AAV-Based Products: Ongoing Clinical Trials

(June 2020)

BioPharmAnalyses OctopusyX BioConsulting 40, rue du petit bois Centre Atlas 78370 Plaisir 24, avenue du Prado France 13006 Marseille. France Phone: 33 (0)686 683 220 Phone: 33 (0)668 071 907 Contact: [email protected]/ Contact:[email protected]

We are happy to propose you an update on ongoing approved clinical trials on AAV-based gene therapy products.

The publication provides an accurate overview to explore the latest trials using AAV vectors for the treatment of: Cardiovascular Diseases, Hematological Diseases, Hepatic Diseases, Infectious Diseases, inherited Metabolic Diseases, Lysosomal Diseases, Neurological Diseases, Neuromuscular Diseases and Ophthalmological Diseases.

Diseases and trials mentioned have been put in context with the most relevant and recent publications and informations selected by our experts.

The trials presented here have been registered and/or updated on Clinicaltrials.gov until 04/30/2020.

GLOBAL CONTENT

■ Diseases mentioned P5

■ Products mentioned P6

■ Companies and Institutions mentioned P7

■ Highlights P8

■ Clinical trials using AAV-based Products by Numbers P10

- Number of Trials by Therapeutic Area - Number of Products by Therapeutic Area - Number of Companies/Acad by Therapeutic Area - Number of Trials by Phase - Number of Products by Phase - Number of Companies/Acad by Phase - Number of Trials by Country

■ Ongoing Clinical Trials

- Cardiovascular Diseases P16 - Hematological Diseases P21 - Hepatic Diseases P48 - Infectious Diseases P51 - Inherited Metabolic Diseases P52 - Lysosomal Diseases P66 - Neurological/Neurodegenerative Diseases P98 - Neuromuscular Diseases P126 - Ophthalmological Diseases P145 - Miscellaneous P199

DISEASES MENTIONED

s Cardiovascular Diseases Neurological/ Critical Limb Ischemia (CLI) P16 Neurodegenerative Diseases Refractory Angina P18 Alzheimer’s Disease P98 Aromatic L-amino Acid DeCarboxylase Hematological Diseases Deficiency P104 Hemophilia A P22 Charcot-Marie-Tooth Neuropathy 1AP108 Hemophilia B P33 Giant axonal neuropathy P110 Huntington’s disease P114 Parkinson’s disease P117 Hepatic Diseases

Crigler Najjar Syndrome P47 Neuromuscular Diseases

Duchenne Muscular Dystrophy P126 Infectious Diseases Limb Girdle Muscular Dystrophy E P133 HIV-1 Infected Adults with Controlled Spinal muscular atrophy P135 Viremia P50 X-linked myotubular myopathy P141

Inherited Metabolic Diseases Ophthalmological Diseases (excluding Lysosomal Diseases) Achromatopsia P147 IA P52 Age-related Macular Degeneration P154 Homozygous Familial P163 Hypercholesterolemia P55 Leber Congenital Amaurosis P169 Ornithine transcarbamylase Leber Hereditary Optic Neuropathy P177 deficiency P58 Retinitis pigmentosa P185 Phenylketonuria P62 X-linked retinitis pigmentosa P192 X-linked juvenile retinoschisis P197 Lysosomal Diseases Batten Disease P66 Miscellaneous P68 Ageing P199 P71 Irradiation-Induced Parotid Salivary GM1 Gangliosidosis P75 Hypofunction/Radiation-induced I P79 Xerostomia P201 Mucopolysaccharidosis II P81 Osteoarthritis of the Knee P203 Mucopolysaccharidosis III P83 Mucopolysaccharidosis VI P89 Pompe Disease P92

HIGHLIGHTS

. Two AAV-based gene therapy products have already obtained the go-ahead from US and European health authorities:

Luxturna® received FDA approval in December 2017 as a one-time gene therapy to restore functional vision in children and adult patients with biallelic of the RPE65 gene (Leber congenital amaurosis, retinitis pigmentosa). The European Commission approved Luxturna® in December 2018. This gene therapy was developed by Children’s Hospital of Philadelphia and Spark Therapeutics, now a Roche company.

Zolgensma® has been approved by the FDA in May 2019 for the treatment of pediatric patients less than 2 years of age with SMA type I with bi-allelic mutations in the SMN1 gene. This gene therapy has been approved in the EU in May 2020. This gene therapy was developed by Avexis, now a Novartis company.

. 116 clinical trials using AAV-based gene products are currently ongoing

. These 116 clinical trials involve 81 products for the treatment of 40 diseases.

. Ophthalmological diseases and lysosomal diseases are the most represented therapeutic areas.

NUMBER OF COMPANIES/ACAD BY THERAPEUTIC AREA

Nber of Companies Nber of Academic Organisations

18 16 14 3 12 4 10 3 8 5 6 13 1 11 9 4 6 2 3 4 3 3 0 1 1

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Examples of Ongoing Clinical Trials Presented in the Study

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7 Hematological Diseases

Hemophilia

Hemophilia is an X-linked genetic disease in which blood doesn’t clot properly. Hemophilia A is a deficiency of factor VIII (FVIII) and Hemophilia B is a deficiency of coagulation factor IX (FIX).

Latest Publications on the Disease

■ « A Molecular Revolution . 2020 Mar 23. ■ « Gene therapy for in the Treatment of doi: 10.1111/hae.13971. hemophilia ». Hemophilia ». (Abstract) Nathwani AC. Butterfield JSS et al. Department of Department of Pediatrics, ■ « Investigational drugs to Haematology, UCL University of Florida, treat hemophilia. » Cancer Institute, Gainesville, FL, USA. Franchini M et al. Italian Katharine Dormandy National Blood Centre, Haemophilia and Diverse molecular National Institute of Health, Unit, Royal medicines, ranging from Rome, Italy. Free London NHS antibody to gene to RNA Foundation Trust, therapy, are transforming This review describes the London,UK; and Freeline treatment of monogenetic preclinical and phase 1/2 Therapeutics. disorders studies investigating the hemophilia A and B .The innovative products, Hemophilias are ideally article provides an overview including factor suited for gene therapy of these approaches, concentrates and non- because a small explains how they differ clotting factor-based increment in blood factor from standard therapies, therapies with extended levels (≥5% of normal) is and predicts how the half-life, for the associated with hemophilia treatment management of significant amelioration of landscape will be reshaped. hemophilia patients with or bleeding phenotype in without coagulation factor severely affected Mol Ther. 2020 Apr inhibitors. Among patients. This review 8;28(4):997-1015. doi: replacement therapies for explores recent progress 10.1016/j.ymthe.2019.11.006. hemophilia A, these results and the remaining (Abstract) indicate that the most limitations that need to interesting products are be overcome for wider ■ « Towards a global those bioengineered using availability of this novel multidisciplinary consensus XTEN fusion technology. treatment of inherited framework on haemophilia The anti-tissue factor bleeding disorders. gene therapy: Report of the pathway inhibitor antibody 2nd World Federation of concizumab is the most Am Soc Haemophilia Gene Therapy innovative and interesting Hematol Educ Program. Round Table. » Pierce GF et agent among non-clotting 2019 Dec 6;2019(1):1-8. al. World Federation of factor products. (Abstract) Hemophilia, Montreal, QC,

Canada. Expert Opin Investig Drugs. 2020 Feb 3:1 -7. (Abstract)

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SB-525 SB-525 is an AAV2/6 vector encoding the cDNA for the B-domain deleted human Factor VIII (FVIII) for the treatment of hemophilia A. The secreted FVIII has the same amino acid sequence as approved Sangamo recombinant anti hemophilic factors (Refacto® and Xyntha®). The SB- Therapeutics 525 vector encodes a liver-specific promotor module and AAV2/6 (USA) exhibits liver tropism, thus providing the potential for long-term hepatic Pfizer production of FVIII in hemophilia A subjects. (USA) SB-525 is developed by Sangamo Therapeutics in collaboration with Pfizer since May 2017. Sangamo led Phase 1/2 clinical trials. In December 2019, the biotech company has completed the transfer to Pfizer of the SB-525 Investigational New Drug application (IND). Pfizer is now advancing SB-525 into a Phase 3 registrational clinical study in 2020 and has already commenced enrolling patients into a Phase 3 lead-in study. The FDA has granted Orphan Drug, Fast Track, and regenerative medicine advanced therapy (RMAT) designations to SB-525, which also received Orphan Medicinal Product designation from the EMA.

Latest Informations/Publications on the Product

■ JULY 2019 The response continues to Sangamo and Pfizer be durable for as long as announce updated Phase 24 weeks, the extent of 1/2 results for follow-up. The two SB-525 showing sustained patients more recently increased Factor VIII levels. treated at the 3e13 vg/kg The Phase 1/2 Alta study dose level are has been designed to demonstrating FVIII assess the safety and activity kinetics that tolerability of SB-525 in ten appear consistent with male patients with severe the first two patients hemophilia A. The data treated in this dose cohort showed that SB-525 was at similar early time points. generally well-tolerated Across the dose cohorts, and demonstrated a dose- patients demonstrated a dependent increase in FVIII dose-dependent increase activity levels. in FVIII levels and a dose- The first two patients dependent reduction in treated at the 3e13 vg/kg the use of FVIII dose rapidly achieved replacement therapy. normal levels of FVIII (Press Release) activity as measured using a chromogenic assay, with no reported bleeding events.

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9 Ongoing Clinical Trials

Six Month lead-in Study to Evaluate Prospective Efficacy and Safety Data of Current FIX Prophylaxis Replacement Therapy in Adult Hemophilia B Subjects (FIX:C≤2%) or Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Subjects (FIX:C≤1%)

The study is an open-label, non-investigational PHASE 3 product, multi-center, lead-in study to evaluate ID: NCT03587116 at least 6 months of prospective efficacy and Recruitment Status: Recruiting selected safety data of current factor IX (FIX) or Start/Planned completion: factor VIII (FVIII) prophylaxis replacement JUL 2018/OCT 2021 therapy in the usual care setting of moderately Estimated Enrollment: 250 severe to severe adult hemophilia b subjects Sites: 64 (AU, AT, BE, BR, CA, DE, ES, FR, (FIX:c≤2%) who are negative for neutralizing GR, IL, IT, JP, KR, SA, SW, TK, TW, UK) antibodies to adeno-associated virus vector- Updated: February 28, 2020 Spark100 (benegene-1) and moderately severe Contact: to severe hemophilia a adult subjects Pfizer CT.gov Call Center - 1-800-718- (FVIII:c≤1%) who are negative for neutralizing 1021 - antibodies to adeno-associated virus vector SB- [email protected] 525 capsid (aav6), prior to the respective

therapeutic phase 3 gene therapy studies.

Dose-Ranging Study of Recombinant AAV2/6 Human Factor 8 Gene Therapy SB-525 in Subjects With Severe Hemophilia A

PHASE 2 The purpose of the study is to evaluate the ID: NCT03061201 safety, tolerability and time-course profile of FVIII Recruitment Status: Recruiting activity levels with adaptive doses of SB-525. The Start/Planned completion: objective of the study is to reduce or eliminate JUN 2017/JUL 2024 the need for FVIII replacement therapy.

Estimated Enrollment: 13 Sites: 8 (USA) Updated: February 27, 2020 Contact: Pfizer CT.gov Call Center - 1-800-718- 1021 - [email protected]

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10 Valoctocogene Roxaparvovec (BMN 270) is an investigational AAV5 Valoctoco- containing a B-domain deleted variant of FVIII gene. In February 2020, the FDA has accepted for Priority Review the Biologics License Application gene Roxa- (BLA) for valoctocogene roxaparvovec, for the treatment of adults with parvovec hemophilia A. The agency has granted priority review designation to (BMN 270 - valoctocogene roxaparvovecand the Prescription Drug User Fee Act AAV5-hFVIII- (PDUFA) action date is August 21, 2020. The FDA has already granted valoctocogene roxaparvovec Breakthrough SQ) Therapy designation and Orphan Drug designation. The EMA also validated BioMarin’s Marketing Authorization Application BioMarin (MAA) for, valoctocogene roxaparvovec, for adults with severe hemophilia (USA) A. The MAA review commenced in January 2020 under accelerated assessment. Valoctocogene roxaparvovec has Orphan Drug designation from the EMA that also granted access to its Priority Medicines (PRIME) regulatory initiative in 2017.

This submission marks the first marketing application under review in Europe for a gene therapy product for any type of hemophilia. If approved by the FDA, valoctocogene roxaparvovec will be the first gene therapy in the US for the treatment of any hemophilia.

Ongoing Clinical Trials

Gene Therapy Study in Severe Patients – A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Haemophilia A

PHASE 1-2 This study is being conducted by ID: NCT02576795 Biomarin Pharmaceutical as an open Recruitment Status: label, dose escalation study in order to Active, not recruiting determine the safety and efficacy of Start/Planned completion: valoctocogene roxaparvovec (an AUG 2015/FEB 2022 Adenovirus-Associated Virus based Estimated Enrollment: 15 gene therapy vector in participants with Sites: 9 (UK) severe Haemophilia A. Updated: April 17, 2019 Contact: -

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Latest Informations/Publications on Clinical Trials 11

■ « Multiyear Follow-up of AAV5-hFVIII- Twelve of these participants also experienced SQ Gene Therapy for Hemophilia A ». a full resolution of target . K. John Pasi et al. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; This article demonstrated that a single EudraCT number, 2014-003880-38.). infusion of valoctocogene roxaparvovec resulted in sustained, N Engl J Med 2020; 382:29-40 (Abstract) clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all 13 participants who had received 4e13vg/kg or 6e13 vg/kg.

Gene Therapy Study in Severe Haemophilia A Patients With Antibodies Against AAV5 (270-203)

PHASE 1-2 This study is being conducted as an ID: NCT03520712 open label, single dose study in order to Recruitment Status: determine the safety of valoctocogene Enrolling by invitation roxaparvovec in participants with Start/Planned completion: severe hemophilia A who also have pre- APR 2018/JUN 2024 existing antibodies against AAV5. Estimated Enrollment: 10 Sites: 2 (UK) Updated: April 8, 2019 Contact: -

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12 Fidanacogene Fidanacogene elaparvovec (PF-06838435 - SPK-9001) is an AAV-based gene therapy that contains a high-activity human coagulation factor IX elaparvovec gene. The product received orphan drug designation from the FDA in

(PF-06838435 - September 2015 and breakthrough therapy designation in July 2016. It has SPK-9001) been granted support through the European Medicines Agency (EMA)

PRIority MEdicines (PRIME) program in February 2017. ODD status has been Pfizer granted in the EU in November 2018.

Spark Therapeutics (USA)

Ongoing Clinical Trials

A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B (BENEGENE-2)

PHASE 3 This study will evaluate the efficacy and ID: NCT03861273 - BENEGENE-2 safety of PF-06838435 in adult male Recruitment Status: Recruiting participants with moderately severe to Start/Planned completion: severe hemophilia B (Factor IX circulating JUL 2019/NOV 2026 activity of 2% or less). Eligible study Estimated Enrollment: 55 participants will have completed a Sites: 31 (AU, CA, GR, JP, SA, TK, TW, UK, USA) minimum 6 months of routine Factor IX Updated: April 10, 2020 prophylaxis therapy during the lead in Contact: study (C0371004). Participants will be Pfizer CT.gov Call Center - 1-800-718-1021 - dosed once and will be evaluated over [email protected] the course of 6 years. The main objectives of the study are to compare the annualized bleeding rate of the gene therapy to routine prophylaxis from the lead-in study and to evaluate the impact that it may have on participant's Factor IX circulating activity.

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13 Long-term Safety and Efficacy Study of SPK-9001 in Individuals With Hemophilia B

The study is a long term follow up (LTFU) PHASE 2 study designed to evaluate the overall ID: NCT03307980 long term safety, durability of transgene Recruitment Status: Recruiting expression, and effect on clinical Start/Planned completion: outcomes of SPK 9001 mediated gene JUN 2017/OCT 2026 transfer. While safety will be monitored Estimated Enrollment: 20 in general, new onset of oncologic, Sites: 7 (USA) hematologic, neurologic, or auto Updated: December 4, 2019 immune events will be of particular Contact: interest. This trial will last for 5 years Pfizer CT.gov Call Center - 1-800-718-1021 - providing a minimum of 6 years of follow [email protected] up post vector administration.

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14 Lysosomal Diseases

Danon Disease

Danon disease is a rare X-linked characterized by , skeletal muscles myopathy and intellectual disability. This lysosomal-associated disorder is leading to early death due to heart failure. Danon disease is caused by mutations in the LAMP2 gene that provides instructions for making lysosomal associated membrane protein-2 (LAMP-2). The absence or reduction of LAMP2 protein leads to disruption of intracytoplasmic trafficking with an accumulation of autophagic material and glycogen in cardiac muscle and cells. There are no therapies available for the treatment of Danon disease.

Latest Publications on the Disease

■ « Danon Disease ». recent breakthrough that An early molecular Matthew RG Taylor Adult characterized a unique diagnosis is of crucial Medical Genetics Program, autophagosome-lysosome importance for genetic University of Colorado fusion mechanism counselling and for Anschutz Medical Campus, employed by therapeutic interventions: Aurora, Colorado, USA. cardiomyocytes through a in male patients, the Eric D Adler, Division of lysosomal membrane prognosis is poor due to Cardiology, University of protein LAMP-2B. This rapid progression towards California San Diego, San finding may impact the heart failure, and only Diego, California, USA. development of future heart transplantation therapeutic applications. modifies the disease GeneReviews® [Internet]. course. Seattle (WA): University of Int J Mol Sci. 2020 Jan Washington, Seattle; 1993– 27;21(3):811. Neuropathol Appl 2020. 2020 Mar 5. (Abstract - Full Text) Neurobiol. 2019 Nov 7. (Abstract - Full Text) (Abstract ■ « Danon Disease: Review ■ « Lysosomal Abnormalities of Natural History and in Cardiovascular Disease ». Recent Advances ». Congwu Chi et al G Cenacchi et al. Division of Cardiology, Department of Biomedical Department of Medicine, and Neuromotor Sciences, University of Colorado "Alma Mater" University of Anschutz Medical Campus, Bologna, Bologna, Italy)

Aurora, CO 80045, USA. The authors surveyed over

In this review, the authors 500 Danon disease highlighted studies that patients reported in the have improved our literature from the first

understanding of the description to the present, connection between in order to summarize the lysosome function and clinical, pathological and

cardiovascular diseases molecular data and with an emphasis on a treatment perspectives. 14

RP-A501 (AAV9.LAMP2B) is a recombinant AAV9 containing the human 15 RP-A501 lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene. The LAMP2 gene, a key mediator of autophagy, has three isoforms: Rocket LAMP2A, LAMP2B, and LAMP2C. LAMP2B is the predominant isoform Pharmaceuticals expressed in cardiomyocytes. In February 2019 Rocket Pharmaceuticals (USA) was notified by the FDA that the company was granted Fast Track designation for RP-A501.

Latest Informations/Publications on the Product

■ « Systemic AAV9.LAMP2B physiologic function in a DD Injection Reverses Metabolic murine model, suggesting that and Physiologic Multiorgan a similar therapeutic approach Dysfunction in a Murine Model may be effective for treating of Danon Disease ». patients with this highly morbid Ana Maria Manso, Division of disease. Cardiology, Department of Medicine, UC San Diego, San Sci Transl Med. 2020 Mar Diego, CA 92037, USA. 18;12(535):eaax1744 (Abstract)

This study evaluates the efficacy ■ MAY 2019 of human LAMP2B gene transfer Rocket Pharmaceuticals has using a recombinant adeno- presented preclinical data of associated virus 9 carrying RP-A501 at the American human LAMP2B (AAV9.LAMP2B) Society of Gene and Cell in a Lamp2 knockout (KO) Therapy 2019 Annual Meeting in mouse, a Danon disease model. Washington, D.C. IND-enabling AAV9.LAMP2B was intravenously toxicology studies were injected into 2- and 6-month-old conducted in wild-type mice Lamp2 KO male mice to assess and non-human primates. Three efficacy in adolescent and dose levels were tested in mice, adult phenotypes. Lamp2 KO including 3×1013 vg/kg, 1×1014 mice receiving AAV9.LAMP2B vg/kg, and 3×1014 vg/kg. The demonstrated dose-dependent highest dose level from the restoration of human LAMP2B murine study, 3×10 vg/kg, was protein in the heart, liver, and tested in non-human primates. skeletal muscle tissue. Impaired No dose-Latest adverse events autophagic flux, evidenced by were observed at all tested increased LC3-II, was doses in both mice and non- abrogated by LAMP2B gene human primates. Vector transfer in all tissues in both genomes, mRNA and protein cohorts. Cardiac function was expression were widely also improved, and distributed across key tissues transaminases were reduced in with high levels of transduction, AAV9.LAMP2B-treated KO mice, transcription and translation indicating favorable effects on detected in the heart, skeletal the heart and liver. Survival was muscle, diaphragm and liver. also higher in the older cohort (Press Release) receiving high vector doses. In summary, LAMP2B gene transfer improves metabolic and

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Ongoing Clinical Trials 16

Gene Therapy for Male Patients With Danon Disease Using RP-A501; AAV9.LAMP2B

PHASE 1 This non-randomized open-label Phase 1 study ID: NCT03882437 evaluates the safety and toxicity of gene Recruitment Status: Recruiting therapy using a recombinant AAV9 containing Start/Planned completion: the human lysosome-associated membrane APR 2019/APR 2023 protein 2 isoform B (LAMP2B) transgene Estimated Enrollment: 24 (investigational product (IP), RP-A501) in male Sites: 1 (USA) patients with Danon Disease (DD). RP-A501 will Updated: December 4, 2019 be administered as a single IV infusion. Contact: Two dose levels are planned to be investigated Clinical Information - 646-901-9276 - in 4 distinct cohorts: [email protected] Cohort 1: Age 15 years and older: Low Dose (n=3-6 subjects) ; Cohort 2: Age 15 years and older: High Dose (n=3-6 subjects) ; Cohort 3: Age 8-14 years: Low Dose (n=3-6 subjects) ; Cohort 4: Age 8-14 years: High Dose (n=3-6 subjects). Clinical data read-outs are expected in the second half of 2020.

Latest Informations/Publications on Clinical Trials

■ JUN 2019 « Rocket Pharmaceuticals Announces Eric Adler is Director of Cardiac Transplant and Patient Dosing Has Commenced for Mechanical Circulatory Support at UC San Phase 1 Clinical Trial of RP-A501, the First Diego Health and Professor of Medicine at Gene Therapy to Treat a Monogenic University of California, San Diego School of Heart Failure Syndrome » Medicine. Barry Greenberg, is the Director of the Patient dosing has commenced in the Advanced Heart Failure Treatment Program at open-label, Phase 1 clinical trial of RP- UCSD Health and Professor of Medicine at UC A501 for the treatment of Danon disease. San Diego School of Medicine, and is principal University of California San Diego (UCSD) investigator of the trial. (Press Release) Health is the initial and lead center for the Phase 1 clinical trial under the leadership of Eric Adler M.D. and Barry Greenberg

M.D.

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17 Ophthalmological Diseases

Latest Publications on Gene Therapy and Inherited Retinal Diseases

■ « Empowering Retinal restoration of high visual Vectors based on AAV have Gene Therapy with a acuity in the rd1 mouse shown the ability for gene Specific Promoter for Human model of late retinal delivery to retinal organoids Rod and Cone ON-Bipolar degeneration. The new derived from hiPSCs. Thus far, Cells » promoter enables precise little work has been carried Elmar Carlos Hulliger, Simon manipulation of the inner out to investigate mecha- Manuel Hostettler,and Sonja retinal network and paves nisms of AAV-mediated gene Kleinlogel. Institute of the way for clinical delivery and the potential Physiology, University of Bern, application of gene advantages of engineered 3012 Bern, Switzerland therapies for high- AAVs to genetically modify resolution optogenetic retinal organoids. In this Optogenetic gene therapy vision restoration, raising study, the authors compared holds promise to restore hopes of significantly the early transduction effi- high-quality vision in blind improving the life quality of ciency of several recom- patients and recently rea- people suffering from binant and engineered AAVs ched clinical trials. Although blindness. in hiPSC-derived RPE cells the ON-bipolar cells, the first and retinal organoids in retinal interneurons, make Mol Ther Methods Clin Dev. relation to the availability of the most attractive targets 2020 Jun 12; 17: 505–519 their cell-surface receptors for optogenetic vision (Full Text) and as a function of time. restoration, they have The genetic variant AAV2- remained inaccessible to ■ « AAV-Mediated Gene 7m8 had a superior trans- human gene therapy due to Delivery to 3D Retinal duction efficiency when the lack of a robust cell- Organoids Derived from applied at day 44 of diffe- specific promoter. The Human Induced rentiation on retinal orga- authors describe the design Pluripotent Stem Cells » noids and provided long- and functional evaluation of Marcela Garita-Hernandez lasting expressions for at least 770En_454P(hGRM6), a et al. Sorbonne Université,, 4 weeks after infection human GRM6 gene-derived, INSERM, CNRS, Institut de la without compromising cell short promoter that drives Vision, 17 rue Moreau, F- viability. All of the capsids strong and highly specific 75012 Paris, France tested transduced the hiPSC- expression in both the rod- RPE cells, with the AAV2-7m8 and cone-type ON-bipolar Human induced pluri- variant being the most cells of the human . potent stem cells (hiPSCs) efficient. Transduction Expression also in cone-type promise a great number of efficiency was correlated ON-bipolar cells is of future applications to with the presence of primary importance, since the cone- investigate retinal cell-surface receptors on the dominated macula development, pathophy- hiPS-derived organoids. mediates high-acuity vision siology and cell therapies and is the primary target of for retinal degenerative Int J Mol Sci. 2020 Feb; 21(3): gene therapies. diseases. Specific approa- 994. 770En_454P(hGRM6)-driven ches to genetically (Full Text) middle-wave opsin modulate hiPSC would be expression in ON-bipolar valuable for all of these cells achieved lasting applications.

genetically modulate 17

hiPSC would be valuable

18 Achromatopsia (ACHM)

Achromatopsia is a rare autosomal recessive inherited retinal disease (IRD) characterized by a partial or total absence of color vision. It prevents cone photoreceptors from functionning. Affected people can also have an increased sensitivity to light and glare, involuntary back-and-forth eye movements, and significantly reduced sharpness of vision. They can also have farsightedness or, less commonly, nearsightedness.

The disease results from mutations in one of several genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, ATF6). These mutations affect cone photoreceptors which are the specialist light-sensing cells responsible for colour vision and vision in bright light. The CNGB3 and CNGA3 genes are the two most common genes that have been identified as causing achromatopsia.

AAV- CNGA3 (AAV2/8-hG1.7p.coCNGA3) is an AAV-based gene therapy designed to restore cone function in patients with achromatopsia (ACHM) AAV-CNGA3 caused by mutations in the Cyclic Nucleotide Gated Channel Alpha 3 (AAV2/8 hG1.7 subunit (CNGA3) gene. This AAV 2/8 is carrying a proprietary engineered p.coCNGA3) promoter (hG1.7p) driving a codon-optimized CNGA3 cDNA. The product is delivered via subretinal injection covering the central macula region of the Meira GTx eye, where most of the cones in the retina are located. (USA - UK) AAV-CNGA3 was granted orphan drug designation by the FDA and by the European Medicines Agency in August 2018. In January 2019, MeiraGTx has established collaboration and license agreement with Janssen with respect to three MeiraGTx’s IRD pipeline, including AAV-CNGA3.

Latest Informations/Publications on the Product ■ APR 2019 « MeiraGTx Announces Upcoming Presentation on Achromatopsia Gene Therapy Candidate AAV-CNGA3 at ARVO 2019 »

A pre-clinical poster on safety and efficacy of AAV-CNGA3 has been presented at the Association for Research in Vision and Ophthalmology (ARVO) 2019 Annual Meeting in Vancouver, British Columbia. In pre-clinical models, treatment with AAV-CNGA3 resulted in long-term visual improvements and cone photoreceptor survival at titers planned for use in a Phase 1/2 clinical trial of AAV-CNGA3. (Press Release)

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Ongoing Clinical Trials 19

Long-Term Follow-Up Gene Therapy Study for Achromatopsia CNGB3 and CNGA3

PHASE 1-2 This study is a longer-term follow-up study for ID: NCT03278873 patients who participated in one of the clinical Recruitment Status: Recruiting trials: AAV - CNGB3 retinal gene therapy for Start/Planned completion: patients with achromatopsia, or AAV - CNGA3 JUN 2017/AUG 2024 retinal gene therapy for patients with Estimated Enrollment: 72 achromatopsia. Sites: 1 (UK) Updated: September 12, 2019 Contact: MeiraGTx UK II Ltd +44 (0)20 3866 4320 - [email protected]

Gene Therapy for Achromatopsia (CNGA3) (CNGA3)

PHASE 1-2 ID: NCT03758404 Recruitment Status: Recruiting Start/Planned completion: JUL 2019/JAN 2022 Estimated Enrollment: 18 Sites: 2 (UK, USA) Updated: March 12, 2020 Contact: MeiraGTx UK II Ltd +44 (0)20 3866 4320 - [email protected]

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AGTC-402 (rAAV2tYF-PR1.7-hCNGA3) is an AAV-based gene therapy 20 AGTC-402 designed to restore cone function in patients with achromatopsia (ACHM) (rAAV2tYF- caused by mutations in the Cyclic Nucleotide Gated Channel Alpha 3 PR1.7-hCNGA3) subunit (CNGA3) gene.

Applied Genetic Technologies Latest Informations/Publications on the Product

Corp - AGTC (USA) ■ MAR 2020 describing real-world received either a « AGTC Announces improve- lower or higher dose Completion of ments in visual func- of the AGTC-402 Enrollment in All Adult tion. A favorable vector, and one Dose Groups of its safety profile with no efficacy control Ongoing Phase 1/2 dose-limiting group (n = 4) Clinical Trials in inflammatory received a vector Patients with responses was similar in design to Achromatopsia » observed. (Press one previously shown Release) to rescue cone The planned photo-receptor enrollment has been ■ « Safety and responses in the day- completed in all dose Efficacy Evaluation of blind sheep model groups for adult rAAV2tYF-PR1.7- (rAAV5-PR2.1- patients, including the hCNGA3 Vector hCNGA3). All vector- two higher dose Delivered by treated eyes showed groups, of the Phase Subretinal Injection in improved cone- 1/2 clinical programs CNGA3 Mutant mediated electrore- with achromatopsia Achromatopsia tinography responses due to in the Sheep » with no change in ACHM CNGB3 or Gootwine E et al. rod-mediated ACHM CNGA3 genes. Agricultural Research electroretinography AGTC continues to Organization, The responses. Behavioral enroll pediatric Volcani Center , maze testing under patients at the higher Rishon LeZion, Israel photopic conditions dose groups in both showed significantly trials. AGTC most The results are herein improved navigation recently reported reported of a study times and reduced interim six-month data evaluating safety numbers of obstacle from the dose and efficacy of collisions in all vector- escalation cohorts of AGTC-402 in CNGA3- treated eyes its ongoing ACHM deficient sheep. compared to their Phase 1/2 clinical trials Thirteen day-blind contralateral control in January 2020. sheep divided into eyes or pre-dose Results from both three groups of four results in the treated studies demonstrated or five animals each eyes. encouraging signs of received a subretinal biologic activity as injection of an AAV Hum Gene Ther Clin shown by positive vector expressing a Dev. 2017 changes in light CNGA3 gene in a Jun;28(2):96-107. discomfort testing as volume of 500 μL in (Abstract) well as encouraging the right eye. Two patient anecdotes groups (n = 9)

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Ongoing Clinical Trials 21

Safety and Efficacy Trial of AAV Gene Therapy in Patients With CNGA3 Achromatopsia

PHASE 1-2 This will be a non-randomized, open-label, ID: NCT02935517 Phase 1/2 study of the safety and efficacy of Recruitment Status: Recruiting AGTC-402, administered to one eye by Start/Planned completion: subretinal injection in individuals with MAY 2017/JUN 2023 achromatopsia caused by mutations in the Estimated Enrollment: 24 CNGA3 gene. The primary study endpoint will Sites: 9 (IL, USA) be safety and the secondary study endpoint Updated: January 14, 2020 will be efficacy. Subjects will be enrolled Contact: sequentially in four groups. Subjects in Groups Jill Dolgin, PharmD + 1833-770-2862 - 1, 2 and 3 will be at least 18 years of age and [email protected] will receive a lower, middle or higher dose of study agent. Subjects in Group 4 will be at least 6 years of age and will receive the maximum tolerated dose identified in Groups 1, 2 and 3. Safety will be monitored by evaluation of ocular and non ocular adverse events and hematology and clinical chemistry parameters. Efficacy parameters will include visual acuity, light discomfort

testing, color vision, static visual field, ERG, adaptive optics retinal imaging and OCT.

Latest Informations/Publications on Clinical Trials

■ JAN 2020 « AGTC Reports Encouraging Interim Six-Month Data from the Dose Escalation Cohorts of its Ongoing Phase 1/2 Clinical Trials in Achromatopsia »

Interim results from the ongoing Phase 1/2 clinical programs in patients with achromatopsia due to mutation in the ACHM CNGA3 gene demonstrate encouraging signs of biologic activity and a favorable safety profile. The company plans to report data from additional dose groups, age groups and time-points in the second half of 2020. The data reported are from 9 patients in the ACHM CNGA3 trial. Additional data are expected to be available in the second half of 2020. (Press Release)

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