o We communicate openly, honestly and respectfully with each other

o We make decisions based on what’s right

o We are accountable for our actions

o We care about our community and strive to be good citizens

● Suceed together

o We’re all part of the solution and help each other be successful

o We innovate by challenging the status quo, taking appropriate risk and encouraging diversity of thought

o We value and foster collaboration, both internally and with our external partners

o We work hard and find ways to make it fun

Our Commitment to Diversity, Equity and Inclusion

We are committed to creating and maintaining a diverse, equitable and inclusive workplace where all of our employees can thrive in an environment that values differences, provides equal opportunities and embraces different backgrounds and perspectives.

We treat all individuals with respect and dignity and provide all of our employees with fair treatment based on merit.

By embracing diversity and inclusion, we create an organization committed to working together to develop innovative solutions in support of our mission.

Our core values include a commitment to diversity, equity, and inclusion, and we have embraced them as integral parts of our business strategy.

Our Compensation and Benefits

We view our employees as one of our most valuable assets in serving our mission.

We compete in the highly competitive biotechnology industry, and attracting, retaining and developing a diverse group of talented employees is crucial to our strategy and our ability to compete effectively.

We are committed to the development and retention of our workforce to support our research, clinical operations, manufacturing and regulatory efforts.

There currently is a shortage of skilled individuals with substantial experience discovering, developing and manufacturing genetic medicines, which is likely to continue.

As a result, competition for these individuals is intense and the turnover rate can be high.

We face substantial competition among numerous companies and academic institutions for individuals with these skills.

Given the highly competitive nature of our industry and the importance of recruitment and retention to our success, we strive to provide our employees with what we believe is a very competitive and comprehensive total rewards package of compensation, benefits and services.

This package includes at or above-market pay, healthcare benefits for employees and family members, life insurance benefits, short and long-term disability benefits, generous paid time off benefits, parental leave, bereavement leave, flexible work schedules, a 5% employer match of employee contributions to our sponsored retirement plans, and an annual stipend for employees to spend on professional development.

Additionally, we also offer every full-time employee the benefit of equity ownership in our Company through our equity plans.

Our principal executive office is located in Philadelphia, Pennsylvania, where we lease a total of approximately 37,000 square feet of office space, which commenced in February 2021 and will expire in December 2031, subject to our option to extend the term of the lease by up to two additional five-year terms .

17 unchanged sentences

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What changed 10-K

Item 1. Business