Trends in Gene Therapy - Report Extract

Datamonitor HealthcarePharma intelligence |

1

Trends in Gene Therapy

Author: Beata Wilkinson and Crispin Bennett


CatalystWill reimbursement prove to be the biggest barrier as three gene therapies gain regulatory approval?

SAMPLE EXTRACT


2

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

2

Report reference: DMKC0162772 Published on: 22/07/2016

About Datamonitor Healthcare Bringing you a clearer, richer and more responsive view of the pharma & healthcare market.

Complete market coverage Our independent research and analysis provides extensive coverage of major disease areas, companies and strategic issues,giving you the perspective to identify opportunities and threats arising from shifting market dynamics and the insights torespond with faster, more effective decision-making.

Unique expert capabilities With teams located across developed and emerging pharma markets, we are uniquely placed to understand localhealthcare trends and provide accurate and reliable recommendations. By working closely with our partners at MedTrack,Citeline, SCRIP Intelligence and Informa Healthcare, our experts are able to share data and resources to produce the mostauthoritative and robust market intelligence. With over 700 clients across the pharma and biotech industries, we are reliedupon to provide strategic guidance, not only through published analysis, but also tailored support solutions.

Cutting-edge delivery Available through single reports or via subscription to our state-of-the art online intelligence service that featuresintuitive design and interactive capabilities, our analysis offers the definitive platform to enhance your productmanagement, market assessment and strategic planning.

Contact Us For more information about our products or to arrange a demo of the our online service, please contact:[email protected]

Disclaimer All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means,electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, DatamonitorHealthcare. The facts of this report are believed to be correct at the time of publication but cannot be guaranteed. Pleasenote that the findings, conclusions and recommendations that Datamonitor Healthcare delivers will be based oninformation gathered in good faith from both primary and secondary sources, whose accuracy we are not always in aposition to guarantee. As such, Datamonitor Healthcare can accept no liability whatsoever for actions taken based on anyinformation that may subsequently prove to be incorrect. For more information about our products or to arrange a demonstration of the our online service, please contact:[email protected]


3



3

CONTENTS

6 EXECUTIVE SUMMARY6 The number of gene therapy products in development has doubled since 20126 Most products in development are in vivo therapies, except in oncology6 The adeno-associated virus is the most popular viral vector6 Cancer is the most common target for gene therapies in development, followed by monogenic

diseases6 Most products in advanced clinical development target cancer indications6 Immunotherapy and oncolytic virotherapy are promising approaches in cancer7 Regulatory and reimbursement strategies will be key to the success of new therapies7 Gene therapy of cancer is the most active area of commercial deal-making

8 GENE THERAPY STRATEGIES8 Introduction to gene therapy11 Bibliography

13 GENE THERAPY PRODUCTS IN COMMERCIAL DEVELOPMENT IN 201513 Cancer is the most common target for products, followed by monogenic diseases

16 INNOVATIONS IN GENE DELIVERY TECHNOLOGIES16 Viruses are efficient gene delivery vectors, but pose several challenges16 Viral vectors can stimulate the host’s immune system with undesirable effects22 Plasmids as gene vectors24 Bacteria as gene vectors25 Cells as gene vectors27 Vectors used in in vivo therapies in commercial development in 201532 Bibliography

38 GENE THERAPIES FOR CANCER38 Conventional cancer treatment has limited long-term success38 A total of 201 cancer gene therapy products are in commercial development40 Immunotherapy is a popular broad anticancer strategy67 Other approaches to cancer gene therapy79 Targeted destruction of tumors encompasses a variety of approaches81 Oncolytic virotherapy offers hope to patients with inoperable tumors83 Anti-angiogenic gene therapies offer an alternative approach83 Bibliography

88 GENE THERAPIES FOR MONOGENIC DISEASES88 There are 102 gene therapy products in commercial development100 Lipoprotein lipase deficiency101 Adenosine deaminase deficiency103 Inherited retinal dystrophies104 X-linked childhood cerebral adrenoleukodystrophy


4



4

LIST OF FIGURES

104 Hemophilia106 Muscular dystrophies107 Bibliography

110 GENE THERAPIES FOR ACQUIRED DISEASES OTHER THAN CANCER110 Infectious diseases114 Cardiovascular disease120 Sensory diseases124 Neurological disease130 Other diseases135 Bibliography

137 REGULATORY ISSUES137 Introduction137 Regulatory framework in the EU143 Regulatory framework in the US148 Bibliography

153 REIMBURSEMENT ISSUES153 In rare diseases, return on investment is typically realized through repeated drug

administration154 An alternative to a high single payment may be annuity payments for effective treatment155 Pay-for-performance models may be suitable for gene therapy reimbursement156 Payers are not ready, but gene therapies may drive rethinking of drug pricing in general156 Glybera’s reimbursement struggles reveal uncertainties around long-term effects to be a key

concern for payers157 Imlygic struggles to gain reimbursement amid increased competition within melanoma157 GlaxoSmithKline to use Strimvelis to test alternative funding mechanisms158 Bibliography

161 DEALS AND ACQUISITIONS161 Five years of deal-making in the gene therapy area

170 APPENDIX170 About the authors170 Scope170 Methodology

13 Figure 1: Gene therapy products in development, by disease and approach employed14 Figure 2: Gene therapy products in development, by disease and phase of development27 Figure 3: Vectors for in vivo delivery in commercial development (preclinical to Phase III and

beyond), by disease type


5



5

LIST OF TABLES

28 Figure 4: Viral gene vectors in advanced commercial development (Phase III and beyond), bydisease type

29 Figure 5: Viral gene vectors in preclinical development, by disease type30 Figure 6: Plasmid vectors used in in vivo gene therapies, by disease type31 Figure 7: Ex vivo therapies, by disease type and stage of development38 Figure 8: Cancer gene therapies in development, by phase of development39 Figure 9: Cancer gene therapies in development, by type of vector40 Figure 10: Approaches to cancer immunotherapy: gene therapy products in development, by

stage of development67 Figure 11: Other approaches to cancer gene therapy: products in development, by type of

therapy88 Figure 12: Gene therapies in development targeting monogenic diseases, by phase of

development162 Figure 13: Licensing deals categorized by disease application, 2011–15

42 Table 1: Immunotherapeutic cancer gene therapy products in Phase III clinical trials45 Table 2: Immunotherapeutic cancer gene therapy products in Phase II clinical trials52 Table 3: Immunotherapeutic cancer gene therapy products in Phase I clinical trials57 Table 4: Immunotherapeutic cancer gene therapy products in preclinical development69 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 trials74 Table 7: Other cancer gene therapy products in Phase I clinical trials76 Table 8: Other cancer gene therapy products in preclinical development90 Table 9: Gene therapies targeting monogenic diseases in commercial development111 Table 10: Gene therapies targeting infectious diseases in commercial development116 Table 11: Gene therapies targeting cardiovascular diseases in commercial development121 Table 12: Gene therapies targeting sensory diseases in commercial development125 Table 13: Gene therapies targeting neurological diseases in commercial development131 Table 14: Gene therapies targeting other diseases in commercial development161 Table 15: Acquisition deals involving gene therapy, 2011–15163 Table 16: Licensing deals versus number of products in commercial development, by disease

application, 2011–15164 Table 17: Average value of licensing deals with disclosed deal values, by disease application,

2011–15165 Table 18: Partnership deals valued at in excess of $100m, 2011–15


6



6

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 andbeyond) worldwide identified a total of 418 products from 162 originating companies and 72licensees. This is twice as many products as were identified in a similar survey in 2012 (a total of 214products).

- 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, orbacterial 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 categoryexcept cancer, where ex vivo approaches predominate.

- There are 123 cell-based ex vivo gene therapies in commercial development, of which the vastmajority (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 genevectors – including the lentivirus, the adenovirus, and the adeno-associated virus (AAV) – and plasmidvectors.

- The AAV vector is attractive as it can mediate long-term tissue-specific gene expression with lowimmunogenicity. 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 bymonogenic diseases

- Out of the 418 gene therapy products identified, 201 address cancer (in 2012, cancer accounted for100 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). Theremaining 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 (15products versus nine products for all other disease categories combined).


7



7

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 productswere classified as belonging to this broad category; 93 use genetically modified autologous orallogeneic 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 preclinicaldevelopment.

- Oncolytic virotherapy offers hope to patients with inoperable tumors. Amgen’s Imlygic is the firstoncolytic viral therapy approved by the US Food and Drug Administration, based on therapeuticbenefit demonstrated in a pivotal study. Imlygic is an oncolytic herpes simplex virus-1 derivativeengineered 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 beconsidered in each jurisdiction.

- The approval of uniQure’s Glybera (alipogene tiparvovec) stimulated ongoing reimbursementdebates. 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 greatestbarriers 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 and121 partnerships. While most of the deal values have not been disclosed, 11 of the disclosed dealswere valued at over $100m. With respect to therapy areas, cancer was the most active area of deal-making.


8



8

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 responseto complex diseases or to provide specific proteins that are lacking in the patient. In most genetherapy studies, a carrier molecule called a vector must be used to deliver the therapeutic gene to thetarget cells. The traditional approach to gene therapy relied on the physical removal and isolation ofrelevant target cells from the patient’s body prior to gene insertion. After transduction of the cells invitro (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 isaccomplished only at the expense of a labor-intensive, invasive procedure that requires hospitalizationof 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 oftumors (Jensen and Riddell, 2015).

More recent approaches to gene therapy include ex vivo allogeneic therapies and in vivo therapies. Exvivo allogeneic therapies use genetically modified donated cells, with allogeneic cells having to beprotected from the host’s immune system. One way to achieve this is to encapsulate them withinbiocompatible, semipermeable polymer membranes; another is to render them invisible to the body’simmune 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 dueto a series of setbacks and safety concerns. A major setback occurred in 1999, when an 18-year-oldpatient participating in a gene therapy trial for ornithine transcarboxylase deficiency died frommultiple organ failures soon after the initiation of treatment. His death is believed to have beentriggered by a severe immune response to the adenoviral gene carrier (Steinbrook, 2011). In January2003, when a child treated in a French gene therapy trial developed a leukemia-like condition, the USFood and Drug Administration (FDA) placed a temporary halt on all gene therapy trials using retroviralvectors in blood stem cells. However, this ban was eased in April 2003 after the FDA's BiologicalResponse Modifiers Advisory Committee met to discuss appropriate safeguards for future retroviralgene therapy trials involving life-threatening diseases.

Traditionally, research in gene therapy has focused on a variety of diseases that involve recessivesingle-gene disorders, which can potentially be corrected by the addition of a functioning gene to theappropriate cells. Although most monogenic diseases are rare, they are often devastating conditionswith ineffective treatment options and, collectively, they affect millions of people worldwide. Thefocus on monogenic diseases led to the approval, in November 2012, of the first gene therapy in theWestern world, uniQure’s Glybera (alipogene tiparvovec) for the treatment of lipoprotein lipasedeficiency (uniQure, 2012).


9



9

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 geneinsertion, often referred to as viral transduction, a modified virus infects the cells and introduces aviral genome containing inserted genes. In virus-derived vectors, the viral multiplication genes arereplaced 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 apermanency that facilitates long-term expression. Retroviral vectors infect rapidly replicating cellssuch as tumor cells, but are of limited usefulness in other applications since most of the cells in thebody are resting or only slowly dividing. For many years, production and use of viral vectors wasplagued by manufacturing scale-up problems, contamination of viral vector preparations, and varioussafety concerns. The retroviral transduction of cells lacked efficiency and the levels of expression ofgenes 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-SPECIFICUPTAKE

Subsequently, other viruses have been adapted for gene therapy, such as lentiviruses. Lentiviruses area 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 viralvectors 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 theability to target genes to specific cells and tissues. Non-specific uptake and immunogenicity of viralvectors comprise two of the greatest impediments to targeting, because they result in prematureremoval 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 areplasmids. In addition to the therapeutic gene, plasmids often contain a gene expression system thatcan modulate both the duration and expression levels of the therapeutic protein. Plasmids can be usednaked, or can be formulated using lipids and/or polymers. Other non-viral delivery vectors includeepisomal vectors and cancer-specific bacterial vectors. Non-viral vectors result primarily in theintroduction of DNA sequences into the nucleus (or the cytoplasm) in an unintegrated form. Thesemethods 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 theuptake and intracellular transport of macromolecules. Often referred to as transfection, this approachto gene delivery includes chemical, physical, or receptor-based methods. Chemical methods – such asliposomes and molecular conjugates – permit the charged DNA, which is soluble in water but not infat, to cross the fatty cell membrane. A major advantage of synthetic vectors is their flexibility of


10



10

manipulation, as well as their capacity to carry more genetic material, although the level of genetransfer is lower than with viral vectors. Physical methods of gene delivery include direct injection ofnaked 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 physicalmethods include electroporation using a high-voltage pulse (which enhances human skin permeabilityto 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 couldconceivably induce tumor-causing mutations or lead to serious gene dysfunction. Researchers havetherefore been engaged in an effort to develop technologies for site-specific integration of genes intopredetermined 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-specificintegration 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 humanchromosome 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, whichmediates 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 genomevia a cut-and-paste mechanism (known as transposition). Recently, high levels of efficiency of genetransfer into human stem cells have been achieved with the use of a hyperactive variant of thesynthetic 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 inpatients’ cells. These approaches utilize artificial nucleases engineered to introduce a targeted cut ingenomic DNA. Artificial nucleases are expected to enable the development of personalized cellreplacement 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 beengineered to modify genomic DNA at a highly precise location. ZFNs are being developed to facilitatecorrection or disruption of a specific gene or addition of a new DNA sequence/gene. In the past, thedevelopment of clinical applications of ZFN technology has been hampered by the lack of widelyavailable, streamlined methods for the synthesis of functional ZFNs. However, Kim et al. (2009) havedescribed modular assembly methods for functional ZFNs, which allow targeted genome editing inhuman cells.

Zinc finger proteins (ZFPs) are naturally occurring transcription factors that recognize a specific DNA


11



11

sequence. Sangamo BioSciences has acquired most of the patent rights for the exclusive productionand use of ZFPs as DNA-modifying molecules – the company creates ZFP transcription factors forcontrolling gene expression by linking its proprietary engineered ZFPs to functional domains thatnormally activate or repress gene expression (Sangamo, 2016). Sangamo can also link ZFPs tonuclease domains to create ZFNs, and is currently conducting a Phase II clinical trial aimed atknocking out the CCR5 HIV receptor in T cells isolated from HIV patients using a CCR5-specific ZFNdelivered in an adenoviral expression vector. The company’s ZFNs have also been successfullyemployed to inactivate or correct disease-related genes in human stem cells, including hematopoieticprecursor cells and induced pluripotent stem cells.

Bibliography

Belay E, Dastidar S, VandenDriessche T, Chuah MK (2011) Transposon-mediated gene transfer intoadult 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 genetherapy 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 GeneTherapy, 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 targettumors. 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 zincfinger 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 genetherapy: 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 EmanuelEJ, Grady CC, Crouch RA, et al.). Oxford University Press. Chapter 10: 110–120.


12



12

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


44



44

Table 2: Immunotherapeutic cancer gene therapy products in Phase II clinical trials

Originator Licensee Drug nameIn vivo vector or

ex vivo cellsCancer 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 MedicalIL-12, OncoSec

MedicalPlasmid 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

TransgeneAscend

BiopharmaceuticalsAd-IFNgamma Adenovirus Lymphoma (B-cell), basal cell Intratumoral

Tumor-associated antigen vaccines

AlphaVax n/a AVX-701Alpha virus replicon

encoding CEAColorectal Intramuscular

Bavarian Nordic n/a MVA-BN-HER2MVA-BN virus

encoding HER2Breast Subcutaneous


45



45




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


46



46




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

TransgenePrescient

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


68



68

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


69



69

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

Cancer type Delivery route

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


117



117

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


118



118

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


119



119

MOST GENE THERAPIES FOR ISCHEMIC CONDITIONS AIM TO STIMULATE ANGIOGENESIS

The natural biologic response to repeated myocardial ischemia is angiogenesis, the growth of newcollateral blood vessels. Newly formed vessels can bypass arterial obstructions, thus improving bloodflow. In many patients, however, including those with recurrent angina, collateral coronary vesselformation remains insufficient to meet the heart’s needs during exercise or stress. Treatments thathelp 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 ischemicinjury; however, uncontrolled angiogenic gene expression can cause adverse side effects, such ashemangioma formation at injection sites.

All six gene therapies in development targeting refractory angina and/or peripheral vascular diseaseare angiogenic treatments designed to stimulate collateral vessel formation.

A GENE THERAPY PRODUCT FOR PERIPHERAL ARTERIAL DISEASE HAS BEEN LAUNCHED INRUSSIA

Neovasculgen, the first gene therapy drug to be approved in Russia (in 2011), is manufactured byRussian company Human Stem Cells Institute, and is used for the treatment of peripheral arterialdisease and its complication critical limb ischemia. During 2016, the company plans to start theprocess of development and US Food and Drug Administration clearance for the launch ofNeovasculgen in the US and China (Human Stem Cells Institute, 2015). Neovasculgen is a plasmidgenetic construction containing human gene vascular endothelial growth factor (VEGF165) andstimulates angiogenesis, leading to improvements in pain-free walking distance and transcutaneousoxygen tension. Further analysis is hindered by the absence of articles in English (Deev et al., 2014). Itshould be noted that randomized controlled trials with other VEGF treatments have not shownadequate efficacy to differentiate themselves from the strong placebo effects observed (Wolfram andDonahue, 2013).

US-based Taxus Cardium Pharmaceuticals has Generx (alferminogene tadenovec), which delivers thefibroblast growth factor 4 (FGF)-4 gene on an adenoviral vector, in Phase III trials for the treatment ofstable exertional angina due to coronary artery disease. Taxus Cardium’s therapeutic approach uses astandard diagnostic cardiac catheter for non-surgical intracoronary delivery of Generx. Generx iscurrently being developed for international markets outside the US for patients who may not haveaccess 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 onover 650 patients (Taxus Cardium Pharmaceuticals, 2016).

In Japan, AnGes is testing its angiogenic product candidate beperminogene perplasmid, which deliversthe hepatocyte growth factor (HGF) gene on a plasmid expression vector, in Phase III trials inperipheral arterial disease.

Four angiogenic gene therapies are in Phase II trials. Reyon Pharmaceutical’s product is a plasmidvector expressing a gene encoding a cDNA hybrid of the HGF gene; the hybrid gene (HGF-X7) wasconstructed by inserting intron sequences into certain sites of HGF cDNA. ID Pharma has a virus-


120



120

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) modifiedby an adenovirus vector to overexpress the stromal cell-derived factor 1 gene. This product is beingtested 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 encodinghuman 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. Differenttypes of viral vectors have been developed for in vivo gene delivery by subretinal injections tophotoreceptor or retinal pigment epithelium (RPE) cells of the retina, but the most efficient vectorsare those based on the AAV virus (Colella and Auricchio, 2012).

In 2015, Spark Therapeutics announced that it was preparing regulatory filings for marketingauthorization of SPK-RPE65 in the monogenic disease Leber's congenital amaurosis (LCA) (SparkTherapeutics, 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 derivedfrom Pharmaprojects, identified a total of 418 gene therapy products, of which 37 address oculardiseases. 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.


131



131

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

Health & Medicine

Transcript of Trends in Gene Therapy - Report Extract