Download Gene Therapies for Diseases Other Than Cancers

White Paper on Gene Therapies
Gene Therapies for Diseases Other
Than Cancers
Vying for Commercial Success
1
A gene therapy
product has yet to
be approved by the
US FDA and despite
an approval in the
EU, Glybera has not
yet launched.
Apart from clinical
development and
regulatory approval,
several challenges
need to be
overcome for gene
therapies to become
commercially viable.
Although 80% of global gene therapy clinical studies have been conducted
for different cancers, the first and only approved gene therapy in the Western
world – Glybera (alipogene tiparvovec) – was approved in the EU for a noncancer monogenic condition (lipoprotein lipase (LPL) deficiency). Glybera,
after several rounds of assessments by the Committee on Advanced Therapies
(CAT) was authorized in 2012 under “exceptional circumstances.” Due to the
small size of clinical trials supporting Glybera’s authorization, the EMA has
required its maker to submit additional clinical data annually for 6 years and to
establish a registry for long-term patient tracking. Despite approval, Glybera
has yet to be marketed in EU countries due to pending pricing negotiations
and other regulatory requirements - even though it made headlines in 2014
for a target €1.1M price tag in Germany.
Over 2,000 gene therapy clinical studies have been
conducted across diverse therapeutic areas, with
80% of these studies conducted in various cancers.
Despite heroic efforts by basic researchers and clinical
investigators alike, no gene therapies have become
commercially available in the US or EU. The lack of
success of gene therapies to date highlights multiple
limitations still to be overcome, e.g. patient selection
for clinical trials, safer and more effective vectors, and
cost. The first gene therapy product approved in the
EU, Glybera, was for a rare genetic disease caused by a
mutation of the pancreatic enzyme lipoprotein lipase
that renders patients unable to break down fatty acids
effectively. The three other gene therapy products
now approved (Table 1) are for the treatment of
different cancers.
TABLE 1: APPROVED GENE THERAPY PRODUCTS
Gene
Therapy
Gene/MoA
Glybera
Lipoprotein
lipase (LPL)
Oncorine
Vector
Adeno
Associated
Virus
Disease/Indication
Country of
Approval
Year of
Approval
Familial LPLD (LPL deficiency)
EU/EMA
2012
Adenovirus Adenovirus
V5 with E1B
and E3B
deleted
Head and neck squamous cell
carcinoma, lung cancer, liver cancer,
malignant pleural and peritoneal
effusion, pancreatic cancer
China
2005
Rexin-G
Cyclin G1
(cytocidal
mutant)
Moloney
murine
leukemia
virus
Retrovirus
Solid tumors refractory to standard
chemotherapy
Philippines
2007
Gendicine
Wt p53
Adenovirus
Head and neck squamous cell
carcinoma
China
2003
Gene therapies for diseases other than cancers are
progressing through late stages of development,
indicating that some of these therapies are likely to
become available in the near future. Herein we have
discussed the characteristics of the diseases that
Copyright©2015 SMARTANALYST®
make them suitable for gene therapies, characteristics
of vectors for such modalities, changing industry
perceptions, and the possible future outlook for
these therapies.
2
Disease-specific characteristics make certain
monogenic disorders tractable for gene-replacement
strategies
The original goal of gene therapies was to treat
monogenic diseases by replacing a non-functional
or defective gene with a healthy copy. Monogenic
hematological disorders such as hemophilias are
particularly amenable to gene therapy because even a
limited increase in expression of the defective gene is
sufficient to offer a phenotypic cure. This notion has
been strengthened with results from recent trials for
hemophilia B. A single intravenous infusion of an adenoassociated virus serotype 8 (AAV-8) vector expressing
Factor IX in 10 patients with severe hemophilia B
resulted in a dose-dependent increase in its circulating
levels to 1-6% of the normal value over a median period
of 3.2 years. In patients who received the high dose
(2×1012 vector genomes per kilogram of body weight),
there was a consistent increase in Factor IX level to over
5%. Despite such low levels of circulating factor, there
was over a 90% reduction in bleeding episodes and the
use of prophylactic Factor IX concentrate. Hemophilias
also tend to be suitable for gene therapy since minimal
logistic issues need to be addressed with respect to
intravenous administration of viral vectors encoding
clotting factors. Production of such vectors is now
routine, and there are very few manipulations of the
product prior to administration.
Other monogenic disorders such as childhood cerebral
adrenoleukodystrophy (CCALD), while certainly tractable
vis-à-vis gene replacement, present additional logistic
issues. This disease is caused by deficiency in ALD
protein – an adenosine triphosphate-binding cassette
transporter encoded by the ABCD1 gene – which can
be corrected by transducing autologous CD34+ cells ex
vivo with a lentiviral vector encoding wild-type gene and
then re-infusing transduced cells into the patients after
they have received myeloablative treatment. These
additional steps are likely to make it expensive and
restricted to the most advanced medical centers.
Polygenic disorders can be amenable to gene therapy
strategies if specific targets are identified
As many disorders such as diabetes, coronary artery
disease, and rheumatoid arthritis are polygenic,
Copyright©2015 SMARTANALYST®
replacement of a single gene is unlikely to cure the
disease. However, if a specific therapeutic target
(common disease pathway) can be identified, then
delivery of a gene product that expresses sufficient
levels of the protein, in theory, can sufficiently
ameliorate symptoms of a polygenic disease and be
a useful therapy. A case in point is Generx® a Phase
III adenoviral FGF-4 gene therapy for patients with
myocardial ischemia due to coronary artery disease,
developed by Cardium Therapeutics. FGF-4 has been
shown to stimulate the growth of microvascular
circulation in the heart, enhancing cardiac perfusion.
Generx®, is designed to be administered only once, by
an interventional cardiologist. The company recently
reported that the benefits from this gene therapy are
similar in magnitude to the large vessel revascularization
procedures such as bypass surgery or angioplasty.
Tissue tropism and viral integration are important
considerations determining the choice of vector
While there has been significant progress in vector
development in the past two decades, it is also clear
that no vectors can be universally utilized for all gene
therapy applications. There are a few important
considerations in this regard. First, the tropism of
vectors used will determine whether the gene product
will be expressed in the tissue of interest. For instance,
in the case of AAV vectors, as compared to other
serotypes, AAV1 is suitable for expression in skeletal
muscle and retina, AAV5 transduces neuronal and lung
cells efficiently and AAV8 demonstrates high levels
of expression in liver cells. A second consideration is
whether the viral vector employed stably integrates into
the host genome or remains episomally in the nucleus.
Lentivirus vectors have the ability to stably integrate
into target cells, thus providing genetic modification
of the cell and all of its progeny. However, insertional
mutagenesis is a potential issue for vectors that
integrate foreign DNA into the genome. On the other
hand, in case of vectors based on the Herpes Simplex
Virus (HSV), the latent HSV genome is maintained as an
episome, and the potential risks of viral integration into
host cell chromatin are avoided.
3
GT Properties
Particle
Characteristics
TABLE 2: COMMONLY USED VECTORS IN GENE THERAPY MODALITIES
Adenovirus
Adeno-associated virus
Herpes virus
Retrovirus/
Pox/vaccinia virus
Genome
dsDNA
ssDNA
dsDNA
ssRNA (+)
dsDNA
Coat
Naked
Naked
Enveloped
Enveloped
Enveloped
Genome size1
30-38 kb
5 kb
120-200 kb
3-9 kb
130-280 kb
Infection/tropism
Dividing and nondividing cells
Dividing and nondividing cells
Dividing and nondividing cells
Dividing cells2
Dividing and non-dividing
cells
Host genome interaction
Non-integrating
Non-integrating3
Non-integrating
Integrating
Non-integrating
Transgene expression
Transient
Potential long lasting
Potential long
lasting
Long lasting
Transient
Packaging capacity
7.5 kb
4.5 kb
>30 kb
8 kb
25 kb
Immunogenicity
High
High
High
Low
High
Other comments
World’s first
approved
gene therapy
‘Gendicine’
EU’s first approved
gene therapy ‘Glybera’
Toxicity related to
lytic infection
X-linked SCID study
where leukemia was
reported
Potent immune
response suitable for live
recombinant vaccines
1 A large genome can be engineered for insertion and simultaneous expression of multiple genes.
2 Lentiviruses also infect non-dividing cells.
3 Adeno-associated viruses are able to integrate with low frequency into chromosome 19.
Immune responses need not be a barrier to their
effective use in gene transfer
While AAV and adenovirus-based vectors are popular
gene therapy vectors, the human immune response to
them might be considered problematic. AAV vectors
often induce immune responses against the capsid or the
transgene, especially when used in large doses required
for clinical benefit, leading to a decrease in transgene
expression. In addition to AAV, the efficacy of in vivo
gene delivery with adenoviral vectors might be expected
to be severely compromised owing to both innate and
acquired immune responses as most immunocompetent
people have been exposed to adenovirus. With up
to 80% of the human population seropositive for
AAV-2 (and vectors based on it), concerns over their
immunogenicity are justified.
However, it is now recognized that although gene
therapy vectors such as adenoviruses and AAV are
highly immunogenic, this need not preclude successful
gene expression, even long-term expression. The
immune-privileged status of the eye makes AAVmediated ocular gene transfer with low doses relatively
efficient with low risk of immune-related events. This
was seen in the trials that used AAV to deliver the RPE65
gene to retinal cells in patients of Leber Congenital
Amaurosis (LCA), an inherited disorder that results in
severe vision loss. As there are many gene therapies
that do not target the eye, diverse strategies have been
developed to overcome immunogenicity concerns
when targeting other tissues. One broadly applicable
strategy has been to transduce cells ex vivo and then
transfer them into the body. Proof of principle for such
a strategy has been obtained in preclinical models where
myoblasts transduced with “gutless” adenoviral vectors
expressing full-length dystrophin cDNA have been shown
to fuse with mature myofibers ex vivo to successfully
deliver the gene. Another strategy has been to use virus
serotypes such as AAV-5 and AAV-8 which have low
Copyright©2015 SMARTANALYST®
sero-prevalence. Several other approaches to generate
immunologically inert AAV vectors have been employed
– including targeted mutagenesis, capsid shuffling, or
directed evolution approaches – to alter the epitopes
on the AAV capsid surface. Chemical modifications of
immunogenic sites by strategies such as PEGylation
or co-administration of immunosuppressive agents or
plasmapharesis to reduce neutralizing antibodies have
also been tried. All these approaches, while useful in
obtaining a vector with immune-escape potential, are
nevertheless fraught with potential problems. These
include loss of infectivity, packaging ability, or tissue
tropism. While not insurmountable, the obvious
disadvantage of all these strategies is additional cost,
as cell culture and lab-based engineering necessitates
several additional manufacturing and quality control
issues.
Large-scale industrialization of vector production makes
“low cost of goods” possible for certain gene therapy
modalities
Limited economical access to large quantities of
GMP grade vector product is another factor that
has hampered progress in this arena. Table 2 lists
the most commonly used vectors currently in gene
therapy modalities along with their packaging capacity,
immunogenicity, tissue tropism, and other features. In
most cases, transient transfection into a human producer
line was found to be an effective vector manufacturing
strategy. With recent innovations, industrial production
of both AAV and lentiviral vector platforms has now
reached such a stage of maturity that robust scalable
manufacturing processes that generate highly
reproducible products are now a reality. In the case of
gene therapy products (e.g. Glybera) that use AAV, this
was facilitated by the introduction of baculovirus vectors,
in combination with Sf9 insect cells, which are easily
grown in animal-derived component-free media, and are
amenable to further processing at any scale.
4
Changing industry perception on risks and benefits of
gene therapies
The pharmaceutical industry is generally risk averse
and understandably so. In 1999, the fatal systemic
inflammatory response syndrome generated
in an 18-year-old patient with partial ornithine
transcarbamylase deficiency – following transfer of a
vector based on human adenovirus type 5 – and the
tough regulatory climate that ensued, were cause for
concern. For many years, this led to a decline in interest
in furthering such therapies, especially for non-lethal
diseases where such risks were unacceptable. Despite
these setbacks, consistent data from various trials
showing sustained clinical benefits has now led to a
re-evaluation by industry experts, and an improved
investor climate. Major pharmaceutical companies
have demonstrated renewed interest and have struck
numerous deals with academic groups and smaller
biotech companies.
In December 2014, Pfizer inked a deal with a privately
owned US biotech firm Spark Therapeutics to develop
a gene therapy for hemophilia B. Among other major
pharmaceutical companies, Bayer AG has struck a
gene therapy deal with Dimension Therapeutics, while
Novartis AG recently established a new cell and gene
therapies unit, and Sanofi has a long-standing tie-up
with Oxford BioMedica. Genzyme recently announced a
major strategic collaboration with Voyager Therapeutics
for gene therapies for CNS disorders. Perceptions are
also changing about accepting the risks associated with
gene delivery for the potential benefits, as evident from
the large number of clinical studies in these indications.
TABLE 3: KEY PLAYERS WITH GENE THERAPIES IN CLINICAL DEVELOPMENT
Company
1
2
3
Uniqure
Oxford Biomedica
Bluebird Bio
4
Sangamo
5
AGTC
6
Spark
Therapeutics
7
AnGes MG
8
Taxus Cardium
9
Genethon
Gene Therapy/ Disease
Status
hF-IX gene/ Hemophilia B
Collaborator: Chiesi Farmaceutici (licensed from St.
Jude Children’s Research Hospital ), Phase I/II
NaGlu gene/ San Fillipo B Syndrome
Collaborator: Institute Pasteur, Phase I/II
StarGen™ (Sanofi) / Stargardt Disease
Phase I/IIa trial ongoing
UshStat® (Sanofi) / Usher Syndrome Type 1B
Phase I/IIa
EncorStat® / Corneal Graft Rejection
Phase I/II trial preparation
OXB-102 / ProSavin® / Parkinson’s Disease
Phase I/II trial completed
Retinostat®/ Wet AMD
Phase 1 trial ongoing
Lenti-D/ Childhood Cerebral ALD
Phase II/III global study initiated
LentiGlobin/ Beta Thalassemia, SCD
Beta thalassemia: Phase I/ II study initiated
SCD: Phase I in US
SB-728/ HIV/AIDS
Phase II
CERE-110/ Alzheimer’s Disease
Phase II
AATD / Alpha-1 Antitrypsin Deficiency
Phase IIb
RS1 gene/ X-linked Juvenile Retinoschisis (XLRS)
IND filed; Phase I/II expected to start 2Q2015
SPK-RPE65/ Inherited Retinal Dystrophies due to RPE65 Gene Mutations
Phase III
SPK-CHM / Choroideremia
Phase I/II
SPK-FIX / Hemophilia B
Collaborator: Pfizer
Phase I/II expected 1H2015
Collategene™ Licensed from Vical (Also Known as Beperminogene
Perplasmid, AMG0001)/ Critical Limb Ischemia
Phase III AMG0001/Primary Lymphedema
Phase I/II (Japan)
AMG0001/ Ischemic Heart Disease
Phase I completed (US)
Generx® (Alferminogene Tadenovec) [Ad5FGF-4]/Cardiac Microvascular
Insufficiency (CMI) in patients with Myocardial Ischemia and Symptomatic
Chronic Stable Angina Pectoris
Phase III
WAS ( Wiskott–Aldrich Syndrome)
Phase I/II
X-Linked CGD Patients
Phase I/II
10
GSK
GSK2696273/ ADA Gene Transfer into Hematopoietic Stem/Progenitor
Cells for the Treatment of ADA-SCID
Phase II
11
Viromed
Critical Limb Ischemia
Phase II completed
Chronic Granulomatous Disease
Phase I/II (Korea)
Painful Diabetic Neuropathy
Phase II
Chronic Stable Angina
Phase I/ II
12
Voyager
Therapeutics
VY-AADC01/ Parkinson’s Disease
Collaborators: UCSF and Genzyme
Phase I
13
Avalanche
Biotechnologies
AVA101/ Wet AMD
Phase IIa
14
Celladon
MYDICAR® (SERCA 2A) / Systolic HF
Phase II/III
MYDICAR® ( (SERCA 2A) /Advanced HF with LVAD
Phase I/II
Copyright©2015 SMARTANALYST®
5
Future Outlook
Although the first gene therapy clinical trial began in
1990, progress has been slow. Recent developments,
including the approval of Glybera and the increasing
level of clinical trial activity, have indicated an upswing
and a renewed interest in the role of gene therapy in
diseases with high unmet need. For instance, in many
hematological or metabolic monogenic disorders, where
allogeneic hematopoeitic stem cell transplantation
(HSCT) from donors has been successfully used to treat
disease, gene therapy may correct the genetic defect and
permit autologous HSCT. This approach will overcome
the challenges associated with arranging a compatible
donor and the consequences of an unmatched or
unrelated transplantation as in case of graft-versus-host
disease.
There is also an increased focus on the issues that
would be relevant to maximizing commercial potential,
including reimbursement, regulatory hurdles,
manufacturing costs, and postmarketing surveillance.
The approval of Glybera, while certainly encouraging, is a
small step in an evolving field with enormous potential.
Glybera’s approval in the EU was accompanied by
requirements for a post-approval study, implementation
of a disease registry, and a risk-management procedure.
All of this can be costly and time-consuming, thereby
hindering initial uptake.
Commercial success will depend on the ability
of companies to develop gene therapy products
with convincing clinical data to support the value
proposition of potential long-term benefit or cure
without any serious safety concern. They will also face
reimbursement challenges as gene therapies may be a
one-time or a short-term treatment, and the actual cost
may be incurred upfront, unlike conventional therapies
where the cost of treatment is incurred over a long
period of time. This may be especially problematic in the
US where commercial payers may balk at incurring the
upfront cost with no certainty of the individual staying
with the insurer to realize the long-term benefit. Further,
specialist training, patient awareness, and dedicated
infrastructure in the form of centers of excellence (to
identify / diagnose patients early, to offer them gene
therapy, and to manage them post treatment) may be
required.
Overall, despite various challenges, gene therapies have
the potential to change the future treatment paradigm
or even become the standard-of-care (SoC) therapies
for certain diseases. While the gene therapy market will
largely depend on the regulatory environment, in view of
the emerging encouraging data, there is a high likelihood
that gene therapy will become a clinical reality in the
near future.
Ophthalmic Diseases
1. Lebers Congenital Amaurosis
2. Stargardt Disease
3. Age Related Macular
Degeneraon
4. Choroideremia
5. Leber's Hereditary Opc Atrophy
Neurological Disorders
1. Parkinson’s Disease
2. Spinal Muscle Atrophy
3. Alzheimer’s disease
4. Diabec Neuropathy
Respiratory Diseases
1. Cysc Fibrosis
2. Alpha-1 Antrypsin
Deficiency
Cardiovascular Disorders
1. Heart Failure
2. Angina/Ischemic Heart
Disease
3. Crical Limb Ischemia/
Intermi†ent Claudicaon
Metabolic Disorders
1. Adrenoleukodystrophy
2. Pompe
3. Ba†en
4. Metachtomac Leukodystrophy
5. San Filippo A
6. Hunter Syndrome
Musculoskeletal Disorders
1. Limb Girdle Muscle Dystrophy
2C/2D
2. Becker Muscle Dystrophy
3. Duchenne Muscular
Dystrophy
Blood Disorders
1. Hemophilia
2. ADA-SCID
3. X Linked- SCID
4. Chronic Granulomatous Disease
5. Wischo† Aldrich Syndrome
6. Sickle Cell Anemia
7. Beta Thalassemia
8. Fanconi Anemia
Figure 1: Clinical applications of gene therapy
Copyright©2015 SMARTANALYST®
Other Diseases
1. HIV
2. Epidermolysis Bullosa
3. Acute Intermi†ent Porphyria
6
About SmartAnalyst
SmartAnalyst helps bio-pharma companies drive pipeline and portfolio value by providing strategic
consulting and analytical support for key decisions at the Disease, Asset, and Portfolio levels. Contact us
to discuss how we can assist you in your biologic portfolio decisions.
Copyright©2015 SMARTANALYST®