New data with novel AAV gene therapy capsids
demonstrate widespread gene transfer to the brain and spinal cord
of non-human primates after a single intravenous administration
Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene
therapy company focused on developing life-changing treatments for
severe neurological diseases announced today multiple data
presentations at the Congress of the European Society of Gene and
Cell Therapy (ESGCT) taking place October 17-20, 2017, in Berlin,
Germany. The data include an oral presentation related to recent
results from Voyager’s ongoing Phase 1b trial of VY-AADC01 in
advanced Parkinson’s disease, as well as six poster presentations
related to Voyager’s novel adeno-associated virus (AAV) capsid
optimization efforts, gene therapy manufacturing, and preclinical
pipeline programs.
“A core competency of Voyager’s gene therapy
platform is vector optimization and a critical component of this is
optimizing and choosing the capsid, or outer shell of the gene
therapy vector,” said Dinah Sah, Ph.D., Voyager’s chief scientific
officer. “At this year’s ESGCT meeting, we describe exciting
progress with novel AAV capsids that enhance the transfer of genes
to the brain and spinal cord of non-human primates and in a
preclinical model of Friedreich’s ataxia, representing unique
opportunities for our current pipeline as well as for future
potential programs. An additional core competency of Voyager is the
production and manufacturing of AAV gene therapy vectors at scale,
and at the meeting, we also describe the high yield and quality of
AAV vectors produced with Voyager’s baculovirus/Sf9 manufacturing
system.”
Clinical, Preclinical, and Manufacturing
Posters and Presentations at ESGCT
“Translation of Intravenous Delivery of AAV Gene
Therapy for the Treatment of CNS Diseases.” Poster P209.
Intravenous dosing of AAV gene therapy vectors in adult large
mammals has resulted in limited transfer across the blood-brain
barrier to achieve gene expression in the central nervous system
(CNS). In these studies in adult non-human primates, novel AAV gene
therapy capsids readily crossed the blood-brain barrier after a
single, intravenous administration resulting in widespread,
enhanced gene transfer to the brain and spinal cord. One month
after dosing of a transgene encoding both a therapeutic protein
(frataxin) and a reporter gene (HA) to facilitate molecular and
immunohistochemical measurements, substantial levels of frataxin-HA
were expressed in the CNS, including motor neurons throughout the
length of the spinal cord, the brain stem, pyramidal neurons in the
motor cortex, and neurons in the substantia nigra, thalamus and
cerebellar dentate nucleus. Voyager continues to conduct additional
studies in non-human primates with these and other novel AAV
capsids to optimize delivery of genes to regions critical for the
treatment of amyotrophic lateral sclerosis (ALS), Parkinson’s
disease and Friedreich’s ataxia (FA), as well as other severe
neurological diseases.
“Rescue of Central and Peripheral Neurological
Phenotype in a Novel Mouse Model of Friedreich's Ataxia by
Intravenous Delivery of AAV Frataxin.” Poster P107.
Friedreich’s ataxia is a severe, inherited neurological disease
caused by mutations in the frataxin gene leading to decreased
expression of frataxin (FXN), which results in severe sensory
impairment, progressive loss of the ability to walk, generalized
weakness, loss of sensation, as well as severe and potentially
fatal cardiomyopathy. In a transgenic mouse model of FA, one-time
intravenous post-symptomatic dosing of an AAV vector composed of a
novel AAV capsid and a frataxin transgene, together with
intracerebral dosing also delivering a frataxin transgene, rapidly
halted and reduced FA disease progression in multiple tests
including three functional tests of motor behavior and one
electrophysiological test. In addition, increasing intravenous
vector doses with the same novel capsid together with a fixed dose
of the intracerebral vector led to a dose-dependent rescue of the
FA phenotype. This novel AAV capsid provided at least 20-fold
greater delivery of the vector to sensory ganglia as measured by
vector genomes, and approximately a three-fold greater expression
of frataxin in the cerebellum, as compared to an AAV9 vector at a
similar dose. Additional preclinical studies are underway at
Voyager including steps to optimize a lead clinical candidate for
the treatment of FA.
“Enabling Large-Scale Manufacturing of rAAV
Vectors with the Baculovirus/Sf9 Production System.” Poster
P324.
Voyager’s manufacturing platform utilizes a baculovirus/Sf9 cell
production process that enables the production of AAV vectors at
clinical and commercial scale, with the potential for increased
yields over traditional production processes. The current study
demonstrated comparability in the quality of AAV vectors produced
with the baculovirus/Sf9 process compared to AAV vectors produced
with a mammalian process. AAV vectors produced with baculovirus/Sf9
cells showed similar analytical characteristics, in vitro and in
vivo pharmacological activity, and CNS bio-distribution when
compared to AAV vectors produced using triple-transfection of human
embryonic kidney (HEK293) cells. Similar, robust knock down of HTT
(huntingtin) gene expression occurred in vivo for vectors produced
in either baculovirus/Sf9 or HEK293 cells. These data demonstrate
that the baculovirus/Sf9 production system can be used to produce
AAV vectors that are indistinguishable with respect to
bio-distribution, potency and expression in vivo compared to AAV
vectors produced in mammalian cells.
“Translation of Intrathecal Delivery of an AAV
Gene Therapy Targeting SOD1 for the Treatment of ALS.” Poster
P207.
ALS is a rapidly progressive, fatal disease characterized by the
degeneration of nerve cells in the spinal cord and brain resulting
in severe muscle atrophy with loss of the ability to walk and
speak, and premature death. Mutations in the superoxide dismutase 1
gene (SOD1), the first mutant gene discovered to be causal for the
development of ALS, lead to motor neuron loss through a toxic gain
of function mechanism and accounts for two to three percent of ALS
cases worldwide. Intrathecal (IT) administration of AAV vectors in
preclinical models of ALS has effectively transferred genes to the
spinal cord, providing less exposure to peripheral tissues and
reducing the impact of pre-existing immunity compared with systemic
dosing. However, the efficacy of an AAV gene therapy directed
against SOD1 has not been reported to date in a large animal model
of ALS.
In this study, Voyager evaluated IT delivery of an AAV gene
therapy vector targeting SOD1 using RNAi for the treatment of
canine degenerative myelopathy, a naturally-occurring disease of
companion dogs that is similar to some forms of human ALS,
including the SOD1 form of disease. The results demonstrated that a
single IT administration of Voyager’s AAV SOD1 RNAi vector resulted
in 74% and 41% suppression, or knock down, of SOD1 mRNA in dorsal
root ganglia and spinal cord, respectively, and was well-tolerated.
Precise and efficient processing of the primary microRNA was also
observed.
“Selection of an AAV Gene Therapy Targeting
Huntingtin for the Treatment of Huntington's Disease.” Poster
P212.
Huntington's disease is a fatal, inherited neurodegenerative
disease that results in the progressive decline of motor and
cognitive functions caused by an expansion mutation in the
huntingtin, or HTT, gene. For the treatment of Huntington’s
disease, suppression of mutant huntingtin as a therapeutic approach
is supported by multiple preclinical studies. Voyager previously
selected VY-HTT01 as a clinical candidate for the treatment of
Huntington’s disease. VY-HTT01 is composed of an AAV capsid and
proprietary transgene that harnesses the RNAi pathway to
selectively knock down the production of HTT mRNA. Direct delivery
of VY-HTT01 to the brain with a one-time administration could
potentially slow or halt the progression of Huntington’s disease.
In the non-human primate putamen (a disease-relevant region of
the brain), VY-HTT01 resulted in 54% suppression of HTT mRNA after
a single administration. The extent of HTT mRNA suppression, as
well as the high precision and efficiency of primary microRNA
processing and tolerability in the non-human primate supported the
selection of VY-HTT01 as the lead clinical candidate. Preclinical
pharmacology and toxicology studies are underway with VY-HTT01 to
support filing of an IND application.
“AAV Gene Delivery of an Anti-Tau Antibody using
a Novel Blood Brain Barrier Penetrant Capsid in Wild Type and P301S
Tauopathy Mice.” Poster P229.
In healthy individuals, tau is an abundant soluble cytoplasmic
protein in neurons that binds to microtubules to promote
microtubule stability and function. In Alzheimer’s disease (AD),
Frontotemporal Dementia (FTD), progressive supranuclear palsy (PSP)
and other tauopathies, tau aggregates and forms insoluble
neurofibrillary tangles that closely correlate to the progression
of neurodegeneration. The use of therapeutic antibodies targeting
various forms of tau to prevent, reduce, or slow the development of
tau pathology is an important potential therapeutic strategy for
these diseases.
Because of the blood-brain barrier, only very low levels of
antibody distribute to the brain from the systemic circulation
after passive immunization, resulting in modestly reduced tau
pathology in animal models. In Voyager’s study, a one-time
intravenous dose of an AAV vector composed of a novel capsid and
transgene encoding an anti-tau antibody penetrated the blood-brain
barrier resulting in widespread and durable expression of a tau
monoclonal antibody in the brain and spinal cord to levels at least
15-fold higher than those achieved following standard passive
immunization.
These data suggest that intravenous dosing of vectorized
anti-tau antibody with a novel AAV capsid represents a new
single-dose therapeutic strategy for treating various tauopathies,
including FTD and AD. Voyager is optimizing the AAV vectored
delivery of monoclonal antibodies directed against tau and other
misfolded proteins to potentially treat a variety of
neurodegenerative disorders.
“Intraputaminal AADC gene therapy for advanced
Parkinson's disease: Interim Results of a Phase 1b Trial.” An oral
presentation is scheduled for October 18, 2017, 2:40 pm CET.
Voyager’s lead program for Parkinson’s disease, VY-AADC01, is
designed to deliver the AADC gene directly into neurons of the
putamen where dopamine receptors are located, bypassing the
degenerating dopamine neurons of the substantia nigra and enabling
neurons of the putamen to express the AADC enzyme and to convert
levodopa into dopamine. The approach with VY-AADC01, therefore, has
the potential to durably enhance the conversion of levodopa to
dopamine and provide clinically meaningful improvements in motor
function in advanced Parkinson’s disease patients, improving their
symptoms at lower doses of levodopa and following a single
administration.
Recently reported data for VY-AADC01 from the ongoing Phase 1b
data will be presented at this year’s ESGCT. The results
demonstrated durable, dose-dependent and time-dependent
improvements across multiple measures of patients’ motor function
after a one-time administration of VY-AADC01, and with meaningfully
lower doses of oral levodopa. These measures include
patient-reported diaries, Parkinson’s disease rating scales, and
activities of daily living. Voyager will continue to follow the
patients in this Phase 1b trial. A pivotal Phase 2-3 program is
scheduled to begin later this year with patient enrollment
commencing the first half of 2018.
Additional information for these poster presentations can be
found on the “Publications” section of Voyager Therapeutics’
website at www.voyagertherapeutics.com.
About Voyager Therapeutics
Voyager Therapeutics is a clinical-stage gene
therapy company focused on developing life-changing treatments for
severe neurological diseases. Voyager is committed to advancing the
field of adeno-associated virus (AAV) gene therapy through
innovation and investment in vector engineering and optimization,
manufacturing and dosing and delivery techniques. Voyager’s
pipeline focuses on severe neurological diseases in need of
effective new therapies, including advanced Parkinson’s disease, a
monogenic form of ALS, Huntington’s disease, Friedreich’s ataxia,
frontotemporal dementia, Alzheimer’s disease and severe, chronic
pain. Voyager has broad strategic collaborations with Sanofi
Genzyme, the specialty care global business unit of Sanofi, and the
University of Massachusetts Medical School. Founded by scientific
and clinical leaders in the fields of AAV gene therapy, expressed
RNA interference and neuroscience, Voyager Therapeutics is
headquartered in Cambridge, Massachusetts. For more information,
please visit www.voyagertherapeutics.com.
Forward-Looking Statements
This press release contains forward-looking
statements for the purposes of the safe harbor provisions under The
Private Securities Litigation Reform Act of 1995 and other federal
securities laws. The use of words such as “may,” “might,” “will,”
“should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,”
“undoubtedly,” “project,” “intend,” “future,” “potential,” or
“continue,” and other similar expressions are intended to identify
forward-looking statements. For example, all statements Voyager
makes regarding the initiation, timing, progress and reporting of
results of its preclinical programs and clinical trials and its
research and development programs; its ability to advance its
AAV-based gene therapies into, and successfully initiate, enroll,
and complete, clinical trials; the potential clinical utility of
its product candidates; its ability to continue to develop its
product engine; its ability to add new programs to its pipeline;
its ability to enter into new partnerships or collaborations; its
expected cash, cash equivalents and marketable debt securities at
the end of a fiscal year and anticipation for how long expected
cash, cash equivalents and marketable debt securities will last;
and the timing or likelihood of its regulatory filings and
approvals are forward-looking. All forward-looking statements are
based on estimates and assumptions by Voyager’s management that,
although Voyager believes to be reasonable, are inherently
uncertain. All forward-looking statements are subject to risks and
uncertainties that may cause actual results to differ materially
from those that Voyager expected. Such risks and uncertainties
include, among others, those related to the initiation and conduct
of preclinical studies and clinical trials, the availability of
data from clinical trials and the expectations for regulatory
submissions and approvals; the continued development of the product
engine; Voyager’s scientific approach and general development
progress; the availability or commercial potential of Voyager’s
product candidates; the sufficiency of cash resources; and need for
additional financing. These statements are also subject to a number
of material risks and uncertainties that are described in Voyager’s
most recent Annual Report on Form 10-K filed with the Securities
and Exchange Commission, as updated by its subsequent filings with
the Securities and Exchange Commission. Any forward-looking
statement speaks only as of the date on which it was made. Voyager
undertakes no obligation to publicly update or revise any
forward-looking statement, whether as a result of new information,
future events or otherwise, except as required by law.
Investor Relations: Matt
OsborneVice President of Investor Relations & Corporate
Communications857-259-5353mosborne@vygr.com
Media: Katie EnglemanPure
Communications, Inc.910-509-3977Katie@purecommunicationsinc.com
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