Cell, Gene, & RNA Therapy Landscape

Gene, Cell, & RNA Therapy Landscape Q2 2021 Q2

Q2 2021 Quarterly Data Report

Information Classification: General About the authors

The American Society of Gene & Cell Therapy (ASGCT) is the primary professional membership organization for scientists, physicians, patient advocates, and other professionals with interest in gene and cell therapy. Our members work in a wide range of settings including universities, hospitals, government agencies, foundations, biotechnology and pharmaceutical companies. ASGCT advances knowledge, awareness, and education leading to the discovery and clinical application of gene and cell therapies to alleviate human disease to benefit patients and society.

Informa Pharma Intelligence powers a full suite of analysis products – Datamonitor Healthcare™, Sitetrove™, Trialtrove™, Pharmaprojects™, Biomedtracker™, Scrip™, Pink Sheet™ and In Vivo™ – to deliver the data needed by the pharmaceutical and biomedical industry to make decisions and create real-world opportunities for growth. With more than 400 analysts, journalists, and consultants keeping their fingers on the pulse of the industry, no key disease, clinical trial, drug approval or R&D project isn’t covered through the breadth and depth of data available to customers. For more information visit pharmaintelligence.informa.com.

Information Classification: General Table of contents 04 Introduction 05 Key takeaways from Q2 2021 06 Key highlights in Q2 2021 11 Gene therapy pipeline 23 Non-genetically modified cell therapy pipeline 29 RNA therapy pipeline 35 Overview of dealmaking 38 Start-up funding 43 Upcoming catalysts 45 Appendix Introduction ASGCT is pleased to provide the second in a quarterly report series with our data partner, Informa Pharma Intelligence. This series provides an iterative, detailed look at progress in the preclinical and clinical development landscape of gene and cell therapies globally, and should collectively tell a complete story of scientific achievement and clinical advancement.

Highlights in Q2 2021 include the approval of a new gene therapy in Japan, the expansion of gene therapy approvals to three new countries, continued growth in early-phase gene therapy development, and growth in studies using a herpes simplex virus.

The dollar value of start-up financing rebounded this quarter to an aggregate of $1.4 billion after a consecutive three-quarter decrease.

You will find new types of information in this quarter’s report, as well, such as new clinical trials, key regulatory events, and listings of therapies in the preregistration phase this quarter, plus changes from Q2 2020 and noteworthy upcoming approval decisions.

ASGCT is excited to continue this series of landscape reports and to tell the story of this emerging technology as it translates to clinics and improves the lives of patients worldwide.

4 / Q2 2021 Information Classification: General Key takeaways from Q2 2021

One new gene therapy was approved, and three previously-approved gene therapies were approved in additional countries/regions • Delytact, a new genetically engineered oncolytic herpes simplex virus type 1, was approved in Japan for malignant glioma • Yescarta gained approval in China, Zolgensma in South Korea, and Abecma in Canada

Oncology remains the most active therapeutic area of research (preclinical through preregistration) • More than 1,300 gene and cell therapy candidates are in development for oncology

Financing for start-ups showed a marked increase • Seed and Series A financing volume nearly doubled in Q2, and the dollar value tripled, due to four $100M+ fundraisers

Overall dealmaking volume was down from Q1 but up from a year ago • A total of 142 deals (financings, alliances, and acquisitions) were signed in Q2, down from 167 in Q1, but up from the 132 transactions in Q2 2020

5 / Q2 2021 Information Classification: General Key highlights in Q2 2021 2021 Q2

Information Classification: General Approved gene therapies as of Q2 2021 Year first Product name Generic name Disease(s) Locations approved Originator company approved Gendicine recombinant p53 gene 2004 Head and neck cancer China Shenzhen SiBiono GeneTech Head and neck cancer; Oncorine E1B/E3 deficient adenovirus 2005 China Shanghai Sunway Biotech nasopharyngeal cancer Rexin-G mutant cyclin-G1 gene 2006 Solid tumors Philippines Epeius Biotechnologies vascular endothelial growth factor Peripheral vascular disease; limb Neovasculgen 2011 Russian Federation, Ukraine Human Stem Cells Institute gene ischemia Imlygic talimogene laherparepvec 2015 Melanoma US, EU, Australia Amgen Strimvelis autologous CD34+ enriched cells 2016 Adenosine deaminase deficiency EU Orchard Therapeutics Acute lymphocytic leukemia; diffuse US, EU, Japan, Australia, Kymriah tisagenlecleucel-t 2017 Novartis large B-cell lymphoma Canada, South Korea Leber’s congenital amaurosis; Luxturna voretigene neparvovec 2017 US, EU, Australia, Canada Spark Therapeutics (Roche) retinitis pigmentosa Diffuse large B-cell lymphoma; non- Yescarta axicabtagene ciloleucel 2017 Hodgkin’s lymphoma; follicular US, EU, Japan, Canada, China Kite Pharma (Gilead) lymphoma Collategene beperminogene perplasmid 2019 Critical limb ischemia Japan AnGes US, EU, Japan, Australia, Zolgensma onasemnogene abeparvovec 2019 Spinal muscular atrophy Canada, Brazil, Israel, Taiwan, Novartis South Korea Transfusion-dependent beta Zynteglo lentiviral beta-globin gene transfer 2019 EU bluebird bio thalassemia Tecartus brexucabtagene autoleucel 2020 Mantel cell lymphoma US, EU Kite Pharma (Gilead) Libmeldy OTL-200 2020 Metachromatic Leukodystrophy EU Orchard Therapeutics Breyanzi lisocabtagene maraleucel 2021 Diffuse large B-cell lymphoma US, Japan Celgene (Bristol Myers Squibb) Abecma idecabtagene vicleucel 2021 Multiple myeloma US, Canada bluebird bio Delytact teserpaturev 2021 Malignant Glioma Japan Daiichi Sankyo Source: Pharmaprojects | Informa, July 2021 Text highlighted in yellow represent new approvals during Q2 2021 7 / Q2 2021 Information Classification: General Approved RNA therapies as of Q2 2021 (1/2) Year first Product name Generic name Disease(s) Locations approved* Originator company approved US, Mexcio, Argentina, South Kynamro mipomersen sodium 2013 Homozygous familial hypercholesterolaemia Ionis Pharmaceuticals Korea Exondys 51 eteplirsen 2016 Dystrophy, Duchenne muscular US Sarepta Therapeutics US, EU, Canada, Japan, Brazil, Switzerland, Australia, South Spinraza nusinersen 2016 Muscular atrophy, spinal Ionis Pharmaceuticals Korea, China, Argentina, Colombia, Taiwan, Tegsedi inotersen 2018 Amyloidosis, transthyretin-related hereditary EU, Canada, US, Brazil Ionis Pharmaceuticals US, EU, Japan, Canada, Onpattro patisiran 2018 Amyloidosis, transthyretin-related hereditary Alnylam Switzerland, Brazil, Taiwan Vyondys 53 golodirsen 2019 Dystrophy, Duchenne muscular US Sarepta Therapeutics Waylivra volanesorsen 2019 Hypertriglyceridaemia; Lipoprotein lipase deficiency EU, UK Ionis Pharmaceuticals UK, Bahrain, Israel, Canada, US, Mexico, Kuwait, Singapore, Saudi Arabia, Chile, Switzerland, EU, Colombia, Comirnaty tozinameran 2020 Infection, coronavirus, novel coronavirus prophylaxis Philippines, Australia, Hong BioNTech Kong, Peru, South Korea, New Zealand, Japan, Brazil, Sri Lanka, Vietnam, Thailand, Oman,

*For COVID-19 vaccines, this includes emergency use authorization and full approvals Source: Pharmaprojects | Informa, July 2021 Text highlighted in yellow represent new approvals during Q2 2021 8 / Q2 2021 Information Classification: General Approved RNA therapies as of Q2 2021 (2/2) Year first Product name Generic name Disease(s) Locations approved* Originator company approved US, Canada, Israel, EU, Switzerland, Singapore, Qatar, Vietnam, UK, Philippines, Moderna COVID-19 COVID-19 vaccine, Moderna 2020 Infection, coronavirus, novel coronavirus prophylaxis Thailand, Japan, South Korea, Moderna Therapeutics vaccine Brunei, Paraguay, Taiwan, Botswana, India, Indonesia, Saudi Arabia Givlaari givosiran 2020 Porphyria US, EU, Canada, Switzerland Alnylam Oxlumo lumasiran 2020 Hyperoxaluria EU, US Alnylam Ampligen rintatolimod 2020 Chronic fatigue syndrome Argentina AIM ImmunoTech Viltepso viltolarsen 2020 Dystrophy, Duchenne muscular US, Japan NS Pharma Atherosclerosis; Heterozygous familial Leqvio inclisiran 2020 hypercholesterolaemia; Hypercholesterolaemia; EU, UK Alnylam Homozygous familial hypercholesterolaemia Amondys 45 casimersen 2021 Dystrophy, Duchenne muscular US Sarepta Therapeutics

Delytact teserpaturev Viral Malignant glioma Approval (Japan) Jun 11, 2021

Viral Gene Therapy Roctavian valoctocogene roxaparvovec Hemophilia A MAA Submission (Europe) Jun 28, 2021

N/A ciltacabtagene autoleucel Cellular* Multiple myeloma MAA Submission (Europe) Apr 30, 2021

Abecma idecabtagene vicleucel Cellular* Multiple myeloma CHMP (European Panel) Results (Positive) Jun 24, 2021

Skysona elivaldogene autotemcel Viral Gene Therapy Cerebral adrenoleukodystrophy CHMP (European Panel) Results (Positive) May 20, 2021

Regenerative Medicine Advanced Therapy (RMAT) N/A ALLO-715 Cellular* Multiple myeloma Apr 21, 2021 Designation

N/A AK-OTOF Viral Gene Therapy Hearing loss Rare Pediatric Disease (RPD) Designation Apr 13, 2021

N/A BBP-631 Viral Gene Therapy Congenital Adrenal Hyperplasia (CAH) Rare Pediatric Disease (RPD) Designation May 14, 2021

N/A LX-2006 Viral Gene Therapy Friedreich's Ataxia Rare Pediatric Disease (RPD) Designation Jun 30, 2021

*These are genetically modified cell therapies (CAR-T therapies)

Source: Biomedtracker | Informa, July 2021

10 / Q2 2021 Information Classification: General

Gene therapy pipeline Q2 2021 Q2

Gene therapy and genetically modified cell therapies

Information Classification: General Gene therapy pipeline

• In May 2021, there were 1,745 Gene Therapy Pipeline updated to include 2021 data* therapies in development from 2000 preclinical through 1800 preregistration. 1600 • Preclinical therapies account for 1400 the majority of the pipeline with 1200 1,223 therapies in preclinical 1000 studies. This accounts for 70% of 800 therapies in clinical development. 600 400

200

Number of Therapies by Year

Preclinical Phase I Clinical Trial Phase II Clinical Trial Phase III Clinical Trial Pre-registration

*These snapshots are taken every May to allow for year-on-year comparisons

Source: Pharmaprojects | Informa, May 2021

12 / Q2 2021 Information Classification: General Gene therapy pipeline – 2020 vs 2021

• When comparing preclinical development between Number of 2020 and 2021, there was a significant increase in Therapies the number of therapies in preclinical development Global Status as of May with 911 in 2020 and 1,223 therapies in 2021 2020 2021 • There was a significant increase in Phase I clinical trials in 2021 (from 180 therapies in 2020 vs 254 Preclinical 911 1,223

therapies in 2021) Phase I Clinical Trial 180 254

Phase II Clinical Trial 199 234 Number of therapies in development as of May

1400 Phase III Clinical Trial 24 26 1200 1000 Pre-registration 7 8 800 600 400 200 Total number of therapies (preclinical to pre-registration) 1,321 1,745 0 Preclinical Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials

2020 2021 Total number of therapies in the clinic 410 522

Source: Pharmaprojects | Informa, May 2021

13 / Q2 2021 Information Classification: General Gene therapy pipeline – Q1 vs Q2 2021

• Over the course of the second quarter, the largest growth was a 9 percent increase in the number of therapies in preclinical development Global Status April 2021 July 2021 • The number of Phase III therapies remained the same, and there is one less therapy in pre-registration with the Preclinical 1,190 1,296 approval of Delytact Phase I Clinical Trials 225 269 • Therapies currently in preregistration: • valoctocogene roxaparvovec (Biomarin) Phase II Clinical Trials 231 236 • lenadogene nolparvovec (Genethon, GenSight Biologics) • elivaldogene autotemcel (Bluebird Bio) Phase III Clinical Trials 27 27 • nadofaragene firadenovec (Ferring, FKD Therapeutics, Trizell) • relmacabtagene autoleucel (JW Therapeutics) Pre-registration 8 7 • ciltacabtagene autoleucel (Johnson & Johnson) • eladocagene exuparvovec (PTC Therapeutics) Total 1,711 1,835

Source: Pharmaprojects | Informa, May 2021

14 / Q2 2021 Information Classification: General Gene therapy pipeline: Most commonly targeted therapeutic areas

• The top 2 therapeutic areas targeted by gene therapies from preclinical through pre-registration are oncology and rare diseases. Rare diseases includes oncology rare diseases • The focus on oncology and rare diseases remains for therapies in clinical development

Number of therapies from preclinical through pre-registration Therapies in the clinic (excludes preclinical therapies)

Anticancer Products 1048 Anticancer Products 375 Rare Diseases 869 Rare Diseases 335 Neurological Products 202 Alimentary/Metabolic Products 35 Alimentary/Metabolic Products 139 Sensory Products 31 Sensory Products 135 Blood and Clotting Products 30 Blood and Clotting Products 76 Neurological Products 24 Musculoskeletal Products 71 Musculoskeletal Products 17 Anti-infective Products 53 Immunological Products 16 Immunological Products 52 Anti-infective Products 15 NA/Unspecified 49 Cardiovascular Products Cardiovascular Products 39 13 Respiratory Products 29 Dermatological Products 10 Dermatological Products 26 Genitourinary (including sex hormones) 3 Genitourinary (including sex hormones) 7 Miscellaneous Products 2 Miscellaneous Products 4 Respiratory Products 2 Hormonal Products (excluding sex hormones) 1 NA/Unspecified 1

Number of therapies Number of therapies

Source: Pharmaprojects | Informa, July 2021 15 / Q2 2021 Information Classification: General Gene therapy pipeline: Most common oncology diseases targeted • From preclinical through pre-registration, 1,048 therapies are being developed for oncology • Multiple myeloma and acute lymphocytic leukemia (ALL) remain the top two specified oncology indications • Non-Hodgkin’s lymphoma is now the third most common indication (acute myelogenous leukemia in Q1)

Cancer, solid, unspecified 275 Cancer, unspecified 157 Cancer, myeloma 118 Cancer, leukaemia, acute lymphocytic 107 Cancer, lymphoma, non-Hodgkin's 83 Cancer, leukaemia, acute myelogenous 82 Cancer, haematological, unspecified 70 Cancer, lymphoma, B-cell 69 Cancer, pancreatic 57 Cancer, liver 55 Cancer, ovarian 54 Cancer, breast 52 Cancer, lung, non-small cell 44 Cancer, colorectal 43 Cancer, brain 42 Cancer, leukaemia, chronic lymphocytic 38 Cancer, melanoma 36 Cancer, gastrointestinal, stomach 35 Cancer, lung, unspecified 35 Cancer, leukaemia, unspecified 33

Number of therapies Source: Pharmaprojects | Informa, July 2021

16 / Q2 2021 Information Classification: General Gene therapy pipeline: Most common non-oncology rare diseases targeted

• There are 869 therapies in development Non-oncology rare diseases for rare diseases from preclinical Retinitis pigmentosa 27 through pre-registration. This number Haemophilia A 21 includes oncology rare diseases. There Amyotrophic lateral sclerosis 19 Dystrophy, Duchenne's… 19 are 435 therapies for non-oncology rare Anaemia, sickle cell 18 diseases in development Cystic fibrosis 16 Haemophilia B 16 Thalassaemia 15 • Retinitis pigmentosa, Hemophilia A, Batten's disease 12 amyotrophic lateral sclerosis (ALS), Gaucher's disease 11 Duchenne’s muscular dystrophy (DMD), Leber's congenital amaurosis 11 and sickle cell anemia make up the top Usher syndrome 11 5 non-oncology rare diseases most Fabry's disease 10 targeted by gene therapies Huntington's disease 9 Dementia, frontotemporal 8 Pompe's disease 8 Hyperphenylalaninaemia 7 Rett Syndrome 7 Angelman syndrome 6 Charcot–Marie–Tooth disease 6

Number of therapies

Source: Pharmaprojects | Informa, July 2021

17 / Q2 2021 Information Classification: General Gene therapy pipeline: Most common additional diseases targeted

• From preclinical through Non-oncology & non-rare diseases targeted by gene therapies pre-registration, there are 356 therapies that are in Undisclosed 48 Neurological disease, unspecified 42 development for diseases Ocular disorder, unspecified 25 outside of oncology or rare Alzheimer's disease 13 diseases Infection, HIV/AIDS 13 Parkinson's disease 13 Hearing loss 12 • Of diseases that are not Diabetes, Type 1 9 oncology or rare diseases Macular degeneration, age-related, wet 9 that are disclosed: Autoimmune disease, unspecified 8 neurological diseases, ocular Macular degeneration, age-related, dry 8 disorders, Alzheimer’s Arthritis, osteo 7 Cardiovascular disease, unspecified 7 disease, HIV/AIDs, and Dermatological disease, unspecified 7 Parkinson’s Disease make up Musculoskeletal disease, unspecified 7 the 5 diseases most targeted Hepatic dysfunction, alpha-1 antitrypsin… 6 by gene therapies Hepatic dysfunction, unspecified 6 Infection, coronavirus, novel coronavirus 6 Infection, hepatitis-B virus 6 Macular dystrophy, Stargardt's 6 Number of therapies

Source: Pharmaprojects | Informa, July 2021

18 / Q2 2021 Information Classification: General Gene therapy pipeline: Most common targets Of the gene therapies in preclinical through pre-registration in which targets are disclosed: • CD19 and B-cell maturation antigen (BCMA), also known as TNF receptor superfamily member 17, remain the most common targets for oncology indications • Coagulation factor VIII is the most common target for non-oncology indications

Non-oncology targets Oncology targets coagulation factor VIII 14 CD19 molecule 147 glucosylceramidase beta 9 TNF receptor superfamily member 17 64 coagulation factor IX 8 CD22 molecule 37 vascular endothelial growth factor A 8 Not applicable 27 CF transmembrane conductance regulator 7 erb-b2 receptor tyrosine kinase 2 22 dystrophin membrane spanning 4-domains A1 21 6 mesothelin 21 hemoglobin subunit beta 6 glypican 3 17 N-acetyl-alpha-glucosaminidase 6 cancer/testis antigen 1B 14 ATP binding cassette subfamily A member 4 5 interleukin 3 receptor subunit alpha 14 collagen type VII alpha 1 chain 5 programmed cell death 1 14 galactosidase alpha 5 CD33 molecule 12 hemoglobin subunit gamma 1 5 CD7 molecule 11 N-sulfoglucosamine sulfohydrolase 5 killer cell lectin like receptor K1 11 serpin family A member 1 5 claudin 18 10 C-C motif chemokine receptor 5 (gene/pseudogene) 4 epidermal growth factor receptor 10 gap junction protein beta 2 mucin 1, cell surface associated 10 4 Not available on LocusLink/Entrez Gene 10 hemoglobin subunit gamma 2 4 CD38 molecule 9 iduronidase alpha-L- 4 Number of therapies Number of therapies Source: Pharmaprojects | Informa, July 2021

19 / Q2 2021 Information Classification: General Gene therapy clinical trial activity in 2021

• A total of 75 clinical trials were initiated in 2021 so far • The top 10 diseases for trial starts in 2021 were all for oncology with the top 3 being the blood cancers non- Hodgkin’s lymphoma (NHL), acute lymphocytic leukemia (ALL), and multiple myeloma

Trials by Disease Oncology: Lymphoma, Non-Hodgkin's 22 Number of trials by phase of study Oncology: Leukemia, Acute Lymphocytic 12 35 Oncology: Multiple Myeloma 10 Oncology: Unspecified Solid Tumor 6 30 Oncology: Breast 4 Oncology: Cervical 4 25 Oncology: Head/Neck 4 20 Oncology: Leukemia, Acute Myelogenous 4 Oncology: Lymphoma, Hodgkin's 4 15 Oncology: Bladder 3 Oncology: Liver 3 10 Oncology: Lung, Non-Small Cell 3 5 Autoimmune/Inflammation: Epidermolysis Bullosa 2 Infectious Disease: HPV 2 0 Metabolic/Endocrinology: Sickle Cell Disease 2 I I/II II III Other Oncology: Colorectal 2 Oncology: Esophageal 2 Oncology: Gastric 2 Oncology: Leukemia, Chronic Lymphocytic 2 Oncology: Ovarian 2

Number of trials Source: Trialtrove | Informa, July 2021 20 / Q2 2021 Information Classification: General Gene therapy pipeline: Most commonly used vectors

• 89% of gene therapies in development use viral vectors for delivery • Adeno-associated virus (AAV) and lentivirus remain most common viral vectors used in development • The largest quarterly growth: 33 percent increase in studies using a herpes simplex virus

Viral vectors used in gene therapies 450 405 400

350

300 288

250

200

150 123

100 73

50 36 24 15 0 Adeno-associated Lentivirus Adenovirus Retrovirus Herpes simplex virus Poxivirus Other viruses virus (AAV) Source: Cell and Gene Therapy dashboard | Informa, July 2021 21 / Q2 2021 Information Classification: General Gene therapy breakdown: CAR Ts dominate pipeline

▪ Of the gene therapies in development, 68% are genetically modified cell therapies ▪ Chimeric Antigen Receptor T cells (CAR Ts) represent 49% while T cell receptor T cells (TCR Ts) account for 12% of the genetically modified cell therapies in development

Gene therapy pipeline Genetically modified cell therapy breakdown

Genetically modified cell therapies Gene therapy CAR-T CAR-NK TCR-T Other

Source: Cell and Gene Therapy dashboard | Informa, July 2021

22 / Q2 2021 22 Information Classification: General Non-genetically modified cell therapy pipeline 2021 Q2

Information Classification: General Non-genetically modified cell therapy pipeline

Non-genetically modified cell therapy pipeline* • In May 2021, there were 771 therapies in 900 development (preclinical through pre-registration): 800 700 • 64% of candidates are in preclinical development 600 • There were 33 therapies in Phase III 500 clinical studies 400 • There are 4 therapies in pre-registration 300 (undergoing regulatory review): 200 • Gliovac (Epitopoietic Research) 100 • Astrostem (K-StemCell/Nature Cell) 0 • Donislecel (CellTrans) • RVT-802 (Enzyvant Sciences/Sinovant Number of Therapies by Year Sciences) Preclinical Phase I Clinical Trial Phase II Clinical Trial Phase III Clinical Trial Pre-registration

*These are snapshots taken every May to allow for year-on-year comparisons Source: Pharmaprojects | Informa, May 2021

24 / Q2 2021 Information Classification: General Non-genetically modified cell therapy pipeline: Most common therapeutic areas targeted Of the cell therapies in development (preclinical through pre-registration): • Similar to gene therapy, oncology and rare diseases are the most targeted therapeutic areas for non-genetically modified cell therapies (rare diseases includes oncology rare diseases).

Anticancer Products 278 Rare Diseases 273 Neurological Products 117 Musculoskeletal Products 109 Alimentary/Metabolic Products 108 Cardiovascular Products 88 Immunological Products 75 Respiratory Products 58 Dermatological Products 50 Miscellaneous Products 48 Sensory Products 45 Anti-infective Products 40 Genitourinary (including sex hormones) 31 Blood and Clotting Products 29 NA/Unspecified 26 Hormonal Products (excluding sex hormones) 4

Number of therapies Source: Pharmaprojects | Informa, July 2021

25 / Q2 2021 Information Classification: General Non-genetically modified cell therapy pipeline: Most common cancers targeted Of the cell therapies in development (preclinical through pre-registration) for oncology: • Of the diseases in which indications are specified, the top three indications are brain cancer, ovarian cancer and non- small cell lung cancer

Cancer, solid, unspecified 96 Cancer, unspecified 53 Cancer, brain 29 Cancer, ovarian 25 Cancer, lung, non-small cell 24 Cancer, leukaemia, acute myelogenous 23 Cancer, haematological, unspecified 21 Cancer, liver 21 Cancer, melanoma 21 Cancer, head and neck 18 Cancer, pancreatic 18 Cancer, myeloma 17 Myelodysplastic syndrome 13 Cancer, breast 12 Cancer, colorectal 10 Cancer, prostate 9 Cancer, lymphoma, unspecified 7 Cancer, renal 7 Cancer, cervical 6 Cancer, gastrointestinal, stomach 6 Number of therapies

Source: Pharmaprojects | Informa, July 2021

26 / Q2 2021 Information Classification: General Non-genetically modified cell therapy pipeline: Most common rare diseases targeted Of the cell therapies in development (preclinical through pre-registration) for non-oncology rare diseases: • Rare diseases: second most targeted therapeutic category for non-genetically modified cell therapies • Of the non-oncology rare diseases being targeted, the top 3 are respiratory distress syndrome (ARDS), graft-versus- host disease (GVHD), and spinal cord injury

Respiratory distress syndrome, acute 38 Graft-versus-host disease 25 Spinal cord injury 24 Amyotrophic lateral sclerosis 18 Cytokine release syndrome 12 Dystrophy, Duchenne's muscular 8 Huntington's disease 8 Retinitis pigmentosa 8 Anaemia, sickle cell 6 Scleroderma 6 Fibrosis, pulmonary, idiopathic 5 Buerger's syndrome 4 Epidermolysis bullosa 4 Neuritis, optic 4 Acute lung injury 3 Anaemia, aplastic, unspecified 3 Anal fistula 3 Dementia, frontotemporal 3 Haemophilia A 3 Hypoplastic left heart syndrome 3 Source: Pharmaprojects | Informa, July 2021 Number of therapies

27 / Q2 2021 Information Classification: General Non-genetically modified cell therapy trial activity in 2021 • A total of 40 clinical trials were initiated in 2021 so far • The top four diseases for trial starts in 2021 were for COVID-19 infections, osteoarthritis, ovarian cancer, fallopian tube cancer and Parkinson’s disease

Trials by Disease Number of trials by phase of study Novel coronavirus (2019-nCoV, COVID-19) 8 14 Osteoarthritis 4 Oncology: Ovarian 4 12 Oncology: Fallopian Tube 3 10 Parkinson's Disease 2 Cytomegalovirus Infection (CMV) 2 8 Respiratory Infections 2 Oncology: Multiple Myeloma 2 6 Oncology: Primary Peritoneal 2 Atopic Dermatitis 1 4 Cytokine Release Syndrome (CRS) 1 Epidermolysis Bullosa 1 2 Rheumatoid Arthritis 1 Transplantation/GVHD 1 0 Congestive Heart Failure 1 I II I/II III II/III Other Alzheimer's Disease 1 Amyotrophic Lateral Sclerosis 1 Autism 1 Cerebral Palsy 1 Movement Disorders 1 Number of trials Source: Trialtrove | Informa, July 2021

28 / Q2 2021 Information Classification: General RNA therapy pipeline 2021 Q2

Information Classification: General RNA therapies pipeline

• In 2021: • More than 600 therapies RNA therapies pipeline* were in development (from 700 preclinical to pre-registration stage), with 73% of 600 therapies in preclinical development 500 • 20 therapies were in Phase 400 III clinical studies 300

• 1 therapy in pre-registration Numbertherapies of (vutrisiran, Alnylam) 200

100

Preclinical Phase I Clinical Trial Phase II Clinical Trial Phase III Clinical Trial Pre-registration

*These are snapshots are taken every May to allow for year-on-year comparisons Source: Pharmaprojects | Informa, May 2021

30 / Q2 2021 Information Classification: General RNA therapy pipeline: Most common modalities

• Between Q1 and Q2 2021, messenger RNA therapeutics overtook RNA interference (RNAi) and antisense oligonucleotides to become the most common modality in development (preclinical through pre-registration

April 2021 July 2021

RNA interference 203 Messenger RNA 219

Antisense therapy 188 RNA interference 211

Messenger RNA 183 Antisense therapy 191

Anticancer, other 86 Anticancer, other 84

Prophylactic vaccine, anti-infective 70 Prophylactic vaccine, anti-infective 79

Anticancer, immunological 63 Anticancer, immunological 78

Oligonucleotide, non-antisense, non-… 58 Oligonucleotide, non-antisense,… 59

Number of therapies Number of therapies

Source: Pharmaprojects | Informa, July 2021

31 / Q2 2021 Information Classification: General RNA therapies: Most common diseases targeted

Of the 692 RNA therapies currently in the pipeline (from preclinical through pre-registration): • Oncology and rare diseases are the top 2 therapeutic areas being targeted. However, unlike gene therapies and non-genetically modified cell therapies, the top therapeutic area being targeted by RNA therapeutics is for rare diseases (please note that rare oncology diseases are included in the rare diseases therapeutic category)

Rare Diseases 241 Anticancer Products 173 Anti-infective Products 142 Neurological Products 96 Alimentary/Metabolic Products 94 Musculoskeletal Products 59 Sensory Products 47 Respiratory Products 44 Cardiovascular Products 42 NA/Unspecified 37 Immunological Products 25 Blood and Clotting Products 19 Genitourinary (including sex hormones) 17 Dermatological Products 16 Miscellaneous Products 7 Antiparasitic Products 3 Hormonal Products (excluding sex hormones) 2

Source: Pharmaprojects | Informa, July 2021 Number of therapies

32 / Q2 2021 Information Classification: General RNA therapies: Most common diseases targeted Of the RNA therapies currently in the pipeline (from preclinical through pre-registration): • Top oncology indications targeted are solid tumors with the top 5 (where specified) being melanoma, breast cancer, liver cancer, non-small cell lung cancer (NSCLC), and pancreatic cancer • For non-oncology rare diseases, Duchenne’s muscular dystrophy, cystic fibrosis, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and retinitis pigmentosa are the top 5 targeted diseases

Oncology indications Non-oncology rare diseases Cancer, solid, unspecified 54 Dystrophy, Duchenne's muscular 23 Cancer, unspecified 52 Cystic fibrosis 10 Cancer, melanoma 25 Huntington's disease 9 Cancer, breast 20 Amyotrophic lateral sclerosis 8 Cancer, liver 20 Retinitis pigmentosa 8 Cancer, lung, non-small cell 20 Dystrophy, myotonic muscular 6 Cancer, pancreatic 20 Respiratory distress syndrome, acute 6 Cancer, colorectal 18 Angelman syndrome 5 Cancer, head and neck 15 COVID-19 complications 5 Cancer, prostate 15 Fibrosis, pulmonary, idiopathic 5 Cancer, brain 13 Primary ciliary dyskinesia 5 Cancer, ovarian 13 Amyloidosis, transthyretin-related hereditary 4 Cancer, renal 7 Hypertriglyceridaemia 4 Cancer, bladder 6 Lipoprotein lipase deficiency 4 Cancer, leukaemia, acute myelogenous 5 Anaemia, sickle cell 3 Cancer, lymphoma, unspecified 5 Angioedema, hereditary 3 Cancer, mesothelioma 5 Ataxia, spinocerebellar 3 Cancer, myeloma 5 Chronic obstructive pulmonary disease 3 Cancer, skin, unspecified 5 Dystrophy, facioscapulohumeral muscular 3 Cancer, lung, unspecified 4 Hyperphenylalaninaemia 3

Number of therapies Number of therapies

Source: Pharmaprojects | Informa, July 2021 33 / Q2 2021 Information Classification: General RNA therapy pipeline: Clinical trial activity

• 162 RNA therapy trials were initiated in the first 6 months of 2021 • Trials evaluating vaccines for COVID-19 infections predominate but there are also trials initiated for dyslipidemia and hepatitis B infections

Trials by Disease Number of trials initiated by phase Novel coronavirus (2019-nCoV, COVID-19) 102 Dyslipidemia 9 60 Infectious Disease: HBV 7 Oncology: Unspecified Solid Tumor 4 50 Hepatic Fibrosis 3 Hypertension 3 40 Amyotrophic Lateral Sclerosis 3 NAFLD 3 30 Muscular Dystrophy 2 Spinal Muscular Atrophies 2 20 Respiratory Infections 2 Oncology: Prostate 2 10 Vaccines (Infectious Disease): Other Viral Vaccines 2 Sjogren's Syndrome 1 0 Acute Coronary Syndromes 1 II IV I III I/II II/III Other Congestive Heart Failure 1 Coronary Artery Disease 1 Peripheral Arterial Disease 1 Thrombotic Disorders 1 Number of trials Source: Trialtrove | Informa, July 2021

34 / Q2 2021 Information Classification: General Overview of dealmaking for gene, cell, and RNA therapy companies 2021 Q2

Information Classification: General Alliance, acquisition, and financing in gene, cell, & RNA therapy

• The gene, cell, & RNA industry has seen a greater volume of alliances, plus a slight uptick in acquisitions in Q2 2021 vs one year ago • Biggest decrease in Q2 2021 was seen in financings, with >20 fewer transactions done in Q2 than in Q1, and this was mainly attributable to fewer follow-on public offerings

Total number of deals by type, most recent five quarters 120 98 100 82 77 80 71 *Financing 60 60 72 Alliance 61 57 40 49

Number of deals of Number 40 17 20 12 10 6 8 Acquisition 0 Q2 2020 Q3 2020 Q4 2020 Q1 2021 Q2 2021

Source: Biomedtracker | Informa, July 2021 *Financings include public financings (IPOs and follow-ons) plus privately raised funding through venture rounds, debt offerings, or private investment in public equity 36 / Q2 2021 Information Classification: General Q2 2021 acquisitions in gene, cell, & RNA therapy Deal Date Deal Title Potential Deal Value (USD) 04/09/2021 Sanofi Acquires Tidal Therapeutics 470,000,000

04/20/2021 SparingVision Acquires GAMUT Therapeutics Undisclosed Athenex Acquires Kuur Therapeutics to Expand Cell Therapy Development with Off-the-Shelf Engineered CAR- 05/04/2021 185,000,000 NKT Platform 05/17/2021 Charles River Laboratories to Acquire Vigene Biosciences to Enhance Gene Therapy Capabilities 350,000,000

06/01/2021 Auris Medical Acquires RNA Therapeutics Company Trasir, Changes Name and Strategic Focus Undisclosed

06/14/2021 Brooklyn ImmunoTherapeutics Executes Letter of Intent to Acquire Novellus Therapeutics 125,000,000

06/14/2021 Avalon GloboCare to Acquire SenlangBio in All Stock Transaction Undisclosed uniQure to Acquire Corlieve Therapeutics and Advance its Gene Therapy Program to Treat Temporal Lobe 06/22/2021 298,300,000 Epilepsy 06/30/2021 Scopus BioPharma Expands Immunotherapy Pipeline with Acquisition of Olimmune Undisclosed

06/17/2021 Danaher Pays $9.6B for Aldevron, Manufacturer of High-Quality Plasmid DNA, mRNA, and Proteins 9,600,000,000

Source: Biomedtracker | Informa, July 2021

37 / Q2 2021 Information Classification: General Start-up funding for gene, cell, & RNA therapy companies 2021 Q2

Information Classification: General Start-up financing for gene, cell, & RNA therapy companies • 23 companies raised seed or Series A financing in Q2 2021, reaching an aggregate $1.4 billion • Nearly 75% (17/23) of biotechs are based in the US (mainly Massachusetts and California), the rest in Europe and Asia • Top financing ($250M) was done by a new company created by Intellia, Cellex (and subsidiary GEMoaB), and Blackstone to develop allogeneic universal CAR-T therapies based on Intellia’s CRISPR/Cas9 platform and CEMoaB’s switchable, universal CAR T-cell platforms Volume and dollar value of Series A and seed financings for gene, cell, & RNA therapy companies, most recent five quarters $1,600.0 23 25 $1,400.0 18 $1,445.3 20 $1,200.0 16 $1,000.0 $1,043.7 13 15 $800.0 11 $600.0 $744.8 10 $400.0 $523.5 $479.8 5

Total raised ($M) raised Total $200.0 Number offinancings Number $- 0 Q2 2020 Q3 2020 Q4 2020 Q1 2021 Q2 2021

Total raised ($M) Number of financings Source: Biomedtracker | Informa, July 2021

39 / Q2 2021 Information Classification: General Q2 2021 start-up financing for gene, cell, & RNA therapy companies (1/2) Potential Deal Deal Date Deal Title Company Location Academic Source Value (USD) Shoreline Biosciences Announces $43M Early Round To Advance United States, California, San 04/07/2021 University of California, San Diego 43,000,000 Pipeline Diego United States, California, San Harvard University: Harvard Medical School and Wyss 04/19/2021 Rejuvenate Bio Raises over $10M in Series A financing 10,000,000 Diego Institute United States, Pennsylvania, 04/20/2021 Code Biotherapeutics Launches with $10M in Seed Financing Undisclosed 10,000,000 Hatfield United States, California, California Institute of Technology: Tianqiao and Chrissy 04/29/2021 Capsida Biotherapeutics Debuts with $50M Series A Round 50,000,000 Newbury Park Chen Institute for Neuroscience United States, Connecticut, 04/30/2021 Treeline Biosciences Launches with $211M Series A Round Undisclosed 211,669,568 Stamford United States, North Carolina, 05/05/2021 Isolere Bio Closes $7M in Seed Funding Duke University 7,000,000 Durham United States, Massachusetts, Harvard University: Harvard Medical School and Wyss 05/06/2021 Dyno Therapeutics Closes $100M Series A Round 100,000,000 Cambridge Institute Gennao Bio Closes $40M Series A Financing to Develop Pipeline of United States, New York, New 05/10/2021 Yale University 40,000,000 Targeted Nucleic Acid Therapeutics York United States, California, Los 05/11/2021 Appia Bio Launches With $52M Series A Financing University of California, Los Angeles 52,000,000 Angeles G2 Bio Companies Launch with $200M to Develop Transformative United States, Pennsylvania, 05/18/2021 University of Pennsylvania: Gene Therapy Program 200,000,000 Genetic-Based Therapies Philadelphia Vedere Bio II Launches with $77M Series A Financing to Develop University of California, Berkeley; University of 05/18/2021 United States 77,000,000 Ocular Gene Therapies Pennsylvania: School of Veterinary Medicine HAYA Therapeutics Completes CHF 18M Seed Financing To 05/20/2021 Switzerland, Vaud Lausanne University Hospital 19,985,500 Advance Anti-fibrotic Therapies Targeting Long Non-coding RNAs United States, Maryland, 05/27/2021 miRecule Inc. Closes $5.7M Seed Funding National Institutes of Health: BioHealth Innovation 5,700,000 Gaithersburg

Source: Biomedtracker | Informa, July 2021 40 / Q2 2021 Information Classification: General Q2 2021 start-up financing for gene, cell, & RNA therapy companies (2/2) Potential Deal Deal Date Deal Title Company Location Academic Source Value (USD) Alcyone Therapeutics Launches with $23M to Advance Gene United States, Massachusetts, Nationwide Children's Hospital: Abigail Wexner Research 06/09/2021 23,000,000 Therapies for CNS Disorders Lowell Institute 06/15/2021 VectorY Raises $37.58M in Seed Financing Netherlands, Amsterdam Undisclosed 37,582,695 Mnemo Therapeutics Announces $90M Series A to Accelerate 06/16/2021 Next Generation Integrated CAR-T and Epigenetic Targeting France, Paris Institut Curie; Memorial Sloan Kettering Cancer Center 90,000,000 Platform 06/16/2021 Ochre Bio Closes $9.6M Seed Financing United Kingdom, Oxford Working in collaboration with Oxford University 9,600,000 Nuevocor Closes $24M Series A Financing to Advance Novel Gene 06/18/2021 Singapore Agency for Science, Technology and Research (A*STAR) 24,000,000 Therapies for Cardiomyopathies Unnamed autologous/allogeneic CAR-T company launched with United States, Massachusetts, n/a – founded around pooled resources from GEMoaB 6/22/2021 $250M from Blackstone Life Sciences, Intellia Therapeutics, and 250,000,000 Cambridge GmbH (Cellex’s parent company) and Intellia Cellex Cell Professionals Co-founders are from Harvard Medical School, United States, Massachusetts, 06/23/2021 Abata Therapeutics Launches with $95M Series A Funding Massachusetts Institute of Technology, and University 95,000,000 Cambridge Hospital of Zurich United States, Maryland, 06/23/2021 Vita Therapeutics Raises $32M in Series A Financing Johns Hopkins University; Kennedy Krieger Institute 32,000,000 Baltimore Strand Therapeutics Raises $52M via Oversubscribed Series A United States, Massachusetts, 06/23/2021 MIT Synthetic Biology Center 52,000,000 Round Cambridge OliX' subsidiary mCureX Therapeutics Raises ₩6.5B in Pre-Series A 06/24/2021 Korea (South) n/a – subsidiary of OliX Pharmaceuticals 5,738,860 Investment

Source: Biomedtracker | Informa, July 2021

41 / Q2 2021 Information Classification: General Notable Q2 2021 start-up gene, cell, & RNA therapy companies

Financing Company details Academic source Lead investor(s) Therapy areas of interest type/amount raised T-cell engineering EnfiniT platform technology, Casdin Capital, including identification of Institut Curie; Sofinnova antigens with greater tumor Memorial Sloan Series A; $90M Partners, and an Oncology specificity and development Kettering Cancer undisclosed of Center investor next-generation CAR-T therapies Harvard Liver, muscle, eye, central CapsidMap platform, which University: Andreessen nervous system, lung, designs AAV vectors using Harvard Medical Series A/$100M Horowitz heart and kidney artificial intelligence School and Wyss diseases Institute

DiscoverHAYA platform to Lausanne discover tissue and cell- Broadview Fibrosis and conditions University Seed/$20M specific long non-coding RNA Ventures related to aging Hospital drug candidates

Source: Biomedtracker | Informa, July 2021; company websites 42 / Q2 2021 Information Classification: General Upcoming catalysts 2021 Q2

Information Classification: General Upcoming Catalysts Below are noteworthy catalysts (forward looking events) that are expected in Q3 2021

Therapy Generic Name Disease Catalyst Catalyst Date elivaldogene autotemcel, Cerebral European Approval Skysona May 21 - Sep 30, 2021 Lenti-D adrenoleukodystrophy Decision

Yescarta axicabtagene ciloleucel Marginal cell lymphoma FDA Approval Decision Jun 18 - Sep 30, 2021

European Approval Abecma idecabtagene vicleucel Multiple myeloma Jun 24 - Aug 30, 2021 Decision

Source: Biomedtracker | Informa, July 2021

44 / Q2 2021 Information Classification: General

Appendix Q2 2021 Q2

Methodology, sources, & glossary of key terms

Information Classification: General Methodology: Sources and scope of therapies

Sources for all data come from Informa Pharma Intelligence Pipeline and trial data • Data derived from Citeline (Pharmaprojects and Trialtrove) • Therapeutic classes included in report categorizations: • Gene therapies: Gene therapy; cellular therapy, chimeric antigen receptor; cellular therapy, T cell receptor; lytic virus • Cell therapies: Cellular therapy, other; cellular therapy, stem cell; cellular therapy, tumor-infiltrating lymphocyte • RNA therapies: Messenger RNA; oligonucleotide, non- antisense, non-RNAi; RNA interference; antisense therapy

Deal, financing, and catalyst data • Data derived from Biomedtracker • The following industry categorizations of deals are included: Gene therapy, cell therapy; antisense, oligonucleotides

46 / Q2 2021 Information Classification: General Glossary of Key Terms Therapy Type Definitions Gene therapy is the introduction, removal, or change in genetic material—specifically DNA or RNA—into the cells of a patient to treat a specific disease. For the purpose of this report, the following terms shall mean the following:

Therapies containing an active ingredient synthesized following vector-mediated introduction of a genetic sequence into target cells in- or ex-vivo. Used to replace defective or missing genes (as in cystic fibrosis) as well as to introduce broadly acting genetic sequences for the treatment of multifactorial diseases (e.g. cancer). Direct administration of Gene therapy oligonucleotides without using vectors is covered separately in the antisense therapy class; RNA interference class; or oligonucleotide, non-antisense, non-RNAi class. Platform technologies for gene delivery are covered separately in the gene delivery vector class.

Cellular therapy, chimeric antigen receptor Cellular therapy consisting of T cells that have been modified to express a chimeric antigen receptor (CAR) – this is a cell *Falls under gene therapy in this report surface receptor that gives the T cells the ability to target a specific protein and fight the targeted cells.

Cellular therapies whereby natural T-cells collected for the patient, are engineered to express artificial receptors (usually Cellular therapy, T cell receptor through viral transfections) that would target specific intracellular antigens (as peptides bound to proteins encoded by *Falls under gene therapy in this report the major histocompatibility complex, MHC).

Lytic virus Therapies which have a replication-competent virus, that lyse pathogenic cells directly. These are normally genetically *Falls under gene therapy in this report modified to render them harmless to normal tissues. Examples include oncolytic viruses which specifically attack cancer cells.

47 / Q2 2021 Information Classification: General Glossary of Key Terms Therapy type definitions, cont.

Cell therapy includes the following therapeutic classes:

Regenerative therapy which promotes the repair response of injured tissue using stem cells (cells from which all other Cellular therapy, stem cell specialized cells would originate).

Adoptive cellular transfer of tumor resident T cells from tumor material, their expansion ex vivo, and transfer back into Cellular therapy, tumor infiltrating lymphocyte the same patient after a lymphodepleting preparative regimen.

Cellular therapies that do not fall under the categories of cellular therapy, stem cell; cellular therapy, CAR; cellular Cellular therapy, other therapy, TIL; cellular therapy, TCR; or the specific cellular therapy are unspecified.

48 / Q2 2021 Information Classification: General Glossary of Key Terms Therapy type definitions, cont. RNA therapy includes the following therapeutic classes:

Therapies that carry the desired mRNA code to overcome genetic mutations. The mRNA sequence will replace the Messenger RNA defective mRNA in a patient and starts producing the desired protein.

Synthetic therapeutic oligonucleotides which operate by a mechanism other than antisense or RNA interference (RNAi). This includes ribozymes, aptamers, decoys, CpGs, and mismatched and immunostimulant oligonucleotides. Sequences Oligonucleotide, non-antisense, non-RNAi delivered using vectors (gene therapy) are covered separately in “gene therapy.“ Antisense and RNAi oligonucleotides are covered separately in “antisense therapy" and "RNA interference,“ respectively. Includes products which act therapeutically via an RNA interference (RNAi) mechanism, including small interfering RNAs (siRNAs). These may be synthetic oligonucleotides, or RNAi sequences may be expressed from a vector as a form of gene therapy (see “gene therapy" therapeutic class). In vivo, these sequences block the expression of a specific protein by RNA interference forming an RNA-induced silencing complex, which then specifically binds to and degrades a complementary mRNA encoding the target protein. The use of RNAi purely as a drug discovery tool (e.g., in transgenic animal model production or in target validation) is not covered in this section. Antisense compounds under development as potential therapeutics. These may be synthetic oligonucleotides, or antisense RNA may be expressed from a vector as a form of gene therapy. They may prevent the expression of a specific Antisense therapy protein in vivo by binding to and inhibiting the action of mRNA, since they have a specific oligonucleotide sequence which is complementary to the DNA or RNA sequence which codes for the protein.

49 / Q2 2021 Information Classification: General Glossary of Key Terms

Development status definitions Deal type categories Pipeline Drugs that are in active development Alliances Co-marketing, co-promotion, disease management, joint venture, manufacturing or supply, marketing- Preclinical Not yet tested in humans licensing, product or technology swap, product purchase, R+D and marketing-licensing, reverse Phase I Early trials, usually in volunteers, safety, PK, PD licensing, trial collaborations Phase II First efficacy trials in small numbers of patients Financing Convertible debt, FOPO, IPO, nonconvertible debt, Phase III Large scale trials for registrational data financing/other, private investment in public equity, private placement, royalty sale, special-purpose Pre-registration Filing for approval made to regulatory authorities financing vehicle, spin-off Approved Approval from relevant regulatory authorities for Acquisitions Buy-out, divestiture, spin-out, full acquisition, partial human use acquisition, reverse acquisition

Unspecified indications Cancer, unspecified Indications for which the specific tumor type is not specified Cancer, hematological, Indications for which the specific hematological cancer unspecified is not specified Cancer, solid, unspecified Indications for which the specific solid tumor is not specified

50 / Q2 2021 Information Classification: General Report Contributors

David Barrett, JD Ly Nguyen-Jatkoe, PhD CEO Executive Director, Americas American Society of Gene + Cell Therapy Informa Pharma Custom Intelligence

Betsy Foss-Campbell, MA Amanda Micklus, MSc Director of Policy and Advocacy Senior Pharma Consultant American Society of Gene + Cell Therapy Informa Pharma Custom Intelligence

Alex Wendland, MSJ Doro Shin, MPH Director of Communications Senior Director, Content Marketing American Society of Gene + Cell Therapy Informa Pharma Intelligence

51 / Q2 2021 Information Classification: General Contact: David Barrett, JD at [email protected]

Contact: [email protected]