Trends in Gene Therapy - Report Extract

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Trends in Gene Therapy
Author: Beata Wilkinson and Crispin Bennett
Catalyst
Will reimbursement prove to be the
biggest barrier as three gene therapies
gain regulatory approval?
SAMPLE EXTRACT

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Trends Hot Topic DMKC0162772 | Published on 22/07/2016
© Informa UK Ltd. This document is a licensed product and is not to be reproduced or redistributed
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Report reference: DMKC0162772
Published on: 22/07/2016
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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 adrenoleukodystrophy

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LIST OF FIGURES
104 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
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

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LIST OF TABLES
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
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

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EXECUTIVE SUMMARY
The number of gene therapy products in development has doubled since 2012
- A survey of gene therapy products in commercial development (from preclinical to Phase III and
beyond) worldwide identified a total of 418 products from 162 originating companies and 72
licensees. This is twice as many products as were identified in a similar survey in 2012 (a total of 214
products).
- There has been a fourfold increase in gene therapy products in preclinical development since 2012.
Most products in development are in vivo therapies, except in oncology
- The majority of products identified in 2015 are in vivo gene therapies employing viral, plasmid, or
bacterial vectors; the remainder are cell-based ex vivo gene therapies.
- The in vivo approach using viral vectors is the most popular approach in every disease category
except cancer, where ex vivo approaches predominate.
- There are 123 cell-based ex vivo gene therapies in commercial development, of which the vast
majority (110) target cancer.
The adeno-associated virus is the most popular viral vector
- Technological advances have resulted in improvements to the safety and efficacy of viral gene
vectors – including the lentivirus, the adenovirus, and the adeno-associated virus (AAV) – and plasmid
vectors.
- The AAV vector is attractive as it can mediate long-term tissue-specific gene expression with low
immunogenicity. AAV is the most frequently employed viral vector in in vivo gene therapies. In total,
64 of the AAV-based gene therapy products are treatments for monogenic diseases, many of which
(44) are in preclinical development.
Cancer is the most common target for gene therapies in development, followed by
monogenic diseases
- Out of the 418 gene therapy products identified, 201 address cancer (in 2012, cancer accounted for
100 of 214 gene therapies). Cancer is followed by monogenic diseases (102), neurological diseases
(34), infections (including HIV) (21), ocular diseases (18), and cardiovascular (CV) diseases (15). The
remaining 27 products address miscellaneous other diseases.
Most products in advanced clinical development target cancer indications
- Most products in advanced clinical development – that is, Phase III and beyond – target cancer (15
products versus nine products for all other disease categories combined).

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Immunotherapy and oncolytic virotherapy are promising approaches in cancer
- Targets for gene therapy for cancer and CV disease are not as clear-cut as with monogenic diseases,
with a range of disease-modifying gene therapy approaches under investigation.
- Immunotherapy represents the most popular gene therapy approach in cancer. In all, 142 products
were classified as belonging to this broad category; 93 use genetically modified autologous or
allogeneic T cells, most of which are modified with genes encoding chimeric antigen receptors (CARs).
Several CAR therapies are in Phase II clinical trials, but the vast majority (58) are in preclinical
development.
- Oncolytic virotherapy offers hope to patients with inoperable tumors. Amgen’s Imlygic is the first
oncolytic viral therapy approved by the US Food and Drug Administration, based on therapeutic
benefit demonstrated in a pivotal study. Imlygic is an oncolytic herpes simplex virus-1 derivative
engineered to produce granulocyte-macrophage colony-stimulating factor.
Regulatory and reimbursement strategies will be key to the success of new therapies
- Regulatory requirements for gene therapies in the two major regulated markets, the EU and the US,
pose some issues specific to the development of different types of gene therapy products that must be
considered in each jurisdiction.
- The approval of uniQure’s Glybera (alipogene tiparvovec) stimulated ongoing reimbursement
debates. Pricing models under discussion include upfront payments, annuity payments, and pay-for-
performance models.
- An absence of evidence on the long-term effectiveness of gene therapy will pose one of the greatest
barriers to reimbursement, coupled with high upfront costs.
Gene therapy of cancer is the most active area of commercial deal-making
- A survey of deals in the gene therapy area during 2011–15 identified a total of six acquisitions and
121 partnerships. While most of the deal values have not been disclosed, 11 of the disclosed deals
were valued at over $100m. With respect to therapy areas, cancer was the most active area of deal-
making.

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GENE THERAPY STRATEGIES
Introduction to gene therapy
GENE TRANSFER CAN BE EX VIVO OR IN VIVO INTO TARGET CELLS
Gene transfer technology involves inserting genes into living cells to enhance the body’s own response
to complex diseases or to provide specific proteins that are lacking in the patient. In most gene
therapy studies, a carrier molecule called a vector must be used to deliver the therapeutic gene to the
target cells. The traditional approach to gene therapy relied on the physical removal and isolation of
relevant target cells from the patient’s body prior to gene insertion. After transduction of the cells in
vitro (using retroviral vectors), the genetically modified cells were then re-introduced into the patient.
Such ex vivo gene therapies involve the use of the patient’s own (autologous) cells, and selectivity is
accomplished only at the expense of a labor-intensive, invasive procedure that requires hospitalization
of the patient. Nevertheless, the ex vivo transfer of sequences encoding chimeric antigen receptors
(CARs) into autologous T cells is currently regarded as a very promising strategy for the treatment of
tumors (Jensen and Riddell, 2015).
More recent approaches to gene therapy include ex vivo allogeneic therapies and in vivo therapies. Ex
vivo allogeneic therapies use genetically modified donated cells, with allogeneic cells having to be
protected from the host’s immune system. One way to achieve this is to encapsulate them within
biocompatible, semipermeable polymer membranes; another is to render them invisible to the body’s
immune system (creating universal cell transplants). In vivo therapies involve the use of viral or non-
viral vectors to introduce therapeutic genes directly into a patient (via systemic or local delivery).
AFTER 25 YEARS IN THE CLINIC AND MANY SETBACKS, GENE THERAPY IS BACK ON TRACK
The first gene therapy clinical trial began in 1990 (Blaese et al., 1995), but progress has been slow due
to a series of setbacks and safety concerns. A major setback occurred in 1999, when an 18-year-old
patient participating in a gene therapy trial for ornithine transcarboxylase deficiency died from
multiple organ failures soon after the initiation of treatment. His death is believed to have been
triggered by a severe immune response to the adenoviral gene carrier (Steinbrook, 2011). In January
2003, when a child treated in a French gene therapy trial developed a leukemia-like condition, the US
Food and Drug Administration (FDA) placed a temporary halt on all gene therapy trials using retroviral
vectors in blood stem cells. However, this ban was eased in April 2003 after the FDA's Biological
Response Modifiers Advisory Committee met to discuss appropriate safeguards for future retroviral
gene therapy trials involving life-threatening diseases.
Traditionally, research in gene therapy has focused on a variety of diseases that involve recessive
single-gene disorders, which can potentially be corrected by the addition of a functioning gene to the
appropriate cells. Although most monogenic diseases are rare, they are often devastating conditions
with ineffective treatment options and, collectively, they affect millions of people worldwide. The
focus on monogenic diseases led to the approval, in November 2012, of the first gene therapy in the
Western world, uniQure’s Glybera (alipogene tiparvovec) for the treatment of lipoprotein lipase
deficiency (uniQure, 2012).

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EARLY RETROVIRAL VECTORS TARGETED RAPIDLY REPLICATING CELLS, AND LACKED EFFICIENCY
Viruses can be seen as nature’s own solution to the gene transfer problem. In this method of gene
insertion, often referred to as viral transduction, a modified virus infects the cells and introduces a
viral genome containing inserted genes. In virus-derived vectors, the viral multiplication genes are
replaced by therapeutic genes, for delivery along with the remaining viral genes into the cell.
Almost all early clinical trials involved transduction, with the majority using retrovirus-derived vectors
(Crystal, 1995). Retroviruses can introduce genes into a single, active chromosomal region, giving a
permanency that facilitates long-term expression. Retroviral vectors infect rapidly replicating cells
such as tumor cells, but are of limited usefulness in other applications since most of the cells in the
body are resting or only slowly dividing. For many years, production and use of viral vectors was
plagued by manufacturing scale-up problems, contamination of viral vector preparations, and various
safety concerns. The retroviral transduction of cells lacked efficiency and the levels of expression of
genes delivered by vectors in early clinical trials of gene therapy were typically low and variable.
VIRAL VECTORS DELIVER GENES TO NON-DIVIDING CELLS, BUT ARE SUBJECT TO NON-SPECIFIC
UPTAKE
Subsequently, other viruses have been adapted for gene therapy, such as lentiviruses. Lentiviruses are
a specific class of retroviruses that include HIV, and lentiviral vectors can deliver genes into non-
dividing cells as well as having the ability to be used directly in vivo. Other well-established viral
vectors that can deliver genes into non-dividing cells include those derived from adenoviruses, adeno-
associated viruses (AAVs), and herpes simplex virus-1.
Targeted gene delivery has long been a goal of gene therapy, but many complex factors influence the
ability to target genes to specific cells and tissues. Non-specific uptake and immunogenicity of viral
vectors comprise two of the greatest impediments to targeting, because they result in premature
removal of the targeting agent before it can effectively localize.
NON-VIRAL METHODS OF GENE DELIVERY RESULT IN TRANSIENT GENE EXPRESSION
Non-viral methods of gene delivery have also been developed, the most frequently used of which are
plasmids. In addition to the therapeutic gene, plasmids often contain a gene expression system that
can modulate both the duration and expression levels of the therapeutic protein. Plasmids can be used
naked, or can be formulated using lipids and/or polymers. Other non-viral delivery vectors include
episomal vectors and cancer-specific bacterial vectors. Non-viral vectors result primarily in the
introduction of DNA sequences into the nucleus (or the cytoplasm) in an unintegrated form. These
methods result in transient gene expression and therefore require repetitive delivery.
Most non-viral methods of gene transfer rely on normal mechanisms used by mammalian cells for the
uptake and intracellular transport of macromolecules. Often referred to as transfection, this approach
to gene delivery includes chemical, physical, or receptor-based methods. Chemical methods – such as
liposomes and molecular conjugates – permit the charged DNA, which is soluble in water but not in
fat, to cross the fatty cell membrane. A major advantage of synthetic vectors is their flexibility of

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manipulation, as well as their capacity to carry more genetic material, although the level of gene
transfer is lower than with viral vectors. Physical methods of gene delivery include direct injection of
naked DNA plasmids, which has been shown to induce gene expression by muscle and other tissues.
The use of hydrodynamic injection can improve the efficiency of cellular uptake. Other physical
methods include electroporation using a high-voltage pulse (which enhances human skin permeability
to DNA) and the high-velocity bombardment of cells by heavy-metal particles covered with DNA.
DNA RECOMBINASES FOR SITE-DIRECTED GENE INSERTION
The random integration of therapeutic genes into the host genome is undesirable as it could
conceivably induce tumor-causing mutations or lead to serious gene dysfunction. Researchers have
therefore been engaged in an effort to develop technologies for site-specific integration of genes into
predetermined locations in the human genome.
DNA recombinases, a conserved class of naturally occurring enzymes with target recognition capacity,
are currently generating considerable interest. DNA recombinases could facilitate site-specific
integration of therapeutic genes into the human genome. A well-studied example is provided by Rep,
the replicase/integrase of the AAV, which inserts genes at a specific integration site on human
chromosome 19, a region believed to be very suitable for gene insertion (Recchia and Mavilio, 2011).
Another promising system for site-directed gene insertion is based on the C31 integrase, which
mediates the integration of plasmid DNA into mammalian genomes in a sequence-specific manner
(Chavez and Calos, 2011).
DNA transposons are discrete pieces of DNA that are able to change their positions within the genome
via a cut-and-paste mechanism (known as transposition). Recently, high levels of efficiency of gene
transfer into human stem cells have been achieved with the use of a hyperactive variant of the
synthetic Sleeping Beauty transposon (SB100X) (Belay et al., 2011).
ZINC FINGER NUCLEASES ALLOW TARGETED GENOME MODIFICATION
New approaches may allow precisely targeted sequence modification to be performed directly in
patients’ cells. These approaches utilize artificial nucleases engineered to introduce a targeted cut in
genomic DNA. Artificial nucleases are expected to enable the development of personalized cell
replacement therapies utilizing stem cells geared toward correcting inborn mutations (Rahman et al.,
2011).
The most prominent artificial nucleases so far are zinc finger nucleases (ZFNs), which can be
engineered to modify genomic DNA at a highly precise location. ZFNs are being developed to facilitate
correction or disruption of a specific gene or addition of a new DNA sequence/gene. In the past, the
development of clinical applications of ZFN technology has been hampered by the lack of widely
available, streamlined methods for the synthesis of functional ZFNs. However, Kim et al. (2009) have
described modular assembly methods for functional ZFNs, which allow targeted genome editing in
human cells.
Zinc finger proteins (ZFPs) are naturally occurring transcription factors that recognize a specific DNA

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sequence. Sangamo BioSciences has acquired most of the patent rights for the exclusive production
and use of ZFPs as DNA-modifying molecules – the company creates ZFP transcription factors for
controlling gene expression by linking its proprietary engineered ZFPs to functional domains that
normally activate or repress gene expression (Sangamo, 2016). Sangamo can also link ZFPs to
nuclease domains to create ZFNs, and is currently conducting a Phase II clinical trial aimed at
knocking out the CCR5 HIV receptor in T cells isolated from HIV patients using a CCR5-specific ZFN
delivered in an adenoviral expression vector. The company’s ZFNs have also been successfully
employed to inactivate or correct disease-related genes in human stem cells, including hematopoietic
precursor cells and induced pluripotent stem cells.
Bibliography
Belay E, Dastidar S, VandenDriessche T, Chuah MK (2011) Transposon-mediated gene transfer into
adult and induced pluripotent stem cells. Current Gene Therapy, 11(5), 406–13
<PMID>21864290</PMID>.
Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, et al. (1995) T lymphocyte-directed gene
therapy for ADA- SCID: initial trial results after 4 years. Science, 270(5235), 475–80
<PMID>7570001</PMID>.
Chavez CL, Calos MP (2011) Therapeutic applications of the PhiC31 integrase system. Current Gene
Therapy, 11(5), 375–81 <PMID>21888619</PMID>.
Crystal RG (1995) Transfer of genes to humans: early lessons and obstacles to success. Science,
270(5235), 404–10 <PMID>7569994</PMID>.
Jensen MC, Riddell SR (2015) Designing chimeric antigen receptors to effectively and safely target
tumors. Current Opinion in Immunology, 33, 9–15 <DOI>10.1016/j.coi.2015.01.002</DOI>.
Kim HJ, Lee HJ, Kim H, Cho SW, Kim JS (2009) Targeted genome editing in human cells with zinc
finger nucleases constructed via modular assembly. Genome Research, 19(7), 1279–88
<DOI>10.1101/gr.089417.108</DOI>.
Rahman SH, Maeder ML, Joung JK, Cathomen T (2011) Zinc-finger nucleases for somatic gene
therapy: the next frontier. Human Gene Therapy, 22(8), 925–33 <DOI>10.1089/hum.2011.087</DOI>.
Recchia A, Mavilio F (2011) Site-specific integration by the adeno-associated virus rep protein.
Current Gene Therapy, 11(5), 399–405 <PMID>21827397</PMID>.
Sangamo (2016) Sangamo BioSciences’ Technology Platform. Available from:
http://www.sangamo.com/technology/index.html [Accessed 17 February 2016].
Steinbrook R (2011) The Geisinger case. The Oxford Textbook of Clinical Research Ethics (eds Emanuel
EJ, Grady CC, Crouch RA, et al.). Oxford University Press. Chapter 10: 110–120.

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uniQure (2012) uniQure's Glybera First Gene Therapy Approved by European Commission. Available
from: http://www.prnewswire.co.uk/news-releases/uniqures-glybera-first-gene-therapy-approved-by-
european-commission-176912061.html [Accessed 9 February 2016].

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Table 2: Immunotherapeutic cancer gene therapy products in Phase II clinical trials
Originator Licensee Drug name
In vivo vector or
ex vivo cells
Cancer type Delivery route
Cytokine-based
Celsion n/a GEN-001 Plasmid Ovarian, fallopian, peritoneal, colorectal Intraperitoneal
Cold Genesys (USA) n/a CG-0070 Adenovirus Bladder -
Inovio OncoSec Medical
IL-12, OncoSec
Medical
Plasmid Merkel cell carcinoma, melanoma, head and neck, lymphoma (T-cell), cutaneous, breast Intratumoral
Intrexon Ziopharm Oncology INXN-2001/1001 Adenovirus Melanoma, breast Intratumoral
Merck & Co FKD Therapeutics Instiladrin Adenovirus Bladder Intravesical
Transgene
Ascend
Biopharmaceuticals
Ad-IFNgamma Adenovirus Lymphoma (B-cell), basal cell Intratumoral
Tumor-associated antigen vaccines
AlphaVax n/a AVX-701
Alpha virus replicon
encoding CEA
Colorectal Intramuscular
Bavarian Nordic n/a MVA-BN-HER2
MVA-BN virus
encoding HER2
Breast Subcutaneous

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In vivo vector or
ex vivo cells
CureVac n/a CV-9201
Naked mRNA
encoding unspecified
antigens
Lung (non-small cell) Intradermal
CureVac n/a CV-9103
Naked mRNA
encoding four
antigens expressed by
prostate cells
Prostate Intradermal
NewLink Genetics n/a NLG-11928
Allogeneic tumor cells
transduced with
retroviral vector
expressing alpha-
(1,3)-
galactosyltransferase
gene
Prostate Subcutaneous
NewLink Genetics n/a dorgenmeltucel-L
Allogeneic tumor cells
transduced with the
alpha-(1,3)-
galactosyltransferase
gene
Melanoma
Intradermal
Subcutaneous

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In vivo vector or
ex vivo cells
Oxford BioMedica n/a TroVax (OXB-301)
Gene therapy,
recombinant vaccine,
anticancer (vaccine),
anticancer
(immunological)
Renal
Injectable,
intradermal
Injectable,
intramuscular
Therion Biologics
(discontinued)
Bavarian Nordic
(continuing)
falimarev +
inalimarev
Pox/vaccinia virus
encoding CEA and
MUC-1
Breast, ovarian, colorectal, bladder
Intradermal
Subcutaneous
Transgene
Prescient
Therapeutics
tipapkinogene
sovacivec
Vaccinia Ankara virus
encoding two HPV
antigens (E6 and E7)
and IL-2
Cervical, cervical dysplasia, infection (HPV) Subcutaneous
Vaccibody n/a VB-1016 Plasmid HPV vaccine Infection (HPV), dysplasia (cervical)
Intramuscular
Subcutaneous
Dendritic vaccines
Geron (discontinued)
Asterias
Biotherapeutics;
Merck & Co; Bellicum
telomerase vaccine,
Geron
Autologous dendritic
cells expressing
telomerase
Leukemia (acute myelogenous)
Injectable,
intradermal

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already on the market in the US and one product on the market in China. In the tables below and in
the discussion that follows, most of the company and product information has been drawn from
Pharmaprojects, except where separate references are provided.

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Table 5: Other cancer gene therapy products in Phase III clinical trials (and beyond)
Originator Licensee Drug name In vivo vector or ex
vivo cells
HS-thymidine kinase suicide therapy
Advantagene n/a ProstAtak Adenovirus Prostate -
Oncolytic virotherapy
Amgen n/a talimogene laherparepvec (approved in the EU and US) HSV-1 Melanoma, colorectal, liver Intra-arterial
Intrahepatic
Intratumoral
Shenzhen SiBiono
GeneTech Co
n/a Gendicine (approved in China) Adenovirus Head and neck, liver Intratumoral
Anti-angiogenic
Guangzhou Double
Bioproducts
n/a Ad5-endostatin Adenovirus Head and neck Injectable, intratumoral
VBL Therapeutics n/a VB-111 Adenovirus Brain Injectable, intravenous
Other cytostatic/apoptotic therapies

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Table 11: Gene therapies targeting cardiovascular diseases in commercial development
Disease Originator Licensee Drug name Origin Target name
Peripheral vascular disease; limb
ischemia; wound healing; heart
failure; bone regeneration,
unspecified; myocardial infarction;
angina, unspecified
Juventas Therapeutics SironRX Therapeutics JVS-100 Non-viral vector Chemokine (C-X-C motif) ligand 12
(stromal cell-derived factor 1)
Phase I
Ischemia, general; peripheral
vascular disease; limb ischemia;
intermittent claudication; heart
failure
Sidus n/a rhVEGF165 Nucleic acid Vascular endothelial growth factor A
Porphyria Digna Biotech uniQure recombinant AAV2/5-PBGD Viral vector Hydroxymethylbilane synthase
Preclinical
Atherosclerosis Kiromic n/a cardiovascular gene therapy Viral vector Oxidized low-density lipoprotein
(lectin-like) receptor 1
Catecholaminergic polymorphic
ventricular tachycardia
CardioGen n/a AT-003 Viral vector Calsequestrin 2 (cardiac muscle)
Heart failure InoCard Bristol-Myers Squibb S100A1 Nucleic acid S100 calcium binding protein A10
Heart failure; cardiovascular disease 4D Molecular Therapeutics n/a cardiac disease gene therapy Nucleic acid Unspecified

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Table 11: Gene therapies targeting cardiovascular diseases in commercial development
Heart failure; myocardial infarction BEAT BioTherapeutics n/a BB-R12 Viral vector Unspecified
Hypercholesterolemia REGENXBIO n/a RGNX-001 Viral vector Unspecified
Source: Pharmaprojects

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MOST GENE THERAPIES FOR ISCHEMIC CONDITIONS AIM TO STIMULATE ANGIOGENESIS
The natural biologic response to repeated myocardial ischemia is angiogenesis, the growth of new
collateral blood vessels. Newly formed vessels can bypass arterial obstructions, thus improving blood
flow. In many patients, however, including those with recurrent angina, collateral coronary vessel
formation remains insufficient to meet the heart’s needs during exercise or stress. Treatments that
help restore blood flow to ischemic areas remain one of the most important therapeutic goals.
Enhancing the innate angiogenesis by exogenous delivery of angiogenic factors lessens the ischemic
injury; however, uncontrolled angiogenic gene expression can cause adverse side effects, such as
hemangioma formation at injection sites.
All six gene therapies in development targeting refractory angina and/or peripheral vascular disease
are angiogenic treatments designed to stimulate collateral vessel formation.
A GENE THERAPY PRODUCT FOR PERIPHERAL ARTERIAL DISEASE HAS BEEN LAUNCHED IN
RUSSIA
Neovasculgen, the first gene therapy drug to be approved in Russia (in 2011), is manufactured by
Russian company Human Stem Cells Institute, and is used for the treatment of peripheral arterial
disease and its complication critical limb ischemia. During 2016, the company plans to start the
process of development and US Food and Drug Administration clearance for the launch of
Neovasculgen in the US and China (Human Stem Cells Institute, 2015). Neovasculgen is a plasmid
genetic construction containing human gene vascular endothelial growth factor (VEGF165) and
stimulates angiogenesis, leading to improvements in pain-free walking distance and transcutaneous
oxygen tension. Further analysis is hindered by the absence of articles in English (Deev et al., 2014). It
should be noted that randomized controlled trials with other VEGF treatments have not shown
adequate efficacy to differentiate themselves from the strong placebo effects observed (Wolfram and
Donahue, 2013).
US-based Taxus Cardium Pharmaceuticals has Generx (alferminogene tadenovec), which delivers the
fibroblast growth factor 4 (FGF)-4 gene on an adenoviral vector, in Phase III trials for the treatment of
stable exertional angina due to coronary artery disease. Taxus Cardium’s therapeutic approach uses a
standard diagnostic cardiac catheter for non-surgical intracoronary delivery of Generx. Generx is
currently being developed for international markets outside the US for patients who may not have
access to or may not be candidates for costly and invasive surgical revascularization procedures
(coronary artery bypass surgery and angioplasty). To date, four clinical trials have been completed on
over 650 patients (Taxus Cardium Pharmaceuticals, 2016).
In Japan, AnGes is testing its angiogenic product candidate beperminogene perplasmid, which delivers
the hepatocyte growth factor (HGF) gene on a plasmid expression vector, in Phase III trials in
peripheral arterial disease.
Four angiogenic gene therapies are in Phase II trials. Reyon Pharmaceutical’s product is a plasmid
vector expressing a gene encoding a cDNA hybrid of the HGF gene; the hybrid gene (HGF-X7) was
constructed by inserting intron sequences into certain sites of HGF cDNA. ID Pharma has a virus-

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derived vector carrying FGF-2 for the treatment of severe leg ischemia, while Juventas Therapeutics’
JVS-100 is a second-generation version of MyoCell (autologous skeletal myoblasts; Bioheart) modified
by an adenovirus vector to overexpress the stromal cell-derived factor 1 gene. This product is being
tested for its ability to regenerate functioning muscle in infarcted or scarred myocardial tissue. Lastly,
Renova Therapeutics is developing a gene therapy using a modified adenovirus-5 vector encoding
human adenylyl cyclase type 6 for the treatment of congestive heart failure.
Sensory diseases
GENE THERAPIES CAN BE DELIVERED BY SUBRETINAL INJECTIONS
The retina is a suitable target for gene therapy due to its small size and immune privilege. Different
types of viral vectors have been developed for in vivo gene delivery by subretinal injections to
photoreceptor or retinal pigment epithelium (RPE) cells of the retina, but the most efficient vectors
are those based on the AAV virus (Colella and Auricchio, 2012).
In 2015, Spark Therapeutics announced that it was preparing regulatory filings for marketing
authorization of SPK-RPE65 in the monogenic disease Leber's congenital amaurosis (LCA) (Spark
Therapeutics, 2015).
THE MAJORITY OF PRODUCTS ARE IN VIVO GENE THERAPIES EMPLOYING VIRAL VECTORS
A review of gene therapy products in commercial development, based primarily on information derived
from Pharmaprojects, identified a total of 418 gene therapy products, of which 37 address ocular
diseases. In addition, one treatment, in Phase II, addresses hearing loss and balance disorders.
In total, 20 of the 37 ocular products address genetic diseases, such as LCA and retinitis pigmentosa,
as described in the section on monogenic diseases. They are not included in the table below.
The majority of gene therapies targeting sensory diseases are in vivo therapies using AAV vectors,
while Oxford BioMedica’s products use proprietary lentiviral vectors.

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Table 14: Gene therapies targeting other diseases in commercial development
Alimentary and metabolic – Phase III
Diabetic ulcer wound healing Taxus Cardium Pharmaceuticals n/a Ad5PDGF-B (Excellarate; GAM-501) Biological, nucleic acid, viral vector Platelet-derived growth factor beta
polypeptide
Alimentary and metabolic – Preclinical
Alimentary/metabolic disease,
unspecified
Shire Ethris MRT ASS1 Biological, nucleic acid Argininosuccinate synthase 1
Alimentary/metabolic disease,
unspecified
Medgenics n/a MDGN-206 Biological, nucleic acid, non-viral
vector
Unspecified
Diabetes, type 1 American Gene Technologies n/a AG-TA1 Biological, nucleic acid, viral vector Unspecified
Diabetes, undisclosed type Apceth n/a APC-001 Biological, cellular Not applicable
GM1 gangliosidosis Lysogene n/a LYS-GM101 Biological, nucleic acid, viral vector Unspecified
Short bowel syndrome;
gastrointestinal disease, unspecified
Medgenics n/a MDGN-205 (TARGTGLP-2) Biological, nucleic acid, non-viral
vector
Glucagon
Ulcerative colitis; inflammatory
bowel disease, unspecified
enGene n/a EG-12 (EG-10) Biological, nucleic acid, non-viral
vector
Interleukin-10

Trends in Gene Therapy - Report Extract

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Trends in Gene Therapy - Report Extract