Gene Therapy: Moving Toward Commercialization

Publisher Name :
Date: 19-Nov-2015
No. of pages: 187

Insight Pharma Reports’ Gene Therapy: Moving Toward Commercialization”, outlines the progress of the gene therapy field since its inception in the 1970s, with a special focus on clinical-stage gene therapy programs that are aimed at commercialization, and the companies that are carrying out these programs. A major theme of this report is whether gene therapy can attain commercial success by the early-to-mid 2020s, which types of gene therapy programs have the greatest likelihood of success, and what hurdles might stand in the way of clinical and commercial success of leading gene therapy programs.

In accord with the focus of this report, we have been asking:


  • Whether gene therapy can attain commercial success by the early-to-mid 2020s,

  • Which types of gene therapy programs have the greatest likelihood of success,

  • What hurdles might stand in the way of clinical and commercial success of leading gene therapy programs.


In addition to chapters that focus on various areas of commercial gene therapy, this report includes:


  • An expert interview with Sam Wadsworth, Ph.D., the Chief Scientific Officer of Dimension Therapeutics and former Head of Gene Therapy R&D at Genzyme.

  • Survey data from 88 researchers involved in gene therapy

  • Companies profiled:  uniQure, Voyager Therapeutics, Oxford BioMedica, GeneQuine Therapeutics, Celladon Corporation, and bluebird


Topics covered:


  • Development of improved vectors (integrating and non-integrating vectors)

  • Gene therapy for ophthalmological diseases

  • Gene therapy for other rare diseases

  • Clinical-stage gene therapies for selected rare diseases other than hemophilias

  • Gene therapy for more common diseases

  • Companies whose central technology platform involves ex vivo gene therapy

  • CAR T-cell immunotherapy as an area of ex vivo gene therapy

  • Gene editing technology

  • Outlook for gene therapy

  • Market outlook for eight gene therapy products


Executive Summary

In addition to chapters that focus on various areas of commercial gene therapy, this report includes:

An expert interview with Sam Wadsworth, Ph.D., the Chief Scientific Officer of Dimension Therapeutics and former Head of Gene Therapy R&D at Genzyme. This interview is appended to Chapter 5.

A survey on gene therapy, which was conducted by Insight Pharma Reports in conjunction with this report, and is discussed in Chapter 9.

Chapter 1 discusses the history of gene therapy, including early FDA-approved human studies of gene therapy in academic and government laboratories in the 1990s. These were based on studies in the 1970s and 1980s, in which researchers applied such technologies as recombinant DNA and development of viral vectors for transfer of genes to cells and animals to the study and development of gene therapies.

Chapter 2 focuses on development of improved vectors, which are designed to circumvent the problems seen in early clinical gene therapy studies. These vectors are of two general types—integrating and non-integrating vectors. Integrating vectors insert themselves into the DNA of the host genome. The advantage of using integrating vectors is that when host cells replicate their chromosomal DNA and divide, they replicate the vector DNA (including inserted therapeutic transgenes) as well. In contrast, non-integrating vectors used in gene therapy would be lost as the result of any cellular proliferation. Thus non-integrating vectors should be used in tissues in which cell division does not occur.

Chapter 3 focuses on one company, uniQure (Amsterdam, the Netherlands). The reason for this is that uniQure is the first company to commercialize a gene therapy. This therapy is Glybera (alipogene tiparvovec), which is a treatment for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD). As of now, it is the only gene therapy product to have received regulatory approval in a regulated market.

Chapter 4 focuses on gene therapy for ophthalmological diseases. Retinal diseases constitute an attractive target for gene therapy. Researchers can target the retina easily via intravitreal injection or subretinal injection. The retina is also an immunoprivileged site. The existence of a contralateral control—the other, untreated eye—also provides an advantage in targeting the eye. There are also non-invasive methods that may be used to monitor therapeutic effects. The small size and compartmentalization of the eye also constitute advantages for gene therapy (especially when compared to targeting much larger organs or tissues such as the skeletal musculature, the liver, or the heart). There is also the issue of medical need, since blindness severely reduces the quality of life.

Chapter 5 focuses on gene therapy for other rare diseases. The first section of this chapter discusses clinical-stage gene therapies for hemophilias. Hemophilias are important genetically determined bleeding disorders, which include hemophilia A and B. Both are X-linked recessive disorders, and thus affect mainly males. Hemophilia A involves a deficiency in factor VIII (FVIII), and hemophilia B involves a deficiency in factor IX (FIX). Both of these are clotting factors that are made in the liver.

Chapter 6 focuses on gene therapy for more common diseases. The great majority of preclinical and clinical gene therapy programs are directed toward treatment of rare diseases. A key question in the gene therapy field is whether gene therapy is applicable (both in terms of technical feasibility and in terms of commercialization strategies) to more common diseases. Chapter 6 focuses on the efforts of four companies—Voyager Therapeutics, Oxford BioMedica, GeneQuine Therapeutics, and Celladon Corporation—to develop gene therapies for common human diseases. It illustrates both the promise and the difficulties of developing gene therapies for such diseases.

Chapter 7 focuses on companies whose central technology platform involves ex vivo gene therapy. Several ex vivo gene therapies discussed in this report are based on studies with retroviral vectors from the earliest days of gene therapy research. In contrast, development of the therapies discussed in Chapter 7 has been initiated much more recently.

The first section of Chapter 7 focuses on bluebird bio (Cambridge, MA). bluebird is a publicly-traded clinical stage biotechnology company that is developing and commercializing gene therapies designed to be one-time treatments for severe genetic and rare diseases and cancer. The company’s technology platforms encompass gene therapy for rare diseases, cancer immunotherapy, and gene editing. The second section of Chapter 7 focuses on CAR T-cell immunotherapy as an area of ex vivo gene therapy.

A full discussion of CAR T-cell therapy, especially a discussion of the technical aspects of this field, belongs in a report on cancer immunotherapy. As such, it is beyond the scope of this gene therapy report. For such a full exposition of CAR T-cell therapy (and of other aspects of cancer immunotherapy), see our September 2014 Insight Pharma Report, “Cancer Immunotherapy: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies”. 195.

Chapter 8 focuses on gene editing technology. In recent years, a growing number of researchers have been seeking to develop gene therapies that work via “gene editing”—directly changing DNA sequences of deleterious genes in a patient’s genome into functional sequences. Gene editing, which is in its early stages, is considered “next generation” gene therapy.

Outlook for gene therapy

In accord with the focus of this report—which we have entitled “Gene Therapy: Moving Toward Commercialization”—we have been asking:


  • Whether gene therapy can attain commercial success by the early-to-mid 2020s,

  • Which types of gene therapy programs have the greatest likelihood of success,

  • What hurdles might stand in the way of clinical and commercial success of leading gene therapy programs.


In Chapter 9, we list eight gene therapy products that in the opinion of leading researchers and corporate leaders in the field have the greatest prospect for reaching the market before 2020. One product (uniQure/Chiesi’s Glybera) has been approved in Europe, another (GSK/TIGET’s GSK2696273) is in preregistration in Europe, and the others are in or nearing pivotal clinical trials. We therefore conclude the answer to the question as to whether gene therapy can attain at least some degree of near term commercial success is yes.

Of the eight therapies highlighted in Chapter 9, six are ex vivo gene therapies, which suggests that the ex vivo strategy (exemplified by bluebird bio) is a potentially successful one for moving gene therapies toward registration and marketing in the near term. Three of these ex vivo gene therapies are CAR T-cell cancer therapies that target CD19.

All of the eight therapies are for rare diseases. However, several of the diseases addressed by these therapies are for some of the more common rare diseases, especially beta-thalassemia and sickle cell disease. Thus the concern that gene therapy will only be applicable to ultra-rare diseases such as lipoprotein lipase deficiency (LPLD) is likely to be unfounded. However the prospect for gene therapies for common diseases has not yet been realized.

In terms of expected revenues for gene therapy products reaching the market in the near term, there is a great deal of uncertainty. However, at least some analysts project sales of Lenti-D of around $250 million and of LentiGlobin of around $4 billion. As for the CAR T-cell therapies, one analyst projects peak sales of around $1.7 billion for Kite’s KTE-C19. Other CAR T-cell therapies may achieve comparable results, depending on competition and payer acceptance of the therapies and their prices. These projections suggest that near-term gene therapies may attain commercial success.

Gene Therapy: Moving Toward Commercialization

Table of Contents

Executive Summary VI
The potential near-term success of ex vivo gene therapies XXII
Outlook for gene therapy XXV

Chapter 1:
History of Gene Therapy 31
Early gene therapy studies in academic and government laboratories 32
The death of Jesse Gelsinger and the moratorium on gene therapy development in the United States 34
Gene therapy as a premature technology 34
Most gene therapy clinical studies still take place in academic and government laboratories 36
The scope of this report 37

Chapter 2:
Vectors for gene therapy 39
Retroviral vectors 39
Gammaretroviral vectors 39
Lentiviral vectors 42
A recent review of the use of retroviral vectors in gene therapy for primary immunodeficiencies (PIDs) 42
Adeno-associated virus (AAV) vectors 44
AAV strains and vector development 45
Helper-dependent adenovirus vectors 46
Non-viral vectors for gene therapy 47
Conclusions 48

Chapter 3:
uniQure, Glybera, and the Beginning ofGene Therapy Commercialization 50
uniQure’s technology platform 50
Approval of Glybera 51
Commercialization of Glybera 53
Iterative improvement of AAV vectors 54
uniQure’s pipeline and collaborations 56
Corporate development as a factor in uniQure’s success 58
Conclusions 58

Chapter 4:
Gene Therapy for Ophthalmological Diseases 60
Why gene therapy for retinal diseases? 60
Companies with clinical-stage gene therapies for retinal diseases 62
Spark Therapeutics 62
Human clinical trials of AAV2- hRPE65v2 64
Breakthrough therapy designation for SPK-RPE65 65
SPK-CHM 65
Spark’s programs in other gene therapies 66
Spark Therapeutics as a company 66
GenSight Biologics 66
GS010 (rAAV2/2-CMV-ND4) 67
GS030, a preclinical-stage gene therapy for treatment of RP 68
NightstaRx’ AAV2-REP1 68
Avalanche Biotech’s AVA-101 69
The Avalanche/Regeneron agreement 70
Oxford BioMedica 70
RetinoStat 71
Sanofi/Oxford BioMedica’s SAR 422459 (StarGen) and SAR 421869 (UshStat) 71
Applied Genetic Technologies Corp (AGTC) 72
AGTC gene therapy for XLRS (rAAV2tYF-CB-hRS1) 72
Genzyme’s AAV-sFLT01 (soluble VEGF-R) for wet AMD 73
Can gene therapy for ophthalmic diseases provide long-term improvement of vision, or does its effects fade with time? 73
Conclusions 74

Chapter 5:
Gene Therapy for Other Rare Diseases 75
Hemophilia and gene therapy 75
The Phase 1 Nathwani studies of gene therapy for hemophilia B 77
Companies with clinical-stage hemophilia genetherapy products 78
Baxalta’s AskBio009 (BAX 335) 79
Spark Therapeutics’ SPK-FIX 80
uniQure/Chiesi’s AMT-060 (AAV5-hFIX) 81
Dimension Therapeutics’ FIX gene therapy 81
Clinical-stage gene therapies for selected other rare diseases 81
Gene therapy for adenosine deaminase severe combined immunodeficiency syndrome (ADA-SCID) (GSK2696273) 82
Gene therapy for acute intermittent porphyria (AIP) 83
Gene therapies for Sanfilippo syndrome 84
Gene therapy for metachromatic leukodystrophy (MLD) 85
Conclusions 85
Sam Wadsworth Interview April 16, 2015 86

Chapter 6:
Gene Therapy for More Common Diseases 90
Introduction 90
Voyager Therapeutics 91
Voyager’s product engine 91
Voyager’s clinical program 92
Voyager’s preclinical portfolio 94
Oxford BioMedica’s PD gene therapy program 95
GeneQuine Therapeutics and gene therapy for osteoarthritis 95
GeneQuine’s product portfolio 96
Celladon Corporation’s gene therapy for heart failure 96
Conclusions 98

Chapter 7:
Ex Vivo Gene Therapy 99
bluebird bio 99
bluebird bio’s clinical-stage candidates 100
Lenti-D 100
LentiGlobin BB305 101
bluebird’s clinical-stage gene therapies—“hot” new company, old technology strategy 103
bluebird’s preclinical programs 104
CAR T-cell immunotherapy as an area of ex vivo gene therapy 105
Selected clinical programs in CAR T-cell based immunotherapy 106
Safety issues with CAR T-cell therapies 109
Leading companies and collaborations working on CAR T-cell therapies 110
Conclusions 111

Chapter 8:
Gene Editing Technology 112
Editas Medicine 113
Editas’ AAV vector-based CRISPR/Cas9 genome editing system 114
Other startup companies pursuing CRISPR/Cas9 genomeediting therapies 116
Sangamo BioSciences, zinc-finger nucleases, and the firstgene-editing clinical studies 116
Sangamo’s preclinical pipeline 118
bluebird bio’s gene editing programs 118
Conclusions 119

Chapter 9:
Summary and Conclusions 121
Chapter 1: History of Gene Therapy 121
Chapter 2: development of improved vectors 123
Chapter 3: uniQure, Glybera, and the beginning of gene therapy commercialization 125
Chapter 4: Gene therapy for ophthalmological diseases 127
Spark Therapeutics 128
GenSight Biologics 129
NightStaRx’ AAV2-REP1 130
Avalanche Biotech’s AVA-101 130
Oxford Biomedica 131
Applied Genetic Technologies Corp (AGTC) 132
Genzyme’s AAV-sFLT01 (soluble VEGF-R) for wet AMD 132
Can gene therapy for ophthalmic diseases provide long-term improvement of vision, or does its effects fade with time? 132
Chapter 5: Gene therapy for other rare diseases 133
Hemophilia and gene therapy 133
The Phase 1 Nathwani studies of gene therapy for hemophilia B 134
Clinical-stage gene therapies for selected other rare diseases 135
Chapter 6: Gene therapy for more common diseases 135
Voyager Therapeutics 136
Oxford BioMedica’s Parkinson’s disease program 136
GeneQuine Biotherapeutics and gene therapy for osteoarthritis 137
Celladon Corporation’s gene therapy for heart failure 138
Outlook for gene therapies for common diseases 138
Chapter 7: Ex vivo gene therapy 139
bluebird bio 139
bluebird bio’s clinical-stage candidates 139
Lenti-D 140
LentiGlobin BB305 140
bluebird’s clinical-stage gene therapies—“hot” new company, old technology strategy 142
bluebird’s preclinical programs 142
CAR T-cell immunotherapy as an area of ex vivo gene therapy 142
Selected clinical programs in CAR T-cell based immunotherapy 143
Safety issues with CAR T-cell therapies 144
Leading companies and collaborations working on CAR T-cell therapies 145
The potential near-term success of ex vivo gene therapies 145
Chapter 8: Gene editing technology 146
Editas’ AAV vector-based CRISPR-Cas9 genome editing system 147
Other startup companies pursuing CRISPR/Cas9 genome editing therapies 148
Sangamo BioSciences, zinc-finger nucleases, and the first gene-editing clinical studies 149
Sangamo’s preclinical pipeline 149
bluebird bio’s gene editing programs 149
Outlook on genome editing technology for gene therapy 150
Insight Pharma Reports survey on gene therapy 151
Outlook for gene therapy 154
Insight Pharma Reports Survey on Gene Therapy (n=88) 157
References 162
About Cambridge Healthtech Institute 183

List of Tables

Table 2.1: Leading Gene Therapy Vectors 48
Table  3.1. uniQure’s Clinical-Stage Pipeline 56
Table 4.1: Clinical Stage Gene Therapies for Ophthalmological Diseases 62
Table 5.1: Clinical-stage gene therapies for hemophilia B 78
Table 5.2: Clinical-Stage Gene Therapies for Selected Other Rare Diseases 82
Table 6.1: Voyager’s Preclinical Programs 94
Table 7.1: bluebird bio’s Clinical-Stage Gene Therapies 100
Table 7.2: Selected Clinical Programs in CAR T-cell-based Immunotherapy 106
Table 8.1: Companies Involved in Gene Editing Technologies 119
Table 9.1: Gene therapy products likely to reach the market before 2020 155

List of Figures

Figure 2.1. Gammaretroviral Vector Construction and Packaging 40
Figure 3.1. The Glybera Vector DNA 52
Figure 4.1. Structure of GenSight AAV2/2-CMV-ND4 Vector (GS010) 68
Figure 7.1. CAR T cell 105

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