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

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