CONTENTS

7 EXECUTIVE SUMMARY

10 INTRODUCTION TO GENE THERAPY
10 Gene therapy is the most active modality in regenerative medicine
11 Historically, gene therapy has been riddled with setbacks
12 Gene therapy involves in vivo and ex vivo approaches
13 Bibliography

15 INNOVATIONS IN GENE DELIVERY TECHNOLOGIES
15 Gene therapy is enabled by viral and non-viral methods
22 Bibliography

26 REGULATORY ISSUES
26 Regulatory pathways are providing incentives for gene therapy development
36 Bibliography

39 KEY COMPANIES IN GENE THERAPY
39 REGENXBIO is building its internal pipeline and out-licensing its NAV platform
42 Juno is delayed, but not out of the CAR-T race
44 Kite Pharma’s cell therapy pipeline will become the foundation of Gilead’s oncology offering
46 Despite shutting down cell and gene therapy unit, Novartis shows clear commitment to CAR-T therapy
48 Through partnerships, Sanofi has many early- and late-stage gene therapies in development
50 Even with portfolio shuffle, GlaxoSmithKline still has a promising Phase III T-cell therapy, and could be next Big Pharma to
introduce a gene therapy
52 Bibliography

55 TRENDS IN APPROVED GENE THERAPIES
55 Fewer than a dozen gene therapies are approved worldwide
59 Key gene therapy approvals
62 Bibliography

64 GENE THERAPY PIPELINE TRENDS
64 After plateauing, the gene therapy pipeline is picking up speed65 The US leads ongoing clinical trial activity in gene therapies
66 Completed gene therapy trials have high success rate
67 Most terminated gene therapy trials are those that were planned, but never initiated
68 Both “gene therapy” and “cell and gene therapy” approaches are on fairly equal ground
69 Across phases, in vivo and ex vivo therapies are split fairly equally
70 Viral vectors are used more than non-viral vectors for delivery
77 Most gene therapies in development aim to attack cancer
87 Macular degeneration is the indication with the most gene therapy activity, outside of oncology
88 Spark Therapeutics could see the next gene therapy approval
89 Bluebird bio is developing two promising Phase III lentiviral candidates with high likelihoods of approval
91 Bibliography

94 ONCOLOGY GENE THERAPY TRENDS
94 High volumes of gene therapies are in the pipeline for solid tumors
97 More than half of the oncology gene therapies in development are modified T-cell therapies
98 Trends in immuno-oncology approaches
101 Trends in additional cancer gene therapy approaches
102 Bibliography

103 APPENDIX
103 Scope
103 Methodology

LIST OF FIGURES
11 Figure 1: Gene therapy defined: EMA and FDA definitions
13 Figure 2: Gene therapy delivery approaches, in vivo versus ex vivo
15 Figure 3: Viral and non-viral vectors – advantages and disadvantages
16 Figure 4: Key viral vector types – highlights of advantages and disadvantages
26 Figure 5: Product class inclusions in EU and US specialized regenerative medicine regulatory pathways
39 Figure 6: Top 20 gene therapy companies by pipeline size
59 Figure 7: Most approved or launched gene therapies are available in Asia
64 Figure 8: Gene therapy pipeline volume, preclinical through pre-registration phase, 1995–2017
65 Figure 9: Gene therapy pipeline volume by phase, 1995–2017
66 Figure 10: Most gene therapy clinical trial activity is in the US
67 Figure 11: Completed gene therapy trials are largely successful; trials by outcomes
68 Figure 12: Top reasons why gene therapy trials are terminated
69 Figure 13: Gene therapy versus “cell and gene therapy”: breakdown of pipeline
70 Figure 14: Gene therapy pipeline by in vivo or ex vivo approach and phase
71 Figure 15: Viral vector delivery is most prominent in gene therapy
72 Figure 16: In viral vector gene delivery, AAVs are most often used
73 Figure 17: Viral vector gene therapy pipeline by vector and phase
74 Figure 18: In vivo gene therapies, viral versus non-viral delivery
75 Figure 19: In vivo gene therapies by vector type
76 Figure 20: Ex vivo gene therapies, viral versus non-viral delivery
77 Figure 21: Ex vivo gene therapies by vector type
78 Figure 22: Oncology dominates gene therapy drug development
79 Figure 23: Gene therapy pipeline by therapy area and phase
80 Figure 24: Cancer and non-oncologic rare disease diverge in ex vivo versus in vivo delivery
81 Figure 25: Viral vectors are largely used in cancer and rare non-oncologic gene therapies
82 Figure 26: Other therapy areas are mostly being addressed by gene therapy
83 Figure 27: Viral vectors are also most prominent in other therapy areas
84 Figure 28: In vivo gene therapies by therapy area and phase of development
85 Figure 29: In vivo gene therapies by therapy area and viral vector
86 Figure 30: Ex vivo gene therapies by therapy area and phase of development
87 Figure 31: Ex vivo gene therapies by therapy area and viral vector
88 Figure 32: Lead indications in non-oncology gene therapy development
94 Figure 33: Oncology gene therapies are mainly addressing solid tumors
95 Figure 34: Lead indications in oncology gene therapy development
96 Figure 35: Developers focus on cell and gene therapy in cancer
97 Figure 36: Tumor type distribution between oncology in vivo and ex vivo therapies
98 Figure 37: Modified T-cells dominate: oncology gene therapies by approach
101 Figure 38: Approaches to cancer immunotherapy: gene therapy products in development, by phase
102 Figure 39: Other approaches to cancer gene therapy, by phase

LIST OF TABLES
31 Table 1: Summary of FDA guidance on cell and gene therapy
41 Table 2: REGENXBIO gene therapy pipeline
43 Table 3: Juno Therapeutics gene therapy pipeline
46 Table 4: Kite Pharma gene therapy pipeline
48 Table 5: Novartis gene therapy pipeline
50 Table 6: Sanofi gene therapy pipeline
52 Table 7: GlaxoSmithKline gene therapy pipeline
56 Table 8: Approved gene therapies worldwide, October 2017
91 Table 9: Select Phase III non-oncology gene therapy candidates, by likelihood of approval
100 Table 10: Cancer gene immunotherapies in Phase III development