Table of Contents

CONTENTS

6 EXECUTIVE SUMMARY
6 The number of gene therapy products in development has doubled since 2012
6 Most products in development are in vivo therapies, except in oncology
6 The adeno-associated virus is the most popular viral vector
6 Cancer is the most common target for gene therapies in development, followed by monogenic diseases
6 Most products in advanced clinical development target cancer indications
6 Immunotherapy and oncolytic virotherapy are promising approaches in cancer
7 Regulatory and reimbursement strategies will be key to the success of new therapies
7 Gene therapy of cancer is the most active area of commercial deal-making

8 GENE THERAPY STRATEGIES
8 Introduction to gene therapy
11 Bibliography

13 GENE THERAPY PRODUCTS IN COMMERCIAL DEVELOPMENT IN 2015
13 Cancer is the most common target for products, followed by monogenic diseases

16 INNOVATIONS IN GENE DELIVERY TECHNOLOGIES
16 Viruses are efficient gene delivery vectors, but pose several challenges
16 Viral vectors can stimulate the host’s immune system with undesirable effects
22 Plasmids as gene vectors
24 Bacteria as gene vectors
25 Cells as gene vectors
27 Vectors used in in vivo therapies in commercial development in 2015
32 Bibliography

38 GENE THERAPIES FOR CANCER
38 Conventional cancer treatment has limited long-term success
38 A total of 201 cancer gene therapy products are in commercial development
40 Immunotherapy is a popular broad anticancer strategy
67 Other approaches to cancer gene therapy
79 Targeted destruction of tumors encompasses a variety of approaches
81 Oncolytic virotherapy offers hope to patients with inoperable tumors
83 Anti-angiogenic gene therapies offer an alternative approach
83 Bibliography

88 GENE THERAPIES FOR MONOGENIC DISEASES
88 There are 102 gene therapy products in commercial development
100 Lipoprotein lipase deficiency
101 Adenosine deaminase deficiency
103 Inherited retinal dystrophies
104 X-linked childhood cerebral adrenoleukodystrophy104 Hemophilia
106 Muscular dystrophies
107 Bibliography

110 GENE THERAPIES FOR ACQUIRED DISEASES OTHER THAN CANCER
110 Infectious diseases
114 Cardiovascular disease
120 Sensory diseases
124 Neurological disease
130 Other diseases
135 Bibliography

137 REGULATORY ISSUES
137 Introduction
137 Regulatory framework in the EU
143 Regulatory framework in the US
148 Bibliography

153 REIMBURSEMENT ISSUES
153 In rare diseases, return on investment is typically realized through repeated drug administration
154 An alternative to a high single payment may be annuity payments for effective treatment
155 Pay-for-performance models may be suitable for gene therapy reimbursement
156 Payers are not ready, but gene therapies may drive rethinking of drug pricing in general
156 Glybera’s reimbursement struggles reveal uncertainties around long-term effects to be a key concern for payers
157 Imlygic struggles to gain reimbursement amid increased competition within melanoma
157 GlaxoSmithKline to use Strimvelis to test alternative funding mechanisms
158 Bibliography

161 DEALS AND ACQUISITIONS
161 Five years of deal-making in the gene therapy area

170 APPENDIX
170 About the authors
170 Scope
170 Methodology

LIST OF FIGURES
13 Figure 1: Gene therapy products in development, by disease and approach employed
14 Figure 2: Gene therapy products in development, by disease and phase of development
27 Figure 3: Vectors for in vivo delivery in commercial development (preclinical to Phase III and beyond), by disease type
28 Figure 4: Viral gene vectors in advanced commercial development (Phase III and beyond), by disease type
29 Figure 5: Viral gene vectors in preclinical development, by disease type
30 Figure 6: Plasmid vectors used in in vivo gene therapies, by disease type
31 Figure 7: Ex vivo therapies, by disease type and stage of development
38 Figure 8: Cancer gene therapies in development, by phase of development
39 Figure 9: Cancer gene therapies in development, by type of vector
40 Figure 10: Approaches to cancer immunotherapy: gene therapy products in development, by stage of development
67 Figure 11: Other approaches to cancer gene therapy: products in development, by type of therapy
88 Figure 12: Gene therapies in development targeting monogenic diseases, by phase of development
162 Figure 13: Licensing deals categorized by disease application, 2011–15

LIST OF TABLES
42 Table 1: Immunotherapeutic cancer gene therapy products in Phase III clinical trials
45 Table 2: Immunotherapeutic cancer gene therapy products in Phase II clinical trials
52 Table 3: Immunotherapeutic cancer gene therapy products in Phase I clinical trials
57 Table 4: Immunotherapeutic cancer gene therapy products in preclinical development
69 Table 5: Other cancer gene therapy products in Phase III clinical trials (and beyond)
72 Table 6: Other cancer gene therapy products in Phase II clinical trials
74 Table 7: Other cancer gene therapy products in Phase I clinical trials
76 Table 8: Other cancer gene therapy products in preclinical development
90 Table 9: Gene therapies targeting monogenic diseases in commercial development
111 Table 10: Gene therapies targeting infectious diseases in commercial development
116 Table 11: Gene therapies targeting cardiovascular diseases in commercial development
121 Table 12: Gene therapies targeting sensory diseases in commercial development
125 Table 13: Gene therapies targeting neurological diseases in commercial development
131 Table 14: Gene therapies targeting other diseases in commercial development
161 Table 15: Acquisition deals involving gene therapy, 2011–15
163 Table 16: Licensing deals versus number of products in commercial development, by disease application, 2011–15
164 Table 17: Average value of licensing deals with disclosed deal values, by disease application, 2011–15
165 Table 18: Partnership deals valued at in excess of $100m, 2011–15