Emerging Gene Therapies – Trends within the Technological, Clinical, Regulatory and Competitive Landscape

GBI Research’s latest report “Emerging Gene Therapies – Trends within the Technological, Clinical, Regulatory and Competitive Landscape” provides a comprehensive overview of the emerging gene therapy market. The report discusses gene therapy and the technology behind gene editing, outlining the advantages, limitations and current evidence for the platforms under development. The report discusses relevant clinical studies targeting specific therapeutic indications and highlights examples of current challenges within the field, with a focus on therapies that target the eye, liver, and blood.

Additionally, the report provides a background to the CRISPR patent litigation, a key factor within the gene editing company landscape. It provides profiles of six companies developing gene editing platforms, considers the gene therapy interests of the main pharmaceutical companies, and discusses current regulatory trends in the development of gene therapies.

The report explores how emerging gene editing products will compete with established products, their relative competitive strengths, and upcoming value inflection points within the field.

Scope

– What are the key emerging products within the gene therapy landscape?

– Which companies have the strongest pipeline of innovative products?

– How will gene editing disrupt existing gene therapy products?

– What are the regulatory trends for emerging gene therapies?

– What are the interests of pharmaceutical companies within the field?

Reasons to buy

- Achieve an up-to-date understanding of the area, with a comprehensive reference of key products within the gene therapy landscape, compared across technology-specific relevant characteristics such as editing mechanism and delivery vector.

- Conduct competitive analysis using indication-specific, side-by-side comparisons of the latest data for key gene therapy products in the strategically relevant areas of eye, blood, and liver.

- Conduct strategic analysis using an overview of gene therapy specific considerations for evaluating and developing gene therapy products - the CRISPR patent space, emerging regulatory trends, innovation leaders and the interests of pharma in gene therapy.

Table of Contents

1 Table of Contents

1 Table of Contents 5

1.1 List of Tables 7

1.2 List of Figures 8

2 Introduction 10

2.1 Gene Therapy - Definitions 10

2.2 Report Coverage - the Emerging Gene Therapy Pipeline 11

2.3 History of Gene Therapy 12

2.4 Limitations of Gene Transfer 13

2.5 The Development of Targeted Gene Editing 13

2.6 Overview of Gene Editing Platforms 13

2.6.1 Zinc Fingers (1996) 13

2.6.2 Transcription Activator-Like Effectors (2011) 14

2.6.3 The CRISPR/Cas System (2013) 15

2.6.4 Effectors for Targeting Domains 19

2.6.5 Comparison of Gene Editing Systems 19

2.6.6 Summary of Gene Editing Systems 19

2.7 Overview of In Vivo Gene Therapy 21

2.7.1 Editing is Dependent on Cell Type, Stage, and Repair Pathway 21

2.7.2 Delivery 21

2.7.3 Emerging Safety Concerns with Editing Platforms 24

2.7.4 Editing Products are Reliant on the Target Cell’s Cycle Stage and DNA Repair Machinery 27

2.7.5 Advantages of Gene Editing over Gene Transfer 28

2.7.6 Integration into ‘Safe Harbor’ Sites 28

2.7.7 The Increasing Complexity of Gene Therapy 30

2.7.8 Summary of In Vivo Gene Therapy 31

3 Gene Therapy - Near Term Product Pipeline 33

3.1 Leber Congenital Amaurosis 33

3.1.1 Unmet Need 33

3.1.2 Molecular Genetics 33

3.1.3 Luxturna (Voretigene neparvovec) 33

3.1.4 Editas Medicine: EDIT-101 35

3.1.5 Trial Design 36

3.1.6 EDIT-101 and Off-Target Effects 37

3.1.7 The Potential Advantage of EDIT-101 is the Longevity of its Therapeutic Effect 37

3.1.8 Summary - LCA 38

3.2 Choroideremia 38

3.3 Hurler Syndrome (MPS I) 39

3.3.1 Key Clinical Studies 40

3.3.2 Regenex: RGX-111 40

3.3.3 Sangamo Therapeutics: SB-318 40

3.4 Hunter Syndrome (MPS II) 41

3.4.1 Unmet Need 41

3.4.2 Sangamo Therapeutics: SB-913 41

3.4.3 Immusoft Corporation: Cell Therapy 43

3.5 Sanfilippo Syndrome (MPS III) 43

3.5.1 Lysogene: LYS-SAF302 43

3.6 Summary - MPS Disorders 44

3.7 Hemophilia 44

3.7.1 Hemophilia A 46

3.7.2 Summary - Hemophilia A 50

3.7.3 Hemophilia B 51

3.7.4 Summary - Hemophilia B 53

3.8 Hemoglobinopathies 54

3.8.1 Beta Thalassemia: Unmet Need 54

3.8.2 Beta Thalassemia: Molecular Genetics 55

3.8.3 Sickle Cell Disease: Unmet Need 56

3.8.4 Sickle Cell Disease: Molecular Genetics 56

3.9 Cellular Therapies for Hemoglobinopathies 57

3.9.1 Blue Bird Bio: BB-305 (‘LentiGlobin’) 57

3.9.2 Sangamo: ST-400 60

3.9.3 CRISPR Therapeutics: CTX-001 61

3.9.4 Summary: Cellular Therapies for Hemoglobinopathies 62

3.10 Duchenne Muscular Dystrophy 63

3.10.1 Unmet Need 63

3.10.2 Molecular Genetics 63

3.10.3 ExonDys 51 - Sarepta Therapeutics 64

3.10.4 Solid BioSciences: SGT-001 66

3.10.5 Exonics Therapeutics: CRISPR Approach 67

3.10.6 Summary - Duchenne Muscular Dystrophy 68

4 Competitive Landscape 69

4.1 Regulatory Considerations for Developing Gene Therapy Products 69

4.1.1 Product Characteristics 69

4.1.2 Clinical Study Design for Gene Therapy Products 69

4.1.3 Disease specific guidance 70

4.1.4 Reimbursement and Payment 71

4.1.5 Summary - Regulatory Considerations 72

4.2 Intellectual Property - CRISPR/Cas 72

4.2.1 Licensing, Exploitation, and MPEG Pool 74

4.3 Company Analysis: Gene Editing Companies 75

4.3.1 Sangamo Therapeutics 75

4.3.2 CRISPR Therapeutics 79

4.3.3 Casebia Therapeutics 81

4.3.4 Editas Medicine 82

4.3.5 Intellia Therapeutics 84

4.3.6 Homology Medicines 86

4.4 Company Analysis: Pharma 87

4.4.1 Amgen 87

4.4.2 Gilead Sciences 87

4.4.3 Novartis 87

4.4.4 Sanofi 88

4.4.5 GlaxoSmithKline 88

4.4.6 Pfizer 88

5 Appendix 89

5.1 References 89

5.2 Report Methodology 98

5.3 About GBI Research 99

5.4 Disclaimer 99

List of Tables

1.1 List of Tables

Table 1: Pipeline Products Covered 13

Table 2: Properties of Standard Gene-Editing Nucleases 20

Table 3: Registered Clinical Trials of CAR-T Cell Therapies Using Gene-Editing 21

Table 4: Gene Therapy Clinical Trials Worldwide by Vector 24

Table 5: Gene Editing Landscape, Vector Differentiation by Target Tissue 25

Table 6: Gene Editing Landscape, Key Off-Target Effect Studies 26

Table 7: Pre-existing Immunity to Cas9 27

Table 8: Characterization of the Rate of Homology Directed Repair in Range of Cell Lines 28

Table 9: Comparison of Gene Editing and Gene Transfer Approaches 29

Table 10: Gene Editing Landscape, Pipeline of Targeted Gene Editing Products by Company 32

Table 11: Luxturna Clinical Studies 35

Table 12: EDIT-101 – Phase I/II Trial Design and Comparison to Luxturna Efficacy Study 38

Table 13: Dose Response in CEP290 Gene Editing and CRISPR Expression 39

Table 14: Gene editing landscape, Mucopolysaccharidosis I (MPS I) (Hurler Syndrome), Diagnosed, Prevalent Cases, 2017-2027 40

Table 15: Key Phase I/II Studies in MPS I 41

Table 16: Gene editing landscape, Mucopolysaccharidosis II (MPS II) (Hunter Syndrome), Diagnosed, Prevalent Cases, 2017-2027. 42

Table 17: SB-913 Trial Design 43

Table 18: SB-913 – Interim Results 43

Table 19: LYS-SAF302 Phase II/III Trial Design 44

Table 20: Gene Editing Landscape, MPS Disorders 45

Table 21: Gene Editing Landscape, Hemophilia Epidemiology and Forecast, 2016-2026. 46

Table 22: Scale of Hemophilia Severity 47

Table 23: Phase I/II Hemophilia A Trials 48

Table 24: BMN-270 Factor VIII Levels at 1.5 Years (High Dose) 49

Table 25: Gene Therapy Landscape, Phase I/II Clinical Trial Design for Hemophilia A 50

Table 26: Gene Therapy Landscape, Summary of Key Pipeline Gene Therapies for Hemophilia A 51

Table 27: Phase I/II Clinical Studies 52

Table 28: Gene Therapy Landscape, Overview Of Key Pipeline Products in Hemophilia B 54

Table 29: Gene editing landscape, Thalassemia, Diagnosed, Prevalent Cases, 2017-2027 55

Table 30: Frequent Mutations Causing SCD 57

Table 31: Phase I/II Clinical Studies 58

Table 32: LentiGlobin – Ongoing Phase III Trials in Beta Thalassemia 59

Table 33: Results of LentiGlobin trials in Thalassemia and Sickle Cell Disease 60

Table 34: ST-400 Trial Design Compared with LentiGlobin 62

Table 35: CTX-001 trial design (Left) against ST-400 and LentiGlobin (Right) 63

Table 36: LentiGlobin (BB-305) may Achieve Blockbuster Status by 2023 64

Table 37: Gene Therapy Landscape, DMD, Global Prevalence (%) 64

Table 38: Exondys 51 – Clinical Studies 66

Table 39: SGT- 001 Study Design 67

Table 40: Gene Therapy Landscape, Key Patents in the CRISPR Dispute 74

Table 41: Gene Therapy Landscape, IP Estates of CRISPR Companies 75

Table 42: Gene Therapy Landscape, ERS Genomics EU Licensing 2004-2018 76

Table 43: Sangamo Therapeutics Pipeline, September 2018 76

Table 44: Sangamo Therapeutics Partnerships 78

Table 45: Sangamo Therapeutics SWOT 79

Table 46: CRISPR Therapeutics Pipeline 80

Table 47: CRISPR Therapeutics Pipeline 81

Table 48: CRISPR Therapeutics SWOT 82

Table 49: Casebia Pipeline, September 2018 82

Table 50: Editas Medicine Pipeline, September 2018 83

Table 51: Editas Medicine Pipeline, September 2018. 84

Table 52: Editas Medicine SWOT 85

Table 53: Intellia Therapeutics Pipeline 85

Table 54: Intellia Therapeutics SWOT 86

Table 55: Homology Medicines Pipeline 87

Table 56: Homology Medicines SWOT 88

List of Figures

1.2 List of Figures

Figure 1: Nucleases Based on Protein-DNA Interactions 14

Figure 2: Transcription Activator-Like Effector Nucleases (TALENs) 15

Figure 3: The CRISPR/Cas System 16

Figure 4: CRISPR/Cas Binding Mechanism 17

Figure 5: Cas9 Orthologs 18

Figure 6: Gene Therapy Clinical Trials Worldwide by Vector 22

Figure 7: Multiple Sangamo Therapeutics Products Use an Albumin Targeting ‘Safe Harbor’ Approach 29

Figure 8: Gene Editing Landscape, Progression of Gene Therapy Applications 30

Figure 9: Gene Editing Landscape, Hemophilia A + B 44

Figure 10: SPK-9001: Factor IX Activity after SPK-9011 in 8 Participants that did not Show AAV Capsid-Directed Immune Response 53

Figure 11: Cost of Beta-Thalassemia Major Treatment as of NHS Tariffs at 2013/14 Prices 55

Figure 12: BCL11A is Involved in Fetal Hemoglobin Silencing 60

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