What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2022-03-17 compared with 2021-03-18 · 253 added, 422 removed, 762 unchanged (47% of the section changed)

1 unchanged sentence

Our company is focused on developing potentially curative ex vivo lentiviral-based gene therapies to treat patients with rare diseases following a single dose treatment regimen.

Our gene therapies employ hematopoietic stem cells that are harvested from the patient and then modified with a lentiviral vector to insert the equivalent of a functional copy of the gene that is defective in the target disease.

We believe that our approach, which is designed to transform stem cells from patients into therapeutic products, has the potential to provide curative benefit for a range of diseases.

1 unchanged sentence

These lysosomal disorders have well-understood biologies, identified patient populations, established standards of care yet with significant unmet needs, and represent large market opportunities with approximately $3.4 billion in worldwide net sales in 2021.

Our initial pipeline is comprised of six lentiviral-based gene therapy programs:

AVR-RD-01 for the treatment of Fabry disease;

Our pipeline is currently comprised of five lentiviral-based gene therapy programs:

AVR-RD-04 for the treatment of cystinosis;

3 unchanged sentences

and AVR-RD-03 for the treatment of Pompe disease.

AVR-RD-01 is currently being evaluated for the treatment of Fabry disease in an investigator-sponsored Phase 1 clinical trial and a Company-sponsored Phase 2 clinical trial.

Five patients have been dosed in the investigator-sponsored Phase 1 clinical trial of AVR-RD-01, and enrollment is complete.

Five patients have been dosed in our Company-sponsored Phase 2 clinical trial of AVR-RD-01, which we refer to as the FAB-GT clinical trial, and we are actively recruiting additional potential patients for our currently active sites in Australia, Canada and the United States.

AVR-RD-04 is currently being studied for the treatment of cystinosis by our collaborators at the University of California, San Diego, or UCSD, in a Phase 1/2 investigator-sponsored clinical trial, and three patients have been dosed.

One patient has been dosed in our Company-sponsored Phase 1/2 clinical trial of AVR-RD-02 for the treatment of Gaucher disease, which we refer to as the Guard1 clinical trial, and we are actively recruiting in Australia and Canada, with additional sites planned in the United States, Israel and Europe.

AVR-RD-05 is being studied for the treatment of Hunter syndrome by our collaborators at The University of Manchester, and a Phase 1/2 investigator-sponsored clinical trial is expected to commence in the first half of 2022.

In November 2020, we announced a new preclinical program, AVR-RD-06 for the treatment of Gaucher disease type 3, and we expect to request a meeting with the Food and Drug Administration, or FDA, this year to discuss a potential path to the clinic.

AVR-RD-04 is currently being studied for the treatment of cystinosis by our collaborators at the University of California, San Diego, or UCSD, in a Phase 1/2 collaborator-sponsored clinical trial, and as of March 1, 2022 four patients have been dosed.

In December 2021 we received feedback from the FDA following a Type C meeting.

Pending the outcome of further planned FDA interactions this year, we expect to initiate a Company-sponsored trial in 2023 with initial sites in the United States, followed by sites in Europe and the United Kingdom.

Our current plan involves a two-part strategy, beginning in a pre-renal transplant population followed by a post-renal transplant population.

Three patients have been dosed as of March 1, 2022 in our Company-sponsored Phase 1/2 clinical trial of AVR-RD-02 for the treatment of Gaucher disease type 1, which we refer to as the Guard1 clinical trial, and we are actively recruiting additional potential patients for our currently active sites.

We currently plan to provide updated interim clinical trial data in 2022.

In October 2021, the FDA granted rare pediatric disease designation for AVR-RD-05 for the treatment of Hunter syndrome.

Under this program, if AVR-RD-05 is approved by the FDA then the Company may qualify for a voucher that can be redeemed to receive a priority review of a subsequent marketing application for a different product candidate.

AVR-RD-06 is our preclinical program for the treatment of Gaucher disease type 3, and we expect to engage with regulatory authorities this year to discuss a path to the clinic, including a potential Phase 2/3 clinical trial.

Our AVR-RD-03 program for Pompe disease has completed planned preclinical development, and we are planning to engage with regulatory authorities this year to discuss a potential path to the clinic with the goal of initiating a clinical trial in 2023.

In January 2022 we announced the deprioritization of AVR-RD-01, our investigational gene therapy program for Fabry disease.

This decision was made due to several factors, including new clinical data showing variable engraftment patterns from the five most recently dosed patients in the Company’s Phase 2 clinical trial of AVR-RD-01 for the treatment of Fabry disease, which we refer to as the FAB-GT clinical trial.

The emergence of such new data would have significantly extended the program’s development timeline.

That development, coupled with an increasingly challenging market and regulatory environment for Fabry disease, were among the primary factors leading to the Company’s deprioritization of its Fabry program.

As a result of the deprioritization, the Company has stopped enrollment of its Phase 2 FAB-GT clinical trial and will focus on its other pipeline programs.

Since its first clinical use in 2003, lentiviral-based gene therapy has been studied in several third parties’ clinical trials for rare diseases such as transfusion-dependent beta thalassemia, cerebral adrenoleukodystrophy, or CALD, metachromatic leukodystrophy, or MLD, and adenosine deaminase severe combined immunodeficiency, or ADA-SCID.

Initially, the use of ex vivo lentiviral-based gene therapies was restricted primarily to the most severe diseases where the risks of the typical requirement for ablating the patients’ bone marrow had a clinically justifiable risk/benefit profile.

To date, over 350 patients have been treated with lentiviral-based gene therapies in third parties’ and our rare disease clinical trials, and we believe the technology can be developed for other serious conditions based on a rigorous risk/benefit assessment.

To date, hundreds of patients have been treated with lentiviral-based gene therapies in third parties’ and our rare disease clinical trials, and we believe the technology can be developed for other serious conditions based on a rigorous risk/benefit assessment.

The ablation procedure, also known as the conditioning regimen, is typically an essential step in the ex vivo gene therapy treatment procedure and is administered prior to the gene therapy.

The higher the level of conditioning, the greater the potential risk of more serious complications, such as veno-occlusive disease.

However, we believe the risk of more serious complications can be managed through utilization of a precision busulfan dosing program, which we refer to as Target Concentration Intervention, or TCI.

We have worked to optimize the conditioning regimen through utilization o f a precision busulfan dosing program, which we refer to as Target Concentration Intervention , or TCI.

TCI is designed to enable careful titrating of exposure to the conditioning drug to a specific area under the curve, or AuC.

The conditioning regimen utilized as part of our plato platform includes TCI to assess how rapidly the individual patient metabolizes the conditioning agent so physicians can adjust the dose as needed, with a goal of minimizing side effects while maximizing the potential of durable engraftment.

We believe our approach, utilizing a single myeloablative conditioning agent, busulfan, coupled with TCI designed to titrate to a specific AuC, has the potential to extend the reach of our gene therapies to a broad range of diseases as first-line therapies.

Our goal is to broaden the applicability of lentiviral-based gene therapy by initially targeting monogenic diseases with an identified gene, recognized biology and that could potentially benefit from the sustained systemic delivery of an active protein.

The conditioning regimen utilized as part of our plato platform includes TCI to assess how rapidly the individual patient metabolizes the conditioning agent so physicians can adjust the dose as needed, with a goal of minimizing side effects from conditioning while maximizing the potential of durable engraftment.

In addition, we are evaluating the potential future use of alternative conditioning agents in lieu of the current busulfan TCI conditioning regimen.

For example, we have entered into collaboration agreements with Jasper Therapeutics, Inc.

and Magenta Therapeutics, Inc.

and are currently evaluating the potential use of their respective monoclonal antibody conditioning agents.

We are also evaluating the potential use of additional agents to tailor the conditioning regimen for certain disease indications.

We believe our approach to conditioning has the potential to extend the reach of our gene therapies to a broad range of diseases as first-line therapies.

Plato is our gene therapy platform designed to provide the foundation for the potential worldwide commercialization of our gene therapies, if approved.

1 unchanged sentence

a closed, automated manufacturing system designed to improve consistency and predictability of the drug product;

and a personalized approach to conditioning using TCI .

Two patients in our FAB-GT clinical trial of AVR-RD-01 and one patient in our Guard1 clinical trial of AVR-RD-02 have been dosed with drug product manufactured utilizing the plato platform , and we intend to utilize the plato platform with these process changes for all future patients enrolling in these two clinical trials.

and a personalized approach to conditioning.

Six patients in our FAB-GT clinical trial of AVR-RD-01, for which enrollment has been halted, and three patients in our Guard1 clinical trial of AVR-RD-02, have been dosed with drug product manufactured utilizing the plato platform, and we intend to utilize the plato platform with these process changes for all future patients enrolling in our Company-sponsored clinical trials.

We believe our innovations in viral vector design, cellular manufacturing, cryopreservation, conditioning and other related processes are important steps towards advancing the field of lentiviral-based gene therapy and realizing its full potential to treat a number of diseases.

4 unchanged sentences

As a result, substrates and their metabolites accumulate to toxic levels in the body’s cells and, in turn, disrupt the function of multiple tissues and organs.

Fabry disease, Gaucher disease (types 1 and 3), Hunter syndrome and Pompe disease are currently primarily managed by bi-weekly (or weekly in the case of Hunter syndrome), multi-hour infusions with ERTs that seek to exogenously replace the missing functional enzyme.

Gaucher disease (types 1 and 3), Hunter syndrome and Pompe disease are currently primarily managed by bi-weekly (or weekly in the case of Hunter syndrome), multi-hour infusions with ERTs that seek to exogenously replace the missing functional enzyme.

However, given their pharmacokinetics, most ERTs typically remain in the plasma only for a short period of time and thus are not ideal because they are only dosed weekly or every two weeks.

7 unchanged sentences

The status of our initial lentiviral-based gene therapy programs is reflected below.

Our lead product candidate, AVR-RD-01 for the treatment of Fabry disease, is derived from hematopoietic stem cells to which the gene encoding plasma α-galactosidase A, or AGA, is added in an ex vivo process using a lentiviral vector.

In February 2021, we reported that a kidney biopsy taken at 12 months post-treatment from the fourth patient in the Phase 2 FAB-GT trial, who was the first in the trial dosed with our plato platform, showed a 100 percent reduction from baseline in the average number of globotriaosylceramide, or Gb3, inclusions per peritubular capillary, or PTC.

These data followed our 2019 announcement that at 12 months post-treatment the first patient in the FAB-GT clinical trial exhibited an 87% reduction in the average number of Gb3 inclusions per PTC as compared to baseline.

In addition, in February 2021 we reported data from the first four patients in the FAB-GT trial measured as of 29, 24, 18 and 12 months, respectively, indicating sustained increased leukocyte and plasma enzyme activity, suggesting that these patients are now producing an endogenous supply of AGA, as well as decreased plasma lyso-globotriaosylsphingosine, or lyso-Gb3, levels in three of four patients, a key biomarker for monitoring Fabry disease.

We have opened two U.S.

sites for our ongoing FAB-GT clinical trial of AVR-RD-01, and we are actively recruiting potential patients for our sites in Australia, Canada and the United States.

We have submitted a briefing book to the FDA outlining our proposal for a potential accelerated approval strategy for AVR-RD-01, including a proposed randomized confirmatory clinical trial of Fabry patients who are being treated with ERT.

We expect to meet with the FDA in the first quarter of 2021 to discuss our proposal.

In February 2021, we announced initial clinical data from the first three patients dosed in the investigator-sponsored Phase 1/2 trial of AVR-RD-04, our investigational gene therapy for cystinosis.

As of January 20, 2021, all three patients had discontinued cysteamine pills and eye drops and remained cysteamine-independent out as far as 16 months post-treatment.

We also announced in February 2021 clinical data from the first patient dosed in our Phase 1/2 Guard1 clinical trial of AVR-RD-02 for Gaucher disease type 1.

The first patient exhibited a 44% reduction in plasma glucosylsphingosine, or lyso-Gb1, levels six months post-administration of AVR-RD-02 as compared to baseline while on ERT.

Lyso-Gb1 is considered a surrogate marker for disease activity and treatment response for Gaucher disease type 1.

In addition, we announced that at six months post-treatment the first patient exhibited a 49% reduction in chitotriosidase levels as compared to baseline while on ERT.

Chitotriosidase is a biomarker of macrophage activation that is found in high levels in Gaucher patients where the macrophages have accumulated an excess lipid burden.

This clinical trial is actively recruiting in Australia and Canada, with additional sites planned in the United States, Israel and Europe .

We continue to seek opportunities to expand our approach to other rare and non-rare diseases.

3 unchanged sentences

Our team has broad expertise in the clinical, regulatory and commercialization aspects of rare diseases as well as process development and manufacturing for cellular therapies.

Members of our management team have held senior positions at Amgen, AstraZeneca, AveXis, Biogen, bluebird bio, GlaxoSmithKline, Lonza, Novartis, Sanofi Genzyme, Shire, Spark Therapeutics, and other companies pursuing development, manufacturing and commercialization of gene, cellular and other therapies to treat rare diseases.

Members of our management team have held senior positions at Axovant Sciences (now Sio Gene Therapies), Biogen, bluebird bio, Freeline Therapeutics, GlaxoSmithKline, Lonza, Novartis, Sanofi Genzyme, Shire, Spark Therapeutics, and other companies pursuing development, manufacturing and commercialization of gene, cellular and other therapies to treat rare diseases.

Our goal is to develop and commercialize lentiviral-based gene therapies that free patients from a lifetime of genetic disease.

1 unchanged sentence

Rapidly advance our pipeline targeting lysosomal disorders.

We are initially targeting lysosomal disorders and are developing a deep pipeline of six gene therapies to treat Fabry disease, cystinosis, Gaucher disease type 1, Hunter syndrome, Gaucher disease type 3 and Pompe disease.

We are initially targeting lysosomal disorders and are developing a pipeline of five gene therapies to treat cystinosis, Gaucher disease type 1, Hunter syndrome, Gaucher disease type 3 and Pompe disease.

We intend to continue rapidly advancing these programs in parallel and to obtain clinical data that could potentially support regulatory filings around the world.

Specifically, we intend to pursue pathways for accelerated review and approval of our product candidates by the FDA and international regulatory authorities through programs such as the Regenerative Medicine Advanced Therapies, or RMAT, program in the United States.

Continue implementing and enhancing our industry-leading plato platform with its personalized approach to conditioning, enhanced vector technology and automated, closed manufacturing processes.

Our end-to-end plato platform is designed to provide the foundation for worldwide commercialization of our gene therapies, if

Our end-to-end plato platform is designed to provide the foundation for worldwide commercialization of our gene therapies, if approved.

We believe our innovations in viral vector design, cellular manufacturing, cryopreservation, and other related processes are important steps towards advancing the field of lentiviral-based gene therapy and realizing its full potential to treat a number of diseases.

1 unchanged sentence

In combination with this vector, in some indications we use a number of proprietary peptide tag technologies to enhance uptake of therapeutic protein in key tissues.

W e have also developed a manufacturing process that we believe is both reproducible and scalable , and we believe this technology could enable us to deliver our gene therapies to patients , if approved, in quantities sufficient for global commercial supply .

We have also developed a manufacturing process that we believe is both reproducible and scalable, and we believe this technology could enable us to deliver our gene therapies to patients, if approved, in quantities sufficient for global commercial supply.

In addition, we believe our personalized approach to conditioning using busulfan with a precision dosing program called Target Concentration Intervention could enable us to deliver durable, ‘head-to-toe’ treatment of symptoms and early intervention in the treatment of lysosomal disorders.

We will continue to leverage advancements in stem cell transplantation in order to improve patient tolerability of our lentiviral-based gene therapies.

Build global infrastructure to reach patients across the world.

Lysosomal disorders afflict patients globally and we intend to continue building global infrastructure in order to provide treatment to patients around the world.

This infrastructure includes clinical sites, specialist physicians and researchers, suppliers and contract manufacturing organizations.

We are currently conducting clinical trials across multiple geographies, including the United States, Canada and Australia, with plans to potentially expand to other geographies including Europe and Israel.

intend to continue to leverage advancements in stem cell transplantation , including e valuating the potential use of monoclonal antibody conditioning .

Leverage our approach beyond our initial indications.

We are initially developing gene therapies for the treatment of six different lysosomal disorders and believe that we will gain significant learnings and technical insights from these programs.

We are initially developing gene therapies for the treatment of five different lysosomal disorders and believe that we will gain significant learnings and technical insights from these programs.

We intend to leverage our technology and insights to treat a number of rare and non-rare diseases where we believe our lentiviral approach has transformative potential.

2 unchanged sentences

We focus on delivering our lentiviral-based gene therapies to patient-derived hematopoietic stem cells, which are primitive stem cells that develop into all types of blood cells, including white blood cells, red blood cells and platelets.

To accomplish this, we harvest a patient’s hematopoietic stem cells and modify them ex vivo to add the equivalent of a functional copy of the gene that is defective in the target disease.

To accomplish this, we harvest a patient’s hematopoietic stem cells and modify them ex vivo to add the equivalent of a functional copy of the gene that is mutated in the target disease.

We then infuse the genetically modified cells back into the patient.

Our gene therapies are designed to be administered to the patient as a one-time therapy following a TCI conditioning regimen.

Our gene therapies are designed to be administered to the patient as a one-time therapy following a conditioning regimen.

We are focused on employing our approach to treat and potentially cure lysosomal disorders.

1 unchanged sentence

We believe our ex vivo lentiviral-based gene therapy approach can be industrialized into a robust, scalable and, if approved, commercially viable process that will allow us to deliver our potentially curative therapies to patients across the world.

Advantages of Ex-Vivo Lentiviral-Based Gene Therapy Approach

We believe ex-vivo lentiviral-based gene therapy provides numerous advantages, including:

Potential Advantages of Ex-Vivo Lentiviral-Based Gene Therapy Approach

We believe ex-vivo lentiviral-based gene therapy has the potential to provide numerous advantages, including:

Durable benefit.

7 unchanged sentences

Broad patient applicability.

of preexisting antibodies that detect viral vectors and trigger the immune system to destroy the vector and cells infected by the vector.

Lentiviral-based gene therapies have been used to deliver treatments to patients of all ages, including children, and to patients who may be ineligible for other types of gene therapy due to the presence of preexisting antibodies that detect viral vectors and trigger the immune system to destroy the vector and cells infected by the vector.

Restoration of protein function.

By contrast to the standard-of-care enzyme replacement therapy, which seeks to clear toxic substrate as a key symptom of a non-functioning gene, restoration of gene function may deliver a wide array of additional biochemical benefits throughout the body.

History of tolerability in clinical trials.

To our knowledge, no instances of insertional oncogenesis or leukemogenesis from lentiviral vectors have been documented in clinical trials of lentiviral gene therapies, with more than 350 total patients treated.

To date, we have not seen any unexpected safety events in 14 patients across our four clinical trials, with the longest follow-up more than 3.5 years to date.

Tolerability in clinical trials.

To date, we have not seen any unexpected safety events in 21 patients across four clinical trials, with the longest follow-up more than 4.5 years to date.

Larger and varied payloads.

2 unchanged sentences

There are approximately 70 identified lysosomal disorders, which are characterized by an abnormal toxic build-up of substrates and their metabolites in the body’s cells.

We are currently targeting Fabry disease, cystinosis, Gaucher disease type 1, Hunter syndrome, Gaucher disease type 3 and Pompe disease.

We are currently targeting cystinosis, Gaucher disease type 1, Hunter syndrome, Gaucher disease type 3 and Pompe disease.

Each of these disorders affects a meaningful number of patients, has a suboptimal standard of care with unmet medical need and, we believe, is appropriate for lentiviral-based gene therapy.

We believe our approach has the potential to address the shortcomings of existing therapies that, despite chronic dosing, cannot halt or reverse disease progression, restore normal lifespan or adequately address symptoms arising in both the peripheral tissues and the central nervous system.

Expanding the Utility of Lentiviral-Based Gene Therapy with TCI-Enabled Conditioning Regimen

Expanding the Utility of Lentiviral-Based Gene Therapy with Optimized Conditioning Regimens

A core part of our approach is to expand the use of lentiviral-based gene therapy to treat numerous lysosomal disorders.

1 unchanged sentence

This maximizes the potential for their long-term engraftment which may enhance durability of therapeutic effect.

We believe that we will be able to demonstrate durable effects in our targeted diseases utilizing a single myeloablative agent, busulfan, which we have transitioned to as part of implementing our plato platform.

We have pioneered precision dosing of busulfan in gene therapy as a single agent in a single treatment cycle, with the goal of enhancing the patient experience.

A body of research has identified an optimal exposure range for busulfan (Bu-90), which we plan to implement for the patients enrolled in our Company-sponsored clinical trials.

We believe enabling patient and physician choice of conditioning agents has the potential to be a substantial advance in the gene therapy field, and are evaluating the implementation of a tailored conditioning approach for certain disease indications.

We plan to continue using busulfan conditioning and intend to strive to optimize its tolerability profile.

We have pioneered precision dosing of busulfan in gene therapy in a single treatment cycle, with the goal of enhancing the patient experience.

A body of research has identified an optimal exposure range for busulfan (Bu-90).

Our approach is to personalize conditioning to each patient using TCI, a precision dosing program.

TCI is designed to allow for continually controlled exposure by assessing via simple blood draws how rapidly the individual patient metabolizes busulfan, to inform further administration.

Use of busulfan in a conditioning regimen causes adverse side effects and can transiently compromise the patient’s immune system, known as neutropenia, and ability to form blood clots, known as thrombocytopenia.

Use of busulfan in a conditioning regimen causes side effects and can transiently compromise the patient’s immune system, known as neutropenia, and reduce blood clotting, known as thrombocytopenia.

The higher the level of conditioning, the greater the potential risk of more serious complications, such as veno-occlusive disease.

However, we believe our approach to conditioning has the potential for reduced, predictable and manageable short- and long-term toxicities and maximized long-term engraftment.

If realized, we believe these benefits may promote lentiviral-based gene therapy as a therapeutic option for less acutely severe diseases or diseases with approved therapies in which large unmet medical needs remain.

We believe our approach has the potential to extend the reach of our gene therapies to a broad range of lysosomal disorders as first-line therapies.

In addition to our utilization of busulfan, we are committed to staying on the forefront of new conditioning approaches.

For example, we are exploring the implementation of monoclonal antibody conditioning for certain indications and have entered into collaboration agreements with Magenta Therapeutics and Jasper Therapeutics.

We believe our approach to conditioning has the potential to extend the reach of our gene therapies to a broad range of lysosomal disorders as first-line therapies.

Our Commercial-Scale Platform

3 unchanged sentences

a closed, automated manufacturing system designed to improve consistency and predictability of the drug product;

and a personalized approach to conditioning using busulfan with TCI, which is designed to optimize safety and engraftment.

We have submitted data on our upgraded lentiviral vector and

automated manufacturing process to the applicable regulatory authorities in the United States and Canada , which allow s us to incorporat e such elements into our FAB-GT and Guard1 clinical trials in those jurisdictions and Australia .

Plato has been used to dose a total of three patients in our clinical trials, and we intend to utilize the plato platform for all future patients enrolling in the FAB-GT and Guard1 clinical trials .

and a personalized approach to conditioning.

Plato has been used to dose a total of nine patients in our clinical trials, which includes six patients from our FAB-GT trial for which enrollment has been halted, and we intend to utilize the plato platform for all future patients enrolling in our Company-sponsored clinical trials.

We believe our plato platform may lead to better patient outcomes and will represent a significant advance in our industry towards achieving the quality and scale required for global commercialization of gene therapies.

5 unchanged sentences

The automated, closed manufacturing system is portable with proprietary AVROBIO algorithms which allow for efficient establishment of manufacturing capabilities in multiple geographies that can be expanded or adjusted as our global supply requirements evolve.

We believe this approach will facilitate global manufacturing and shipping of our gene therapies, and will promote access to our products by patients and caregivers.

We believe this approach will facilitate global

manufacturing and shipping of our gene therapies, and will promote access to our products by patients and caregivers.

Quality of manufacturing :

10 unchanged sentences

We have made and expect to continue to make enhancements to our lentiviral vectors to improve safety, efficacy and efficiency.

For example, clinical trials of AVR-RD-01 have primarily utilized our original academic three-plasmid-produced lentiviral vector, which we refer to as LV1.

However, we dosed the fourth and fifth patient in our ongoing FAB-GT clinical trial of AVR-RD-01 and the first patient in our ongoing Guard1 clinical trial of AVR-RD-02 using our proprietary four-plasmid lentiviral vector, which we refer to as LV2, and expect to dose all future patients in these trials with LV2.

For example, clinical trials of AVR-RD-01 first utilized our original academic three-plasmid-produced lentiviral vector, which we refer to as LV1.

However, we dosed six patients in our now halted FAB-GT clinical trial of AVR-RD-01 and the first three patients in our ongoing Guard1 clinical trial of AVR-RD-02 using our proprietary four-plasmid lentiviral vector, which we refer to as LV2, and expect to dose all future patients in our Company-sponsored trials with LV2.

Our goal is to employ vectors that are state-of-the-art and that can be produced in a cost-effective and scalable manner.

3 unchanged sentences

In contrast to a number of other gene therapy companies that have not developed their commercial scale plans from the outset, we have executed on our plans to move to a closed suspension bioreactor system for vector production, as well as a closed, automated system for manufacturing our gene therapy product.

Our move to a closed, automated manufacturing system was completed in 2019 as part of implementing upgrades from our plato platform, and the fourth and fifth patients in our ongoing FAB-GT clinical trial of AVR-RD-01 and the first patient in our ongoing Guard1 clinical trial of AVR-RD-02 were each dosed using this system.

We believe our plato platform features the first automated, closed manufacturing system in CD34+ gene therapy.

Our manufacturing approach is intended to allow for the production of drug product using relatively small, self-contained devices, which may reduce our reliance on large traditional clean rooms that are expensive to establish and

Our move to a closed, automated manufacturing system was completed in 2019 as part of implementing upgrades from our plato platform, and six patients in our now halted FAB-GT clinical trial of AVR-RD-01 and the first three patients in our ongoing Guard1 clinical trial of AVR-RD-02 were each dosed using this system.

We believe our manufacturing approach may result in greater flexibility in the location of manufacture and help to control costs associated with traditional manufacturing.

In addition, we believe our automated manufacturing process may reduce operator error and yield greater consistency and less variability in the manufactured drug product.

We currently have one CMO partner in the United States and two partners in Australia for the production of AVR-RD-01 and AVR-RD-02 drug product.

We also are in the process of establishing a CMO partnership in Europe.

We currently plan to rely on one CMO site, located in the United States, as a sole source provider of drug product for our Company-sponsored clinical trials worldwide.

Optimization of Conditioning Regimen

4 unchanged sentences

It has also been used as a single-agent, or in combination with an immunosuppressive agent, such as cyclophosphamide, in conditioning regimens prior to ex vivo gene therapy transplants.

We believe that the transition to busulfan for our conditioning regimen may confer several advantages.

For example, busulfan will permit utilization of TCI in our conditioning regimen, thereby enabling physicians to personalize the dosing to each patient by titrating over four days to potentially enhance patient tolerability to the conditioning procedure and promote cell engraftment.

Busulfan permits utilization of TCI in our conditioning regimen, thereby enabling physicians to personalize the dosing to each patient by titrating over four days to potentially enhance patient tolerability to the conditioning procedure and promote cell engraftment.

By contrast, melphalan is administered once with no TCI, and may cause concern of conditioning-related toxicity across patients due to individual differences in metabolism of the drug.

In addition, we believe that the utilization of busulfan in our single-agent myeloablative conditioning regimen has the potential to allow our gene therapies to cross the blood-brain barrier, a feature which may yield therapeutic benefit in diseases that have a central nervous system component, such as Fabry disease, Gaucher disease type 3, Hunter syndrome, Pompe disease and other rare and non-rare diseases.

In addition, we believe that the utilization of busulfan in our conditioning regimen has the potential to allow our gene therapies to cross the blood-brain barrier, a feature which may yield therapeutic benefit in diseases that have a central nervous system component, such as Gaucher disease type 3, Hunter syndrome, Pompe disease and other rare and non-rare diseases.

Finally, our busulfan conditioning regimen is designed to create more space in the ablated bone marrow compared to melphalan and may increase the average VCN of the patient bone marrow following treatment with the drug product, which are features that we believe will promote better cell engraftment and durability of the gene therapy.

We are aware that there have been cases of therapy-related myelodysplastic syndrome, or t-MDS, a type of blood disorder that is a potential precursor to acute myeloid leukemia, in patients with preexisting cancer where busulfan treatment was posited to be a contributing factor to this secondary malignancy.

However, we have reviewed over 700 published cases of busulfan exposure preceding bone marrow transplant, hematopoietic cell transplant, or ex-vivo gene therapy for non-malignant indications, of which 649 were from peer-reviewed literature.

Based on our review of these cases, we found only one case of t-MDS, which involved a report from December 2018 that a patient with preexisting sickle cell disease developed t-MDS.

In that case, busulfan treatment was posited to be a contributing factor.

We believe that due to the presence of other confounding factors in the patient, the cause of that patient’s t-MDS has not been conclusively determined.

In response to these potential risks, we are investigating a plan to potentially implement molecular cytogenetic screening.

While the busulfan conditioning regimen is more intensive than the original conditioning regimen that utilizes melphalan, we believe it is still milder than some of the more aggressive conditioning regimens associated with gene therapies for other diseases, such as when busulfan is used in combination with cyclophosphamide, used at a higher dose, or when TCI is not applied.

Furthermore, we believe our conditioning regimen may produce the desired effect while potentially allowing for a limited hospital stay.

In February 2021, we announced data from the fourth patient dosed in our ongoing FAB-GT clinical trial of AVR-RD-01, who was the first patient dosed using our plato platform.

At 12-months post-gene therapy, this patient exhibited plasma and leukocyte AGA enzyme levels that were 4.2x and 6.3x higher, respectively, than the mean plasma and leukocyte AGA activity levels of the other three dosed patients in the FAB-GT clinical trial measured as of 12-months post-gene therapy.

Additionally, the fourth patient’s kidney biopsy taken at 12 months post-treatment showed a 100% clearance of Gb3 substrate.

Advantages of Our Approach over Existing Therapies

1 unchanged sentence

Curative impact that has the potential to halt or reverse disease progression.

Existing ERTs for Fabry, Gaucher, Hunter and Pompe, and oral therapies for cystinosis, provide some therapeutic benefit to patients.

Existing ERTs for Gaucher, Hunter and Pompe, and oral therapies for cystinosis, provide some therapeutic benefit to patients.

However, because of their suboptimal pharmacokinetics, these ERTs only transiently increase plasma enzyme levels and the therapies for cystinosis require multiple doses throughout the day.

9 unchanged sentences

Our single-dose gene therapies are designed to replace the costly chronic intravenous and oral therapies that are the current standard of care for patients with lysosomal disorders.

AVR-RD-01, Our Gene Therapy for Fabry Disease

We are developing AVR-RD-01 for the treatment of Fabry disease.

We manufacture AVR-RD-01 from stem cells that are first harvested from the patient, modified to add the gene that encodes for AGA, and then infused into the patient.

AVR-RD-01 is currently being evaluated in an investigator-sponsored Phase 1 clinical trial and a Company-sponsored Phase 2 clinical trial.

A total of 10 patients have been dosed across both trials as of March 1, 2021.

Disease Overview

Fabry disease is a rare lysosomal disorder associated with significant morbidity and early mortality.

It is caused by a gene defect that causes a deficiency of AGA, which breaks down a particular type of fat in the body’s cells known as globotriaosylceramide, or Gb3.

As Gb3 and other related substrates increase in patients with Fabry disease, these become toxic to the patient’s cells.

Gb3 and other glycosphingolipids accumulate and result in damage to the kidneys, heart and brain.

Accumulation of Gb3 in tissues such as the heart and the vascular system can lead to life threatening vascular blockages and thus stroke and heart attacks.

In addition, high levels of Gb3 substrate accumulation in the kidney can cause kidney failure.

Gb3 can also accumulate in other tissues, such as the nervous system where it leads to debilitating pain.

Due to end-stage renal disease and other life-threatening complications associated with Fabry disease, the average life expectancy in affected males is approximately 58 years of age.

Most patients with Fabry disease begin experiencing chronic pain in childhood but are often not diagnosed with Fabry disease until their twenties, due to a broad variation in patient symptoms.

Over 1,000 gene mutations associated with Fabry disease have been identified.

It is estimated that Fabry disease is diagnosed in approximately one in 40,000 males and one in 118,000 females in the United States, but studies have suggested that a larger number of patients may be undiagnosed.

Fabry disease is an X-linked disorder, meaning the gene that is responsible is located on the X chromosome.

Because males have only one X chromosome, an abnormal copy of the gene that causes Fabry disease is sufficient to cause the disease.

However, unlike other X-linked disorders, where female carriers of an abnormal gene are usually unaffected, Fabry disease also often causes significant morbidity in females who inherit one abnormal copy and one normal copy of the gene associated with the disease.

Limitations of Current Therapies

Fabry disease is primarily treated with periodic infusions of ERT consisting of AGA enzyme over the patient’s lifetime.

The most commonly prescribed ERTs for Fabry disease are Fabrazyme, marketed by Sanofi Genzyme, and Replagal, marketed by Shire, which was acquired by Takeda Pharmaceutical Company Ltd.

In 2020, Fabrazyme and Replagal generated worldwide net sales of approximately €817 million euros and ¥51.6 billion Japanese yen, respectively.

We estimate that the average five-year cost to the healthcare system per Fabry patient prescribed standard of care treatment in the United States is approximately $1.7 million.

In addition, because ERTs are not curative and only slow, but do not halt, the progression of disease, patients deteriorate and the healthcare system incurs significant costs associated with recurring medical interventions.

Although ERT provides therapeutic benefit and can reduce Gb3 substrate levels and extend a patient’s life expectancy, ERT requires chronic infusions throughout the patient’s life.

Patients prescribed ERT generally receive an infusion every other week.

However, because of their suboptimal pharmacokinetics, ERTs only temporarily increase plasma enzyme levels.

As a result, patients with Fabry disease prescribed ERT continue to have disease progression, including ongoing decline in renal function, potentially including renal failure, cardiovascular disease and ongoing debilitating pain including periods of severe pain crisis.

Physicians report that patients have recurrence of symptoms as the therapeutic effect of ERT wanes between bi-weekly treatments.

Alternatives to ERT for patients with Fabry disease are limited.

Galafold (migalastat), an oral therapy marketed by Amicus, was approved by the European Medicines Agency, or EMA, in May 2016, and by the FDA in August 2018.

Amicus has reported that only 35% to 50% of the gene mutations associated with Fabry disease are amenable to migalastat.

We are developing AVR-RD-01 to halt or reverse disease progression and potentially provide a functional cure to patients with Fabry disease with a single dose of the patient’s own hematopoietic stem cells modified in an ex vivo procedure.

AVR-RD-01 is a lentiviral-based gene therapy that contains a codon-optimized human gene and is designed to maximize the likelihood of sustained AGA production by hematopoietic stem cells and their progeny.

We believe that AVR-RD-01 offers a promising treatment for Fabry disease for the following reasons:

One-time delivery.

Lentiviral-based gene therapy provides the potential to transform a patient’s own cells into a drug product that enables the continuous delivery of active enzyme throughout the body after a single dose.

Proven biology.

Years of observations of patients prescribed ERT indicate that even partial plasma AGA activity is associated with improved outcomes.

Increased AGA enzyme activity is able to reduce Gb3 levels in multiple cells and tissues supporting the ability of AGA in the plasma to enter lysosomes and degrade Gb3 in a process referred to as cross correction.

Wide therapeutic window.

We believe that even partial enzyme activity, if continuous, has the potential to provide long-term therapeutic benefit.

A wide range of levels of plasma AGA activity has been demonstrated to be both safe and effective in preclinical studies, reducing the need for precise regulation of enzyme expression levels and reinforcing that overexpression of AGA is not associated with increased safety risks.

Mutation i ndependent.

AVR-RD-01 is designed to increase plasma and leukocyte AGA levels in a patient’s cells, regardless of which of the more than 1,000 specific mutations underlie the patient’s disease.

Ongoing Multicenter Investigator-Sponsored Clinical Trial

In an ongoing Phase 1 clinical trial of AVR-RD-01 being conducted by the University Health Network, or UHN, and sponsored by Fabry Disease Clinical Research and Therapeutics, or FACTs, at three centers in Canada, a total of five patients with Fabry disease who have been treated with ERT for at least six months have been enrolled, and enrollment is complete.

The protocol for this clinical trial originally provided that ERT for these patients would be suspended one month prior to receiving AVR-RD-01 and then resumed one month after the AVR-RD-01 treatment and continued at bi-weekly intervals.

The trial protocol was subsequently amended to allow the investigator team, at their discretion, to discontinue ERT six months after treatment with AVR-RD-01.

Three of the five patients in the clinical trial have discontinued the regular bi-weekly treatments with ERT and all three remain off ERT as of January 11, 2021.

The primary goal for this clinical trial is to assess the safety and toxicity of AVR-RD-01 as measured by the frequency or severity of clinically notable abnormal vital signs and laboratory values and the frequency or severity of treatment-related adverse events.

The safety of our initial, academic-based conditioning regimen is also being assessed in this clinical trial.

A secondary objective for this clinical trial is to obtain preliminary efficacy signals of AVR-RD-01 therapy as assessed by AGA enzyme activity.

Plasma and leukocyte AGA enzyme activity derived from administration of ERT decreases rapidly after administration with no residual plasma or leukocyte activity remaining approximately one day after treatment.

To evaluate the ability of AVR-RD-01 to increase enzyme activity, the level of AGA activity was assessed in a patient immediately prior to the administration of the patient’s next dose of ERT, when limited or no plasma or leukocyte AGA activity from previously-administered ERT dose would be expected.

All five patients in this clinical trial have been dosed.

To date, the treatment was generally well-tolerated with no serious adverse events, or SAEs, related to the study drug.

In addition, in all five patients, all of whom are males with classic Fabry disease, the level of plasma and leukocyte AGA enzyme activity began to rise after infusion.

In each of the patients, plasma and leukocyte AGA enzyme activity was observed to increase from nearly undetectable levels before treatment to a peak within approximately three to six months after treatment, followed by a decline and trending to stabilize to levels above the range for males with classical Fabry disease, defined as less than 1 nmol/hr/ml.

We believe that the steep initial increase reflects AGA enzyme activity from the early progeny of the transduced stem cells, while the subsequent decline and stabilization in AGA enzyme levels reflect a shift from short term progenitor cells towards the gradual secretion of AGA enzyme by long-term engraftment cells that become more predominant over time.

AGA Enzyme Activity

As of 42 months after receiving AVR-RD-01, the first patient’s plasma and leukocyte AGA enzyme activity levels continued to be above the range for males with classical Fabry disease.

Based on the level of endogenously produced enzyme activity, at the 18-month follow-up visit for this patient, the investigator team for the trial made a clinical decision to discontinue the bi-weekly ERT and the patient remains off ERT as of 42 months post-treatment with AVR-RD-01.

Additionally, the third and fourth patients in this clinical trial discontinued ERT and both remain off ERT as of 24 months post-treatment with AVR-RD-01.

The second and fifth patients have elected to continue receiving concurrent ERT.

Plasma and leukocyte AGA enzyme activity levels in all five patients remained above the range for males with classical Fabry disease, defined as less than 1 nmol/hr/ml, as of 42 months, 36 months, 24 months, 24 months and 18 months after treatment, respectively.

We believe these results, particularly from the patients in the trial with longer-term AGA data points reported, support the potential of AVR-RD-01 to drive functional enzyme production for long durations.

Lyso-Gb3 Levels

The substrate, Gb3, and its toxic metabolite, known as lyso-Gb3, are considered surrogate markers for disease activity and treatment response for Fabry disease.

In the case of ERT-naïve patients and patients who have discontinued ERT, we believe that reductions in Gb3 levels following treatment with gene therapy are likely driven by the therapeutic effect of gene therapy.

In four of the five patients in the Phase 1 clinical trial of AVR-RD-01, we have observed plasma lyso-Gb3 at levels post-treatment that are lower than the levels observed when the patient received only ERT prior to administration of AVR-RD-01, which we refer to as baseline ERT levels.

We define baseline ERT for these Phase 1 patients as the mean of the plasma lyso-Gb3 values reported prior to initiating mobilization.

Based on the latest interim data we presented in February 2021, these four Phase 1 patients exhibited reductions in plasma lyso-Gb3 levels ranging between 25% and 48% compared to

their baseline ERT levels.

With respect to the fourth patient, who discontinued ERT six months following administration of AVR-RD-01, we observed an initial decline in plasma lyso-Gb3 levels through six months post-treatment compared to baseline ERT, and a 35 % increase in plasma lyso-Gb3 levels at 24 months post-treatment compared to baseline ERT.

This patient’s plasma lyso-Gb3 levels remain within the range for the Fabry disease patients on ERT observed in this Phase 1 clinical trial.

Vector Copy Number

VCN, which is expressed as VCN per diploid genome, refers to the average number of copies of the lentiviral-vector inserted gene that are integrated into the genome of a cell, and is another measure that can be used to help assess the durability of a gene therapy.

We believe that different diseases may require varying levels of VCN based on the underlying condition, and therefore VCN measurements across different diseases should be assessed separately.

For example, a VCN of 0.1 may represent 5% to 10% of all nucleated circulating blood cells carrying one to two copies of the inserted gene, which we believe may be sufficient to result in clinically meaningful AGA enzyme activity in the case of Fabry disease, as suggested by our interim data from our ongoing clinical trials of AVR-RD-01.

Based on the latest interim data we presented in February 2021, these five Phase 1 patients exhibited VCN levels of 0.04, 0.16, 0.24, 0.12 and 0.86 at 42 months, 36 months, 24 months, 24 months and 18 months after treatment, respectively .

Preliminary interim safety data indicate AVR-RD-01 has been generally well-tolerated with no SAEs related to the study drug.

Adverse events, or AEs, were consistent with expectations for the melphalan conditioning regimen prescribed by the study protocol.

As of the most recent safety cut-off date of November 26, 2020, there were 94 AEs reported, 14 of which were Grade 3 or 4.

The remainder of the AEs were Grade 2 or Grade 1.

Two SAEs were reported through the safety data cut-off date of November 26, 2020, which included one report of AE Grade 3 febrile neutropenia and one report of AE Grade 2 thrombophlebitis, each occurring following the conditioning regimen and treatment with AVR-RD-01.

Both SAEs have subsequently resolved without clinical sequelae.

One event, the development of a left thigh mass, was originally reported as an SAE but has now been considered by the study investigator as not serious and has resolved in the patient.

No new AEs have been reported for the first patient since January 2018, the second patient since May 2018, the third patient since August 2018, the fourth patient since March 2019 or the fifth patient since August 2019.

In addition, investigators observed a temporary suppression of absolute neutrophil counts and platelets, which is an expected consequence of the conditioning regimen.

These decreases were transient and not associated with any negative long-term impact on the patients.

Neutrophil and platelet counts recovered after dosing.

Pre-existing low anti-AGA antibody titers have been detected in four patients in the Phase 1 trial.

We believe none of these are of clinical relevance.

Because this clinical trial is ongoing, safety and efficacy data are preliminary and subject to change.

As is typical in open-label studies in which interim reports are provided, the data are regularly reviewed and validated.

As a result, certain data may change over time, including reductions or increases in the number of reported safety events, until the database is locked at the end of the study.

Ongoing Phase 2 Multinational Clinical Trial (FAB-GT)

We are sponsoring an open label, multinational Phase 2 clinical trial of AVR-RD-01, which we refer to as the FAB-GT clinical trial.

This study was initiated in June 2018 in Australia and enrollment in this Phase 2 clinical trial is ongoing.

Eight to 12 treatment-naïve males, 16 to 50 years old, with Fabry disease are expected to be enrolled in this trial.

Our objectives for this trial are to assess safety and efficacy as measured by multiple indicators, such as AGA enzyme activity, Gb3 and lyso-Gb3 levels in blood and various tissues, kidney and cardiac function, gastrointestinal symptoms, and pain and quality of life scores.

All enrolled patients will receive a single treatment with AVR-RD-01 and will be followed for 48 weeks to measure safety and efficacy.

We have opened two U.S.

sites for our ongoing FAB-GT clinical trial and are actively recruiting potential patients for our sites in Australia, Canada and the United States.

We are also engaged in discussions with the Pharmaceuticals and Medical Devices Agency, or PMDA, regarding potential future clinical development of AVR-RD-01 in Japan.

As of March 1 , 2021 , five patients have been dosed in the FAB-GT clinical trial.

For the fourth and fifth patient s , we transitioned the lentiviral vector from LV1 to our optimized proprietary LV2 from our plato platform.

All future patients in this clinical trial will be dosed using the plato platform, which we believe will further improve the efficacy and further enhance the safety of our lentiviral-based gene therapy.

Because the transition to LV2 only impacts the ex vivo cell transduction process, and not the actual AGA enzyme that is produced by the transduced cells, or drug product, we believe this transition will be supported with in vitro comparability studies.

Kidney Biopsy

The primary efficacy endpoint of our FAB-GT clinical trial is the change from baseline in the average number of Gb3 inclusions per peritubular capillary, or PTC, as measured in a patient kidney biopsy one year (48 weeks) after treatment with AVR-RD-01.

Gb3, also referred to as GL-3, is a type of fatty substrate that builds in the cells of Fabry patients, resulting in damage to organs such as kidneys and heart.

PTCs, also referred to as kidney interstitial capillaries, or KICs, in Fabry clinical trials, convey blood after filtration in the glomeruli, enabling the blood to eventually exit the kidney and return to the circulatory system.

In February 2021, we announced that the fourth patient in our FAB-GT clinical trial exhibited a reduction from an average of 4.02 Gb3 inclusions per PTC at baseline to zero inclusions per PTC one year after administration of AVR-RD-01, representing a 100% clearance of Gb3 substrate.

These data followed our 2019 announcement that the first patient in the FAB-GT clinical trial exhibited a reduction from an average of 3.55 Gb3 inclusions per PTC at baseline to an average of 0.47 inclusions per PTC one year after administration of AVR-RD-01, representing an 87% reduction and a numerical decrease of 3.08.

The assessments for these two patients were each made by two blinded pathologists who independently scored digital images of the sectioned kidneys from the 12-month biopsies.

The second patient in the FAB-GT clinical trial has an N215S genotype, which is associated with a late-onset cardiac variant phenotype.

This patient’s cardiac variant phenotype does not typically result in Gb3 accumulation in the kidney, and accordingly this patient’s kidney biopsy had low levels of Gb3 and lyso-Gb3 at all measurements, including at baseline.

Although we expect that data obtained from this patient will not provide meaningful insight on the primary efficacy endpoint in our FAB-GT clinical trial, including kidney biopsies, other important efficacy and safety measures continue to be derived from data collected from this patient.

A kidney biopsy was conducted on the third patient in the FAB-GT clinical trial, but due to human error in processing the biopsy sample at the external laboratory vendor, the kidney Gb3 inclusions could not be evaluated and will not be available.

The fifth patient in this clinical trial was dosed in February 2021 and we expect to have kidney biopsy data available for that patient in the first half of 2022.

The following figure illustrates the decrease in average Gb3 inclusions per PTC for the first and fourth patients in the Phase 2 FAB-GT clinical trial.

Phase 2 FAB-GT :

Patients 1 and 4 substrate reduction in kidney biopsy

The last available, non-missing observation prior to AVR-RD-01 infusion

With respect to Fabry disease clinical trials, Gb3 inclusions per PTC is interchangeable with GL-3 inclusions per KIC

Lyso-Gb3 Levels

The first patient in our FAB-GT trial had an 86% reduction in plasma lyso-Gb3 levels as of 29 months post-treatment with AVR-RD-01, the third patient had a plasma lyso-Gb3 reduction of 55% as of 19 months post-treatment, and the fourth patient had a plasma lyso-Gb3 reduction of 69% as of 12 months post-treatment with AVR-RD-01, in each case as compared to baseline.

The second patient has an N215S genotype, which is associated with a late-onset cardiac variant phenotype and does not typically result in Gb3 accumulation in the kidney or skin.

AGA Enzyme Activity

In the first two patients in our FAB-GT clinical trial, for whom we have presented data out to 29 and 24 months, respectively, plasma and leukocyte AGA enzyme activity was observed to increase from nearly undetectable levels before treatment to a peak within three months after treatment, followed by a decline and trending to stabilize to levels above the range for males with Fabry disease, defined as less than 1 nmol/hr/ml.

The third patient in the FAB-GT trial exhibited a rapid increase in plasma and leukocyte AGA enzyme activity from nearly undetectable levels before treatment to a peak within the first seven days after treatment in the case of plasma enzyme activity and within the first 14 days after treatment in the case of leukocyte enzyme activity, followed by a decline and subsequent increase which is trending toward a stable level above the range for males with Fabry disease at 18 months after treatment.

The fourth patient in the FAB-GT trial, who was dosed with the plato platform, exhibited a rapid increase in AGA enzyme activity post-treatment and had not exhibited a substantial decline in AGA levels at 12 months after treatment.

Similar to the results observed in the investigator-led Phase 1 trial of AVR-RD-01, we believe that the steep initial increase reflects AGA enzyme activity from the early progeny of the transduced stem cells, while the subsequent decline and stabilization in AGA enzyme levels reflect a shift from short-term progenitor cells towards the gradual secretion of AGA enzyme by long-term engraftment cells that become more predominant over time.

Skin biopsies have been performed in the FAB-GT trial and evaluated by two independent blinded readers using a standard scoring system for Gb3 accumulation and clearance.

The scoring system has a range of zero to three, with a score of zero representing none or trace accumulation, and a score of three representing severe accumulation.

The first patient scored a three at baseline, a two at six months after treatment with AVR-RD-01 and a one at 12 months post-treatment with AVR-RD-01.

The second patient in the FAB-GT trial, whose cardiac variant phenotype does not typically result in Gb3 accumulation in the kidney and skin, scored a zero at baseline and at six months post-treatment with AVR-RD-01 .

The third patient scored a two at baseline and a two at six months post-treatment with AVR-RD-01.

After consideration of the clinical relevance of substrate inclusion in the skin of Fabry patients and the lack of direct, strong correlation with substrate in the kidney, we have changed this trial’s exclusion criteria so that patients with no or minimal substrate in their skin at screening will still be eligible to participate in the clinical trial.

We expect to continue collecting skin biopsy data as an exploratory measurement.

Vector Copy Number

The first four patients in our FAB-GT clinical trial have exhibited consistent VCN trends following administration of AVR-RD-01.

Based on the latest interim data we presented in February 2021, these four FAB-GT patients exhibited VCN levels of 0.04, 0.06, 0.19 and 0.95 at 29 months, 18 months, 19 months and 12 months after treatment, respectively .

Kidney and Cardiac Function

Secondary endpoints of our FAB-GT trial include measurements of kidney function, as measured by estimated glomerular filtration rate, or eGFR, and measured glomerular filtration rate, or mGFR, as well as measures of cardiac function, as assessed by Left Ventricular Mass Index, or LVMI.

eGFR is determined using the Chronic Kidney Disease Epidemiology Collaboration, or CKD-EPI, formula and mGFR is determined using plasma clearance of iohexol.

The left ventricular mass, or LVM, is assessed by cardiac magnetic resonance imaging, or cardiac MRI, which is an imaging technology that enables non-invasive assessment of the function and structure of the heart.

In general, for a patient with Fabry disease, an increase over time in LVM could potentially be expected.

Improving patient outcomes by slowing or halting the progression of organ damage is a key mission of our Company and our investigational gene therapy programs.

In February 2021, we presented eGFR data for all five patients in the Phase 1 clinical trial of AVR-RD-01 and the first four patients in our FAB-GT clinical trial.

We believe these data suggest that eight out of nine patients are exhibiting stable kidney function, with the first patient from the Phase 1 clinical trial out 42 months post-treatment.

One patient, who remains

on ERT as of January 11, 2021, entered the Phase 1 clinical trial with advanced kidney disease and a baseline eGFR level of less than 50 mL/min/1.73m 2 .

As expected, this patient’s kidney function has not stabilized.

Also in February 2021, we presented mean average data on measures of cardiac function and structure in all four patients in the FAB-GT clinical trial at 12-months post-treatment as compared to mean baseline.

The mean measurements of ejection fraction, end diastolic volume, cardiac output and LVMI at 12-months post-treatment showed an average percent change from baseline of 2.2%, 0.2%, 0.8% and 9.8%, respectively.

Preliminary interim safety data from the ongoing FAB-GT study indicate that AVR-RD-01 has been generally well-tolerated in the first four patients enrolled in the study.

As of the safety cut-off date of December 7, 2020, there were 111 AEs reported, 22 of which were Grade 3 or 4.

The remainder of the AEs were Grade 2 or Grade 1.

No AEs were deemed by the investigator to be possibly, probably, or definitely related to drug product.

AEs in this study can be assigned to more than one causality assessment.

As of December 7, 2020, six SAEs were reported, one pre-treatment and five post-treatment.

No events were related to AVR-RD-01 and five events were related to the conditioning regimen.

All six SAEs subsequently resolved without clinical sequelae.

After beginning stem cell mobilization but prior to undergoing the conditioning regimen and treatment with AVR‑RD‑01, the first patient experienced a seizure.

In addition, during a scheduled protocol visit after dosing, the same patient experienced nausea and vomiting, dehydration and was admitted to the hospital for fluid hydration.

Because this event warranted hospital admission, the event was categorized as an SAE.

An additional SAE of febrile neutropenia was reported in each of the second and third patient post-treatment.

The fourth patient experienced two post-treatment SAEs of culture negative fevers and mucositis Grade 2.

In addition to the above, each of the FAB-GT patients experienced a temporary suppression of absolute neutrophil counts and platelets, which is an expected consequence of the conditioning regimen.

These decreases were transient and not associated with any negative long-term impact on the patients.

Neutrophil and platelet counts recovered after dosing.

Because this clinical trial is ongoing, safety and efficacy data are preliminary and subject to change.

As is typical in open-label studies in which interim reports are provided, the data are regularly reviewed and validated.

As a result, certain data may change over time, including reductions or increases in the number of reported safety events, until the database is locked at the end of the study.

AVR-RD-04, Our Gene Therapy for Cystinosis

1 unchanged sentence

AVR-RD-04 is manufactured from hematopoietic stem cells that are first harvested from the patient, modified to add the gene that encodes for cystinosin, and then infused into the patient.

AVR-RD-04 is currently being studied by our collaborators at UCSD in a Phase 1/2 investigator-sponsored clinical trial.

As of March 1, 2021 three patients have been dosed with AVR-RD-04 and as of January 20, 2021 all three remained off cysteamine pills and eye drops.

AVR-RD-04 is currently being studied by our collaborators at UCSD in a Phase 1/2 collaborator-sponsored clinical trial.

As of March 1, 2022 four patients have been dosed with AVR-RD-04.

In March 2021, we announced that the European Commission granted orphan drug designation for AVR-RD-04.

In July 2021, we received clearance from the FDA for an IND application for AVR-RD-04 for the treatment of cystinosis.

This IND clearance allows the Company to initiate a Company-sponsored long-term follow-up study for patients enrolled in the Phase 1/2 collaborator-sponsored clinical trial, as well as potentially initiate a new Company-sponsored clinical trial, subject to regulatory clearance.

Also in July 2021, the FDA granted Fast Track Designation for AVR-RD-04 for the treatment of cystinosis to improve renal function.

Disease Overview

Cystinosis is a rare, genetic, autosomal recessive, lysosomal disorder caused by the accumulation of the amino acid cystine that is produced in the lysosomes of cells as the result of protein degradation.

Cystinosis is a rare, genetic, autosomal recessive, lysosomal disorder caused by the accumulation of cystine, the oxidized dimer of the amino acid cysteine.

Cystine is normally transported through the lysosomal membrane to the cytosol where it is reutilized after its transformation to cysteine.

In cystinosis, cystine accumulates inside the lysosomes because of a defect in the gene that encodes cystinosin, a protein that transports cystine across the lysosomal membrane.

In cystinosis, cystine accumulates inside the lysosomes because of a defect in the gene that encodes cystinosin, the protein that transports cystine across the lysosomal membrane.

Cystine is poorly soluble and forms crystals as its concentration increases.

4 unchanged sentences

By the time the patient is approximately two years old, cystine crystals may be present in the cornea, and the buildup of these crystals in the eye causes pain and an increased sensitivity to light.

children with cystinosis may experience complete kidney failure by the age of ten.

Other signs and symptoms that may occur in untreated patients, especially after adolescence, include muscle deterioration, blindness, inability to swallow, diabetes, thyroid and nervous system problems.

Untreated children with cystinosis may experience complete kidney failure by the age of ten.

Other signs and symptoms that may occur in untreated patients, especially after adolescence, include muscle deterioration, blindness, inability to swallow, type 1 diabetes mellitus, hypothyroidism, and central nervous system problems.

More than 90% of untreated patients require a kidney transplant before the age of 20.

15 unchanged sentences

AVR-RD-04 is a lentiviral-based gene therapy containing a human gene for cystinosin designed to maximize the likelihood of sustained cystinosin production in hematopoietic stem cells and their progeny.

Ongoing Phase 1/2 Investigator-Sponsored Clinical Trial

In the Phase 1/2 clinical trial of AVR-RD-04 that is being conducted by our collaborators at UCSD, six patients with cystinosis who are currently being treated with cysteamine will be enrolled.

Ongoing Phase 1/2 Collaborator-Sponsored Clinical Trial

In the ongoing collaborator-sponsored Phase 1/2 clinical trial of AVR-RD-04, up to six patients with cystinosis who are currently being treated with cysteamine will be enrolled.

This clinical trial is being conducted by UCSD and has been funded in part by grants to UCSD from the California Institute for Regenerative Medicine, Cystinosis Research Foundation and National Institutes of Health.

The clinical trial’s primary endpoints are safety and tolerability, assessed for up to two years after treatment.

4 unchanged sentences

As a result, the protocol for this clinical trial was amended in 2020 to retain safety and tolerability as the primary endpoint, as is appropriate for this stage of development, and shift measurement of cystine in granulocytes to a secondary endpoint.

Because this is an investigator-sponsored clinical, the study drug will not be manufactured using our plato platform, and neither the automated, closed manufacturing system nor LV2 will be used in connection with this clinical trial.

Kidney Function

Assessment of kidney function includes measurements of eGFR and serum creatinine, or sCR.

eGFR is determined using the CKD-EPI formula and sCR is measured as part of the comprehensive metabolic panel.

The first patient in the Phase 1/2 clinical trial exhibited an eGFR value of 42 mL/min/1.73m 2 16 months post-treatment as compared to a baseline value of 55 mL/min/1.73m 2 .

This patient’s eGFR values had been trending downward in the three years prior to administration of

However, at three and 16 months post-treatment the patient’s eGFR values were 43 mL/min/1.73m 2 and 42 mL/min/1.73m 2 , respectively .

While these data suggest potential kidney function stabilization after years of pathological decline, this patient’s eGFR levels could resume declining at an accelerated rate due to the irreversible nature of end-stage renal disease.

A t six months post-treatment the second patient in the clinical trial , who has received two kidney transplants, exhibited an eGFR value of 81 mL/min/1.73m 2 as compared to a baseline value of 71 mL/min/1.73m 2 .

Because this is a collaborator-sponsored clinical, the study drug is not manufactured using our plato platform, and neither the automated, closed manufacturing system nor LV2 is used in connection with this clinical trial.

As of December 1, 2021, the first three patients in the trial had discontinued and remained off oral cysteamine, with the first patient out to 26 months post-treatment.

Additionally, the first and third patients had discontinued and remained off cysteamine eye drops as of December 1, 2021.

The second patient in the trial, who had stopped cysteamine eye drops one-month post-treatment with AVR-RD-04 per the trial protocol, resumed cysteamine eye drops in July 2021.

Vector Copy Number

In February 2022 we presented interim VCN data for the first three patients dosed in the Phase 1/2 clinical trial.

At 27 months post-treatment with AVR-RD-04, the first patient exhibited VCN level of 1.03, and at 12 months post-treatment the second and third patients exhibited VCN level of 1.52 and 2.59, respectively.

Cystine Crystals in Skin and Rectal Biopsy Tissues

Skin and rectal biopsies were performed on the first patient at baseline and 12-months post-treatment with AVR-RD-04.

The data from the biopsies are intended to show the average skin intracytoplasmic crystals per cell, which is a measurement of the number of toxic crystals in each cell, as well as the occupancy of cytoplasmic volume with crystals.

In November 2020, we announced that at 12-months post-treatment the first patient’s skin and rectal biopsies exhibited a 44% and 76% reduction, respectively, in average intracytoplasmic crystals per cell, and a 72% and 87% reduction, respectively, in occupancy of cytoplasmic volume, in each case as compared to the patient’s baseline levels.

We believe these data suggest that the patient is now producing an endogenous supply of functional cystinosin that is reducing the accumulation of toxic cystine crystals.

Levels of Cystine in Skin

Levels of cystine in the skin are measured with in vivo confocal microscopy, or IVCM, on two separate areas of the skin:

behind the ear and in a location determined by the treating physician.

The two measurements are analyzed and quantified with 3D Image-Pro software and averaged.

The first patient in the Phase 1/2 clinical trial exhibited a 56% reduction from baseline in skin cystine levels measured 12 months post-treatment with AVR-RD-04.

These skin measurements are considered experimental methodologies and will require additional study to determine their validity and significance.

Skin and rectal biopsies were performed on the first three patients at baseline and post-treatment with AVR-RD-04.

The data from the biopsies are intended to show the average skin intracytoplasmic crystals per cell, which is a measurement of the number of toxic crystals in each cell.

In February 2022, we announced that at 12-months post-treatment the first three patients’ skin biopsies exhibited a 35%, 64% and 81% reduction, respectively, in average intracytoplasmic crystals per cell.

At 12- and 18-months post-treatment, the first patient’s rectal biopsies exhibited a 76% and 53% reduction, respectively, in average intracytoplasmic crystals per cell as compared to baseline.

The rectal biopsies for the second and third patients at 12-months post-treatment exhibited reductions of 28% and 86%, respectively, in average intracytoplasmic crystals per cell as compared to baseline.

Previously, we reported measurements of the occupancy of cytoplasmic volume from skin and rectal biopsies from the first patient, who exhibited reductions of 72% and 87%, respectively, in each case at 12-months post-treatment as compared to the patient’s baseline levels.

We believe these data suggest that the first three patients are producing an endogenous supply of functional cystinosin that is reducing the accumulation of toxic cystine crystals.

Levels of Cystine in Cornea

Levels of corneal cystine crystals are being assessed in this clinical trial using IVCM.

In November 2020, we presented one set of images of the first patient’s cornea measured at baseline and 12-months post-administration of AVR-RD-04, and another set of images measured at baseline, seven-, nine- and 12-months post-administration.

In February 2022, we presented a set of images of the first patient’s cornea measured at baseline and 18-months post-administration.

The baseline IVCM images were taken using a Nidek ConfoScan microscope and the subsequent images were taken using a Heidelberg (HRT3) with Rostock Cornea Module microscope.

Each of the post-treatment images showed a noticeable decline in the presence of corneal crystals.

Granulocyte Cystine Levels

The first patient in the Phase 1/2 clinical trial exhibited granulocyte cystine levels of 4.2 nmol half cystine per milligram 12 months post-treatment with AVR-RD-04 as compared to the baseline value of 7.8.

This patient’s baseline value was measured two weeks after discontinuation of cysteamine treatment and prior to initiating mobilization.

Vector Copy Number

In February 2021 we presented interim VCN data for the first three patients dosed in the Phase 1/2 clinical trial.

At 12 months post-treatment with AVR-RD-04 the first patient exhibited VCN level of 0.9;

at six months post-treatment the second patient exhibited VCN level of 1.7;

and at one month post-treatment the third patient exhibited VCN level of 2.55.

Photophobia, or light intolerance, is a symptom of cystinosis that is caused by the buildup of cystine crystals in the cornea, inflammatory cell infiltration and corneal nerve damage.

In the Phase 1/2 clinical trial, photophobia is being assessed on a grade of zero to five.

The first patient in the clinical trial scored a three at baseline and a one at 12-months post-treatment.

Exploratory Measurement – Skin and Hair Melanin

Photographs of the first patient in this clinical trial taken at four-, six- and nine-months post-treatment suggest that the patient’s complexion, eyebrows and hair color have darkened following administration of AVR-RD-04.

As is typical of many

people with cystinosis, this patient had fair hair color and skin tone prior to dosing.

Cystinosin has been demonstrated to impact the regulation of melanin synthesis, and the protocol for this trial has been amended to prospectively assess changes in melanin.

As of the safety cut-off date of January 27, 2021, preliminary interim clinical data for the first three patients dosed in the Phase 1/2 clinical trial appear to indicate that the AVR-RD-04 investigational gene therapy has been generally well tolerated with no unexpected safety events identified.

The images were preliminarily scored by a physician, on a scale of zero to four, to quantify crystal deposition in each corneal layer of the central cornea.

At baseline, the preliminary scoring for the first patient was 4.0 across all three eye layers in both eyes, and at 12-months post-treatment the scores for the anterior stroma, middle stroma and posterior stroma of the right eye were 3.0, 3.0 and 2.13, respectively, and 1.86, 1.71 and 2.0, respectively, for the left eye.

Kidney Function

Assessment of kidney function includes measurements of serum creatinine, or sCR, and eGFR, which is determined using the CKD-EPI formula.

The first patient in the Phase 1/2 clinical trial exhibited an eGFR value of 36.3 mL/min/1.73m 2 at 19 months post-treatment as compared to a baseline value of 55 mL/min/1.73m 2 .

This patient’s eGFR values had been trending downward in the three years prior to administration of AVR-RD-04.

We expect this patient’s eGFR levels to continue declining at a level consistent with the irreversible nature of nephropathic cystinosis.

At six months post-treatment the second patient in the clinical trial, who received two kidney transplants prior to treatment in the clinical trial, exhibited an eGFR value of 81 mL/min/1.73m 2 as compared to a baseline value of 71 mL/min/1.73m 2 .

As of the safety cut-off date of December 12, 2021, preliminary interim clinical data for the first four patients dosed in the Phase 1/2 clinical trial appear to indicate that the AVR-RD-04 investigational gene therapy has been generally well tolerated with no unexpected safety events identified.

There have been no reports of safety events attributed to the AVR-RD-04 drug product.

As of the safety data cut-off date of January 27, 2021 one SAE of appendicitis was reported, which occurred post-treatment and was deemed by the investigator to be unrelated to AVR-RD-04 or the treatment procedures.

A total of 48 AEs were reported as of the safety cut-off date of January 27, 2021, a majority of which were reported by the investigator to be moderate or mild.

All reported AEs were consistent with expectations for the underlying disease and conditioning regimen prescribed by the study protocol.

Because this clinical trial is ongoing, safety and efficacy data are preliminary and subject to change.

As of the safety data cut-off date of December 12, 2021, one serious adverse event, or SAE, of appendicitis was reported, which occurred post-treatment and was deemed by the investigator to be unrelated to AVR-RD-04 or the treatment procedures.

A total of 84 adverse events, or AEs, were reported as of the safety cut-off date of December 12, 2021, a majority of which were reported by the investigator to be moderate or mild.

All reported AEs were consistent with expectations for the underlying disease, stem cell mobilization and conditioning regimen prescribed by the study protocol.

The foregoing data on the Phase 1/2 clinical trial of AVR-RD-04 have been provided by our collaborators at UCSD and are subject to change.

Additionally, because this clinical trial is ongoing, safety and efficacy data are preliminary and subject to change.

As is typical in open-label studies in which interim reports are provided, the data are regularly reviewed and validated.

3 unchanged sentences

We plan to manufacture AVR-RD-02 from hematopoietic stem cells that are first harvested from the patient, modified to add the gene that encodes for glucocerebrosidase, or GCase, and then infused into the patient.

Patient enrollment has commenced for the Phase 1/2 Guard1 clinical trial of AVR-RD-02 in patients with Gaucher disease type 1, and we dosed the first patient in the second quarter of 2020.

The Guard1 trial is actively recruiting in Australia and Canada, with additional sites planned in the United States, Israel and Europe .

As of March 1, 2021 one patient has been dosed.

Patient enrollment has commenced for the Phase 1/2 Guard1 clinical trial of AVR-RD-02 in patients with Gaucher disease type 1, and as of March 1, 2022 we have dosed three patients.

The Guard1 trial is actively recruiting additional potential patients for our currently active sites .

Disease Overview

13 unchanged sentences

Twenty-five percent of patients with Gaucher disease continue to experience physical limitations following two years of ERT, and a clinically significant percentage of patients continue to experience bone pain, thrombocytopenia and enlargement of spleen following ten years of ERT.

In a published study of ERT therapy for Gaucher disease type 1, six target goals were evaluated, including parameters for hemoglobin and platelet levels, spleen and liver

volumes, and general bone pain and severe disabling bone pain known as bone crisis.

In a published study of ERT therapy for Gaucher disease type 1, six target goals were evaluated, including parameters for hemoglobin and platelet levels, spleen and liver volumes, and general bone pain and severe disabling bone pain known as bone crisis.

Following at least four years of ERT in this study, approximately 60% of patients failed to achieve one or more of these six target goals.

10 unchanged sentences

We have initiated our Guard1 Phase 1/2 clinical trial of AVR-RD-02 in patients with Gaucher disease type 1.

Patient enrollment has commenced, and as of March 1, 2021 one patient has been dosed.

This clinical trial is actively recruiting in Australia and Canada, with additional sites planned in the United States, Israel and Europe .

Our initial clinical trial will be an adaptive trial that will include both treatment-naïve patients and patients that are currently stable on ERT.

Patient enrollment has commenced, and as of March 1, 2022, three patients have been dosed.

This clinical trial is actively recruiting additional potential patients for our currently active sites .

Our initial clinical trial is open to treatment-naïve patients;

patients that have been stable on ERT for at least 24 months;

and patients who have not received ERT or substrate reduction therapy, or SRT, in the past 12 months.

We intend to enroll eight to 16 patients, between the ages of 18 and 50, with Gaucher disease type 1.

Patients currently prescribed ERT will cease treatment throughout the clinical trial.

All enrolled patients will receive a single treatment with AVR-RD-02 and will be followed for 52 weeks to measure safety and efficacy.

Patients currently prescribed ERT will cease treatment for the duration of the clinical trial.

All enrolled patients will

receive a single treatment with AVR-RD-02 and will be followed for 52 weeks to measure safety and efficacy.

We intend to utilize our plato platform for all patients enrolling in our Phase 1/2 clinical trial of AVR-RD-02.

Our efficacy endpoints for this clinical trial will include measures of clinical efficacy, such as liver and spleen volumes, hemoglobin, platelet counts, bone pain and bone density measures along with other blood markers used in Gaucher disease type 1.

In February 2021 we presented data on the first patient in the Guard1 clinical trial, who discontinued ERT one month prior to dosing of AVR-RD-02 and remains off ERT as of February 8, 2021.

Our efficacy endpoints for this clinical trial will include visceral domain and hematologic measures such as liver and spleen volumes, hemoglobin, platelet counts, bone pain and bone density measures, and quality of life measures along with critical biological blood markers used to track the disease progression in Gaucher disease type 1.

In February 2021 we presented data on the first patient in the Guard1 clinical trial, which are described below.

We currently expect to provide an update on interim clinical data in 2022.

Vector Copy Number

In February 2021 we presented VCN data for the first patient dosed in the Guard1 trial.

At six months post-treatment, the patient exhibited a VCN of 0.6.

In addition, at three months post-treatment an exploratory assessment of VCN in specific cell populations showed a VCN ≥ 0.7 in the myeloid cell lines, which we believe could be indicative of transgene presence in the macrophages, the essential cell impacted in Gaucher patients.

Plasma Lyso-Gb1 Reductions

13 unchanged sentences

Both six-month measurements are within the normal range for a healthy individual.

Vector Copy Number

In February 2021 we presented VCN data for the first patient dosed in the Guard1 trial.

At six months post-treatment, the patient exhibited a VCN of 0.6.

As of the safety cut-off date of January 4, 2021, preliminary interim clinical data for the first patient dosed in the Guard1 clinical trial appear to indicate that the AVR-RD-02 investigational gene therapy has been generally well tolerated with no unexpected safety events identified.

As of the most recent safety cut-off date of August 31, 2021, preliminary interim clinical data for the first patient dosed in the Guard1 clinical trial appear to indicate that the AVR-RD-02 investigational gene therapy has been generally well tolerated with no unexpected safety events identified.

There have been no reports of safety events attributed to the AVR-RD-02 drug product, and no SAEs were reported as of the safety data cut-off date.

A total of 29 AEs were reported as of the safety cut-off date, two of which were Grade 4 and seven of which were Grade 3.

The remainder of the AEs were Grade 2 or Grade 1.

All reported AEs were consistent with expectations for the underlying disease and conditioning regimen prescribed by the study protocol and have resolved.

A total of 37 AEs were reported as of the safety cut-off date, 11 of which were Grade 3 or 4 and 26 of which were Grade 1 or 2.

All reported AEs were consistent with expectations for the underlying disease, conditioning regimen and drugs mandated by the study protocol or procedures.

As of the safety cut-off date of August 31, 2021, all AEs had resolved except for one AE of amenorrhea which remained unresolved and ongoing.

Because this clinical trial is ongoing, safety and efficacy data are preliminary and subject to change.

4 unchanged sentences

AVR-RD-05 involves ex vivo transduction of the patient’s own hematopoietic stem cells with a therapeutic transgene, in-licensed from the University of Manchester, or UoM, designed to express functional iduronate 2-sulfatase, or IDS, which is the enzyme the patient needs to maintain cellular health, coupled to a proprietary ApoE2 protein tag that is designed to improve stability of the enzyme in the bloodstream and facilitate uptake by tissues.

AVR-RD-05 will be studied by our collaborators at UoM and a Phase 1/2 investigator-sponsored clinical trial of AVR-RD-05 is expected to commence in the first half of 2022.

AVR-RD-05 will be studied by our collaborators at UoM, and a Phase 1/2 investigator-sponsored clinical trial of AVR-RD-05 is expected to be initiated in 2023.

Disease Overview

4 unchanged sentences

Hunter syndrome is an X-linked disorder, meaning the gene that is responsible is located on the X chromosome.

Because males have only one X chromosome, an abnormal copy of the gene that causes Hunter syndrome disease is sufficient to cause the disease.

Because males have only one X chromosome, an abnormal copy of the gene that causes Hunter syndrome is sufficient to cause the disease.

The overall diagnosed incidence of Hunter syndrome is estimated to be approximately one in 100,000 to one in 170,000 males worldwide.

7 unchanged sentences

ERT does not treat the neurological symptoms of the disease, and therefore a significant unmet need remains in a majority of patients with Hunter syndrome.

Furthermore, anti-ERT antibodies are a limitation for a significant part of the entire patient population.

Furthermore, anti-ERT antibodies are a limitation for a significant part of the patient population.

We, together with our collaborators at UoM, are developing AVR-RD-05 to potentially provide a functional cure to patients with Hunter syndrome.

6 unchanged sentences

We believe these data support the potential of AVR-RD-05 to treat this progressive disease, and potentially prevent the onset of severe symptoms if treated early.

Planned Phase 1/2 Investigator-Sponsored Clinical Trial

Our collaborators at UoM plan to initiate a Phase 1/2 clinical trial in the first half of 2022.

Planned P hase 1/2 Investigator-Sponsored Clinical Trial

Our collaborators at UoM plan to initiate a Phase 1/2 clinical trial in 2023.

The Phase 1/2 clinical trial is expected to enroll five male patients, age three months to 12 months, with an early progressive form of the disease.

1 unchanged sentence

The clinical trial’s primary endpoints are expected to be safety and tolerability.

Secondary endpoints to assess preliminary efficacy are expected to include measurements of IDS levels and its activity as well as levels of glycosaminoglycans .

Neurocognitive evaluations will also be conducted to evaluate therapeutic activity in the brain.

Secondary endpoints to assess preliminary efficacy are expected to include measurements of peripheral expression of IDS activity in plasma, cerebrospinal fluid, or CSF, and leukocytes;

heparin sulfate concentration in CSF, plasma and urine;

VCN per diploid genome, proportion of cells containing the inserted gene in total bone marrow colony forming units;

cognitive function;

and various behavioral and quality of life measurements.

AVR-RD-06, Our Gene Therapy for Gaucher disease type 3

In November 2020, we announced an expansion of our lysosomal disorder pipeline with a new preclinical product candidate, AVR-RD-06, our investigational gene therapy for Gaucher disease type 3.

AVR-RD-06 is our gene therapy program for Gaucher disease type 3.

Gaucher disease type 3 is the subacute neurological form of Gaucher disease characterized by progressive encephalopathy and associated with the systemic manifestations of Gaucher type 1.

2 unchanged sentences

AVR-RD-06 is expected to use the same vector and drug product that we use in AVR-RD-02, our investigational gene therapy for Gaucher disease type 1.

We currently expect to request a meeting with the FDA this year to discuss a potential path to the clinic for AVR-RD-06.

We currently expect to engage with regulators in 2022 to discuss a path to the clinic, including a potential Phase 2/3 clinical trial.

Disease Overview

11 unchanged sentences

Limitations of Current Therapies

Current therapies used to treat Gaucher disease type 1, namely, ERT and substrate reduction therapy, or SRT, do not penetrate the brain and therefore have no effect on the neurological aspects of Gaucher disease type 3.

Current therapies used to treat Gaucher disease type 1, namely, ERT and SRT, do not penetrate the brain and therefore have no effect on the neurological aspects of Gaucher disease type 3.

The most commonly prescribed ERTs for Gaucher disease are Cerezyme, marketed by Sanofi Genzyme, and VPRIV, marketed by Shire.

12 unchanged sentences

We are developing AVR-RD-03 for the treatment of Pompe disease.

We will manufacture AVR-RD-03 from hematopoietic stem cells that are first harvested from the patient, modified to add the gene that encodes for acid alpha glucosidase A, or GAA, attached to a peptide sequence known as a glycosylation-independent lysosomal targeting, or GILT,

tag and then infused into the patient.

AVR-RD-03 will incorporate a GILT tag because the GILT tag has been found to increase the uptake of GAA into cells, especially in muscle cells by a multiple of 25, which is a particularly important target tissue for patients with Pompe disease and a target tissue that is considered difficult to access for ERT.

16 unchanged sentences

Pompe disease is currently treated with ERT delivered by bi-weekly intravenous infusion.

The only approved therapy for Pompe disease is Lumizyme (known as Myozyme outside of the United States), marketed by Sanofi Genzyme, which generated worldwide net sales of approximately €948 million euros in 2020.

We estimate that the average five-year cost to the healthcare system per Pompe patient prescribed standard of care treatment in the United States is approximately $3.2 million.

4 unchanged sentences

The FDA approval of Lumizyme carries a black box warning related to the risk of severe allergic and immune mediated reactions, including life-threatening anaphylaxis.

Our AVR-RD-03 program for Pompe disease is currently in preclinical development, and in 2020 we completed IND-enabling proof-of-concept preclinical studies, with toxicology studies expected to be completed in 2021.We are developing AVR-RD-03 to be a gene therapy product containing a codon-optimized human gene for GAA attached to a GILT tag designed to increase uptake of GAA in muscle cells.

We are developing AVR-RD-03 to be a gene therapy product containing a codon-optimized human gene for GAA attached to a GILT tag designed to increase uptake of GAA in muscle cells.

AVR-RD-03 will target patients with late onset Pompe disease, which represent the majority of patients with this disease.

2 unchanged sentences

In November 2020 we presented data from a study in which mice with the equivalent of classic infantile-onset Pompe disease were treated with AVR-RD-03.

We these data believe support the potential of lentiviral-based gene expression of

GAA to prevent some of the symptoms of GAA deficiency.

We these data believe support the potential of lentiviral-based gene expression of GAA to prevent some of the symptoms of GAA deficiency.

These results also demonstrated the need to further increase the uptake of GAA into muscle cells to treat patients, which is a known challenge for ERTs and leads to the use of large quantities of enzyme to attempt to deliver effective treatment levels.

13 unchanged sentences

Industrializing Our Gene Therapies Through Our Outsourced Manufacture and Supply Network

We are establishing global manufacturing relationships that we believe will provide us with drug product manufacturing capabilities to support all aspects of the development and eventual commercialization of our gene therapies.

Our team has leveraged their broad expertise in the manufacturing of gene and cellular therapies to build a global network of CMO partners for the development and manufacture of drug products and outsourced suppliers for the supply of vectors and plasmids.

We believe that our third-party CMO partners and suppliers have capacity to accommodate current and future clinical trials and we are continuing to build a global network that we expect will have capacity to generate sufficient quantities to meet our expected commercial needs.

We have established manufacturing relationships that we believe will provide us with drug product manufacturing capabilities to support all aspects of the development and eventual commercialization of our gene therapies.

Our team has leveraged their broad expertise in the manufacturing of gene and cellular therapies to build a network of CMO partners for the development and manufacture of drug products and outsourced suppliers for the supply of vectors and plasmids.

We currently rely, and expect to continue to rely, on sole source suppliers for vector supply, plasmid supply and cell culture media.

In addition, although we have historically relied on multiple CMO partners for drug product manufacturing, we currently plan to use a sole source CMO as the provider of drug product for our ongoing and future Company-sponsored clinical trials.

However, we believe that our third-party CMO partner and suppliers have capacity to accommodate current and future clinical trials and we are continuing to build a network that we expect will have capacity to generate sufficient quantities to meet our expected commercial needs.

To optimize production of our gene therapies, we have moved our cell processing to an automated, closed system using disposable supplies.

We believe this industrialized manufacturing process will enable a repeatable approach through which we can design and manufacture commercially viable lentiviral gene therapies to potentially treat a large variety of genetic disorders.

We believe this industrialized manufacturing process will enable a repeatable approach through which we can design and manufacture commercially viable ex vivo lentiviral gene therapies to potentially treat a large variety of genetic disorders.

We expect that our automation of the manufacturing processes will further increase our CMO partners’ manufacturing capacity.

Producing a Patient’s Gene Therapy

We start the process to produce a patient’s gene therapy with the mobilization of a patient’s stem cells from the bone marrow to the blood stream and isolate them using a standard procedure used in stem cell transplants.

We then treat these cells with a lentiviral vector to insert the equivalent of a functional copy of the gene that is defective in the target disease in a 48-hour process.

We start the process to produce a patient’s gene therapy with the mobilization of a patient’s stem cells from the bone marrow to the blood stream and collect them via apheresis, a standard procedure used in stem cell transplants.

The apheresis material is then transported to the manufacturing facility where we isolate the stem cells and treat these cells with a lentiviral vector to insert the equivalent of a functional copy of the gene that is mutated in the target disease.

The manufacturing process typically takes approximately three days to complete.

We preserve patients’ modified cells at a very low temperature, using cryopreservation to maintain the cellular material in optimal condition until it is thawed prior to being infused into the patient.

The cryopreservation allows us to conduct a number of tests to validate the modified cells prior to introducing them into the patient.

We believe cryopreservation will also enable us to supply our products globally, as well as significantly increase the convenience of

infusion scheduling for clinicians and patients, compared to fresh ex vivo gene therapy products that may have shelf-lives of only 24 hours.

Cryopreservation of the product allows for long-term storage and the ability to conduct a number of quality control tests to validate the modified cells prior to introducing them into the patient.

We believe cryopreservation will also enable us to supply our products globally, as well as significantly increase the convenience of infusion scheduling for clinicians and patients, compared to fresh ex vivo gene therapy products that may have shelf-lives of only 24 hours.

Prior to infusion of the gene therapy-modified cells into the patient, the patients undergo a conditioning regimen to remove some of the patient’s unmodified cells from the bone marrow to create sufficient space for the modified hematopoietic stem cells to engraft and produce their progeny.

After the conditioning regimen is complete, the lentivirally-modified stem cells are infused into the patient by intravenous administration in an outpatient setting.

After infusion, these cells engraft into the bone marrow, replicate and differentiate into all the various types of blood cells that will distribute throughout the body.

These widely distributed cells lead to sustained expression of the desired therapeutic enzyme or other protein.

The sustained expression of the functional enzyme is a direct substitute for the protein currently delivered by ERTs, which require periodic infusions.

After the conditioning regimen is complete, the ex vivo lentiviral-modified stem cells are infused into the patient by intravenous administration.

After infusion, these cells are expected to engraft into the bone marrow, replicate and differentiate into all the various types of blood cells that will distribute throughout the body.

These widely distributed cells potentially lead to sustained expression of the desired therapeutic enzyme or protein.

The sustained expression of the functional enzyme or protein is a direct substitute for the protein currently delivered by ERTs, which require periodic infusions.

Intellectual Property and Other Barriers to Entry

The proprietary nature of, or protection for, our gene therapy technology, our product candidates, our production methods and supply chain are an important part of our strategy to develop and commercialize novel therapies.

To maximize the commercial opportunity for our gene therapies, if approved, we and our partners have been building and continue to build barriers to entry by our competitors, including:

the commercial opportunity for our gene therapies, if approved, we and our partners have been building and continue to build barriers to entry by our competitors, including:

We in-license and develop know-how, including data, relating to certain of our product candidates.

9 unchanged sentences

See “—Government Regulation.”

We currently in-license, and we expect to file our own, patents and patent applications relating to certain of our product candidates.

We currently in-license patents and patent applications relating to certain of our product candidates.

We have also filed our own patent applications, which are positioned to further protect certain of our product candidates.

We have in-licensed patents and patent applications from BioMarin Pharmaceutical Inc., GenStem Therapeutics, Inc.

7 unchanged sentences

AVR-RD-03 (Pompe program) :

patents, projected to expire in 2022 and 2023, and two U.S.

patent applications, which if granted, would be projected to expire in 2022 and 2029, as well as corresponding patents and patent applications in certain foreign jurisdictions, as they pertain to compositions and methods for promoting lysosomal uptake of acid alpha-glucosidase and the treatment of Pompe disease.

patents, projected to expire in 2022 and 2023, and one U.S.

patent application, which if granted, would be projected to expire in 2029, as well as corresponding patents and patent applications in certain foreign jurisdictions, as they pertain to compositions and methods for promoting lysosomal uptake of acid alpha-glucosidase and the treatment of Pompe disease.

These patents and patent applications are licensed to us by BioMarin and relate to the GILT tag.

5 unchanged sentences

These patent applications are licensed to us by the University of Manchester.

As of March 1, 2022, our Company-owned patent portfolio also included the following:

AVR-RD-03 (Pompe program) :

one international (PCT) application, which , if granted in the U.S.

, would be projected to expire in 2041 , containing claims directed to CD34+ stem cells expressing acid alpha-glucosidase and methods of using the same for the treatment of Pompe disease.

The term of any given patent depends upon the legal term of patents in the countries in which they are obtained.

26 unchanged sentences

UHN may terminate the agreement if we fail to meet these performance milestones despite using commercially reasonable efforts and we are unable to reach agreement with UHN on revised timeframes.

As consideration for the licenses, we paid to UHN a one-time upfront fee in the amount of C$75,000 and are obligated to pay an additional annual fee until the first sale of a licensed product in certain markets.

We are also required to make payments to UHN in connection with the achievement of certain development and regulatory milestones, in an aggregate amount of C$2.45 million, as well as royalties on a country-by-country basis of a low to mid-single digit percentages on annual sales of licensed products and a lower single digit royalty in certain circumstances.

As consideration for the licenses, we paid to UHN a one-time upfront fee in the amount of CAD$75,000 and are obligated to pay an additional annual fee until the first sale of a licensed product in certain markets.

We are also required to make payments to UHN in connection with the achievement of certain development and regulatory milestones, in an aggregate amount of CAD$2.45 million, as well as royalties on a country-by-country basis of a low to mid-single digit percentages on annual sales of licensed products and a lower single digit royalty in certain circumstances.

Additionally, we will pay a low double-digit percentage of all sublicensing revenue.

Our royalty obligation expires on a licensed product-by-licensed product and country-by-country basis upon the latest to occur of the expiration or termination of the last valid claim under the licensed patent rights in such country (if and when any such patent rights come into existence under the license agreement in the future), the tenth anniversary of the first commercial sale of such licensed product in such country and the expiration of any applicable regulatory exclusivity in such country.

In addition, under this agreement we made a philanthropic commitment to donate funds to organizations for the benefit of the Canadian Fabry community in an amount equal to a low double-digit percentage of our royalty payments and regulatory milestone payments, up to a maximum amount of C$0.5 million in any calendar year.

Unless terminated earlier, this exclusive license agreement with UHN will expire upon the expiration of our royalty obligation for all licensed products.

25 unchanged sentences

We may terminate the agreement for any reason upon notice to BioMarin.

License Agreement with GenStem Therapeutics, Inc.

License Agreement with Papillon Therapeutics, Inc.

(previously GenStem Therapeutics, Inc.)

In October 2017, we entered into a license agreement with GenStem Therapeutics, Inc., or GenStem, pursuant to which GenStem granted us an exclusive worldwide license, subject to certain retained rights, under certain intellectual property rights owned or controlled by GenStem related to our cystinosis program, including certain rights licensed to GenStem from the University of California, San Diego, to develop, commercialize and sell products for use in the treatment of cystinosis.

1 unchanged sentence

We also agreed to comply with certain access requirements consistent with the California Institute for Regenerative Medicine regulations and to manufacture certain licensed products substantially in the United States.

In October 2021, we received noticed that the license agreement with GenStem had been assigned to Papillon Therapeutics, Inc., or Papillon.

As consideration for the license, we paid an initial license fee in the amount of $1.0 million and are required to make payments upon completion of certain development milestones up to an aggregate of $16.0 million.

For example, i n November 2019 we made a $2.0 million payment in connection with the dosing of the first patient in the investigator-sponsored Phase 1/2 clinical trial of AVR-RD-04 in cystinosis in the United States.

Additionally, we will pay to GenStem a tiered mid to high-single digit royalty percentage on annual net sales of licensed products as well as a low double-digit percentage of sublicense income received from certain third party sublicensees.

Additionally, we will pay to Papillon a tiered mid to high-single digit royalty percentage on annual net sales of licensed products as well as a low double-digit percentage of sublicense income received from certain third party sublicensees.

Our royalty obligation expires on a licensed product-by-licensed product and country-by-country basis on the eleventh anniversary of the first commercial sale of such licensed product in such country or the expiration of the last valid claim under the licensed patent rights covering such licensed product in such country, which is currently projected to occur in 2038, whichever is later.

Unless terminated earlier, our license agreement with GenStem will terminate upon the expiration of our royalty obligation for all licensed products throughout the world.

Either we or GenStem may terminate the license agreement if the other party commits a material breach and fails to cure such breach within a certain period of time.

In addition, we may terminate the agreement for any reason upon notice to GenStem.

Unless terminated earlier, our license agreement with Papillon will terminate upon the expiration of our royalty obligation for all licensed products throughout the world.

Either we or Papillon may terminate the license agreement if the other party commits a material breach and fails to cure such breach within a certain period of time.

In addition, we may terminate the agreement for any reason upon notice to Papillon.

Our industry is highly competitive and subject to rapid and significant technological change.

Our potential competitors include larger pharmaceutical, specialty pharmaceutical and biotechnology companies, as well as academic institutions,

government agencies and private and public research institutions.

Our potential competitors include larger pharmaceutical, specialty pharmaceutical and biotechnology companies, as well as academic institutions, government agencies and private and public research institutions.

Key competitive factors affecting the commercial success of our gene therapies are likely to be efficacy, safety and tolerability profile, reliability, convenience, price and reimbursement.

7 unchanged sentences

Finally, the development of new treatment methods for the diseases we are targeting could render our gene therapies non-competitive or obsolete.

See “Risk Factors—Risks related to the discovery and development of our product candidates—We face significant competition and our competitors may achieve regulatory approval before us or develop therapies that are more advanced or effective than ours, which may adversely affect our ability to successfully market or commercialize any of our product candidates,” and elsewhere in this Annual Report on Form 10-K for more information regarding competitors and competitive products.

See “Risk Factors—Risks related to the discovery and development of our product candidates—We face significant competition in our industry and there can be no assurance that our product candidates, if approved, will achieve acceptance in the market over existing established therapies.

In addition, our competitors may develop therapies that are more advanced or effective than ours, which may adversely affect our ability to successfully market or commercialize any of our product candidates,” and elsewhere in this Annual Report on Form 10-K for more information regarding competitors and competitive products.

Government Regulation

1 unchanged sentence

Both the FD&C Act and the PHS Act and their corresponding regulations govern, among other things, the testing, manufacturing, safety, efficacy, labeling, packaging, storage, record keeping, distribution, reporting, advertising and other promotional practices involving biological products.

Each clinical study protocol for a gene therapy product must be reviewed by the FDA and, in some instances, the National Institute of Health, or NIH, through its Recombinant DNA Advisory Committee, or RAC.

FDA approval must be obtained before the marketing of biological products.

Each clinical study protocol for a gene therapy product must be reviewed by the FDA, and FDA approval must be obtained before the marketing of biological products.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources and we may not be able to obtain the required regulatory approvals.

Within the FDA, the Center for Biologics Evaluation and Research, or CBER, regulates gene therapy products.

The CBER works closely with the NIH and its RAC, which makes recommendations to the NIH on gene therapy issues and engages in a public discussion of scientific, safety, ethical and societal issues related to proposed and ongoing gene therapy protocols.

The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols.

The FDA also has published guidance documents related to, among other things, gene therapy products in general, their preclinical assessment, observing subjects involved in gene therapy studies for delayed adverse events, potency testing, and chemistry, manufacturing and control information in INDs for gene therapies.

The FDA has published guidance documents related to, among other things, gene therapy products in general, their preclinical assessment, observing subjects involved in gene therapy studies for delayed adverse events, potency testing, and chemistry, manufacturing and control information in INDs for gene therapies.

Ethical, social and legal concerns about gene therapy, genetic testing and genetic research could result in additional regulations restricting or prohibiting the processes we may use.

22 unchanged sentences

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical study can begin.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules had historically been subject to review by the Recombinant DNA Advisory Committee, or RAC, of the National Institutes of Health, or NIH, Office of Biotechnology Activities, or the OBA, pursuant to the NIH Guidelines for Research Involving Recombinant DNA Molecules, or NIH Guidelines.

On August 17, 2018, the NIH issued a notice in the Federal Register and issued a public statement proposing changes to the oversight framework for gene therapy trials, including changes to the applicable NIH Guidelines to modify the roles and responsibilities of the RAC with respect to human clinical trials of gene therapy products, and requesting public comment on its proposed modifications.

During the public comment period, which closed October 16, 2018, the NIH announced that it will no longer accept new human gene transfer protocols for review as a part of the protocol registration process or convene the RAC to review individual clinical protocols.

In April 2019, NIH announced the updated guidelines, which reflect these proposed changes, and clarified that these trials will remain subject to the FDA’s oversight and other clinical trial regulations, and oversight at the local level will continue as set forth in the NIH Guidelines.

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an institutional biosafety committee, or IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety committees, or IBCs, as set forth in the National Institutes of Health, or NIH, Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.

Under the NIH Guidelines, recombinant and synthetic nucleic acids are defined as:

(i) molecules that are constructed by joining nucleic acid molecules and that can replicate in a living cell (i.e., recombinant nucleic acids);

(ii) nucleic acid molecules that are chemically or by other means synthesized or amplified, including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules (i.e., synthetic nucleic acids);

or (iii) molecules that result from the replication of those described in (i) or (ii).

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial.

While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

The FDA also may impose clinical holds on a biological product candidate at any time before or during clinical studies due to safety concerns or non-compliance.

30 unchanged sentences

The NIH has a publicly accessible database, the Genetic Modification Clinical Research Information System which includes information on gene transfer studies and serves as an electronic tool to facilitate the reporting and analysis of adverse events on these studies.

Concurrent with clinical studies, companies usually complete additional animal studies and also must develop additional information about the physical characteristics of the biological product as well as finalize a process for manufacturing the product in commercial quantities in accordance with CGMP requirements.

To help r educe the risk of the introduction of adventitious agents with use of biological products, the PHS Act emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined.

69 unchanged sentences

As a condition of approval, the FDA may require that a sponsor of a drug or biological product receiving accelerated approval perform adequate and well-controlled post-marketing clinical studies.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

In addition, for products being considered for accelerated approval, the FDA generally requires, unless otherwise informed by the agency, that all advertising and promotional materials intended for dissemination of publication within 120 days of marketing approval be submitted to the agency for review during the pre-approval review period.

Regenerative Medicine Advanced Therapies Designation

14 unchanged sentences

We will rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of any products that we may commercialize.

Manufacturers of our products are required to comply with applicable requirements in the CGMP regulations, including quality control and quality assurance and maintenance of records and documentation.

Other post-approval requirements applicable to biological

products, include reporting of CGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information, and complying with electronic record and signature requirements.

Manufacturers of our products are required to comply with applicable requirements in the cGMP regulations, including quality control and quality

assurance and maintenance of records and documentation.

Other post-approval requirements applicable to biological products, include reporting of c GMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information, and complying with electronic record and signature requirements.

After a BLA is approved, the product also may be subject to official lot release.

10 unchanged sentences

Biological product manufacturers and other entities involved in the manufacture and distribution of approved biological products are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMPs and other laws.

Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterate products or products that are otherwise unfit for distribution in the United States.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

15 unchanged sentences

The ACA , signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 which created an abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-licensed reference biological product.

This amendment to the PHS Act attempts to minimize

duplicative testing.

This amendment to the PHS Act attempts to minimize duplicative testing.

Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical study or studies.

21 unchanged sentences

Certain countries outside of the United States have a similar process that requires the submission of a clinical study application much like the IND prior to the commencement of human clinical studies.

In the European Union, for example, a Clinical Trial Application, or CTA, must be submitted for each clinical trial to each country’s national health authority and an independent ethics committee, much like the FDA and an IRB, respectively.

In the European Union, for example, a

Clinical Trial Application, or CTA, must be submitted for each clinical trial to each country’s national health authority and an independent ethics committee, much like the FDA and an IRB, respectively.

Once the CTA is approved in accordance with a country’s requirements, the corresponding clinical study may proceed.

37 unchanged sentences

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

On December 2, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to an order entered by the U.S.

District Court for the District of Columbia, the portion of the rule eliminating safe harbor protection for certain rebates related to the sale or purchase of a pharmaceutical product from a manufacturer to a plan sponsor under Medicare Part D has been delayed to January 1, 2023.

Further, implementation of this change and new safe harbors for point-of-sale reductions in price for prescription pharmaceutical products and pharmacy benefit manager service fees are currently under review by the Biden administration and may be amended or repealed;

federal civil and criminal false claims laws and civil monetary penalty laws, including the FCA, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, false or fraudulent claims for payment to, or approval by Medicare, Medicaid, or other federal healthcare programs, knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim or an obligation to pay or transmit money to the federal government, or knowingly concealing or knowingly and improperly avoiding or decreasing or concealing an obligation to pay money to the federal government.

29 unchanged sentences

Notably, on January 21, 2019, Google was fined almost $57 million by French regulators for violating GDPR.

European Data Collection

European and UK Personal Data Collection

The collection and use of personal health data in the European Union is governed by the provisions of the Data Protection Directive, and as of May 25, 2018 the GDPR.

3 unchanged sentences

The GDPR and other changes in laws or regulations associated with the enhanced protection of certain types of personal data, such as healthcare data or other sensitive information, could greatly increase our cost of providing our products and services or even prevent us from offering certain services in jurisdictions that we may operate in.

In addition, further to the UK’s exit from the EU on January 31, 2020, the GDPR ceased to apply in the UK at the end of the transition period on December 31, 2020.

However, as of January 1, 2021, the UK’s European Union (Withdrawal) Act 2018 incorporated the GDPR (as it existed on December 31, 2020 but subject to certain UK specific amendments) into UK law, referred to as the “UK GDPR.” The UK GDPR and the UK Data Protection Act 2018 set out the UK’s data protection regime, which is independent from but aligned to the EU’s data protection regime.

Non-compliance with the UK GDPR may result in monetary penalties of up to £17.5 million or 4% of worldwide revenue, whichever is higher.

Although the UK is regarded as a third country under the EU’s GDPR, the European Commission has now issued a decision recognizing the UK as providing adequate protection under the EU GDPR and, therefore, transfers of personal data originating in the EU to the UK remain unrestricted.

Like the EU GDPR, the UK GDPR restricts personal data transfers outside the UK to countries not regarded by the UK as providing adequate protection.

The UK government has confirmed that personal data transfers from the UK to the EEA remain free flowing.

Healthcare Reform

9 unchanged sentences

and established the Center for Medicare Innovation at Centers for Medicare & Medicaid Services, or CMS, to test innovative payment and service delivery models to lower Medicare and Medicaid spending.

Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.

Various portions of the ACA are currently undergoing legal and constitutional challenges in the United States Supreme Court and members of Congress have introduced several pieces of legislation aimed at significantly revising or repealing the ACA.

The United States Supreme Court is expected to rule on a legal challenge to the constitutionality of the ACA in early 2021.

The implementation of the ACA is ongoing, the law appears likely to continue the downward pressure on pharmaceutical pricing, especially under the Medicare program, and may also increase our regulatory burdens and operating costs.

Litigation and legislation related to the ACA are likely to continue, with unpredictable and uncertain results.

In addition, the Budget Control Act of 2011 and the Bipartisan Budget Act of 2015 led to aggregate reductions of Medicare payments to providers of up to 2% per fiscal year that will remain in effect through 2030 unless additional Congressional action is taken.

Pursuant to the Coronavirus Aid, Relief, and Economic Security Act, also known as the CARES Act, as well as subsequent legislation, these reductions have been suspended from May 1, 2020 through March 31, 2021 due to the COVID-19 pandemic.

Proposed legislation, if passed, would extend this suspension until the end of the pandemic.

Further, on January 2, 2013, the American Taxpayer Relief Act was signed into law, which, among other things, reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

More recently, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which have resulted in several recent Congressional inquiries and proposed bills designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products.

Individual states in the United States have also become increasingly active in proposing and passing legislation and implementing regulations designed to control pharmaceutical

product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Finally, on May 30, 2018, the Right to Try Act, was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase I clinical trial and that are undergoing investigation for FDA -approval.

Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Prior to the Supreme Court's decision, President Biden issued an Executive Order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The Executive Order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

It is unclear how other healthcare reform measures of the Biden administrations or other efforts, if any, to challenge repeal or replace the ACA, will impact our business.

In addition, other legislative and regulatory changes have been proposed and adopted in the United States since the ACE was enacted:

On August 2, 2011, the US Budget Control Act of 2011, among other things, included aggregate reductions of Medicare payments to providers of 2% per fiscal year.

These reductions went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2030, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic.

Following the temporary suspension, a 1% payment reduction will occur beginning April 1, 2022 through June 30, 2022, and the 2% payment reduction will resume on July 1, 2022.

On January 2, 2013, the U.S.

American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several types of providers.

On April 13, 2017, CMS published a final rule that gives states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces.

On May 30, 2018, the Right to Try Act, was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA -approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.

There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.

On May 23, 2019, CMS published a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.

On December 20, 2019, former President Trump signed into law the Further Consolidated Appropriations Act (H.R.

1865), which repealed the Cadillac tax, the health insurance provider tax, and the medical device excise tax.

It is impossible to determine whether similar taxes could be instated in the future.

Additionally, there has been increasing legislative and enforcement interest in the United States with respect to drug pricing practices.

Specifically, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several U.S.

Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs.

At the federal level, President Biden signed an Executive Order on July 9, 2021 affirming the administration’s policy to (i) support legislative reforms that would lower the prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and biosimilars;

and (ii) support the enactment of a public health insurance option.

Among other things, the Executive Order also directs the U.S.

Department of Health and Human Services, or HHS, to provide a report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the price that the Federal government pays for drugs, and address price gouging in the industry;

and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.

FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

On September 25, 2020, CMS stated drugs imported by states under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report these drugs for “best price” or Average Manufacturer Price purposes.

Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these drugs.

If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.

Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation, or MFN, Model under which Medicare Part B reimbursement rates would have been be calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita.

However, on December 29, 2021 CMS rescinded the Most Favored Nations rule.

Additionally, on November 30, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the point-of-

sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs .

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

27 unchanged sentences

Efforts to control prices and utilization of pharmaceutical products and medical devices will likely continue as countries attempt to manage healthcare expenditures.

Employees and Human Capital Resources

As of December 31, 2021, we had 122 full-time employees, 30 of whom have Ph.D.

2 unchanged sentences

We consider our relationship with our employees to be good.

Website Access to Reports

Our human capital resources objectives include, as applicable, retaining, incentivizing and integrating existing and new employees, and identifying and recruiting prospective new employees.

The principal purposes of our 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.

Available Information

We are subject to the informational requirements of the Exchange Act and are required to file annual, quarterly and current reports, proxy statements and other information with the SEC.

3 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business