Voyager Therapeutics, Inc. (Nasdaq: VYGR), a biotechnology company
dedicated to advancing neurogenetic medicines, today announced the
presentation of data related to its TRACER™ capsid discovery
platform and TRACER-driven gene therapy programs at the American
Society of Gene & Cell Therapy’s (ASGCT) 27th annual meeting.
Second-generation, intravenously (IV)-delivered capsids, evolved
through the TRACER platform, showed further enhanced blood-brain
barrier (BBB) penetrance, greater liver detargeting, and
transduction of 50-75% of cells across diverse brain regions, with
upwards of 95% transduction in certain key cell types such as
Purkinje Neurons. Further, a gene therapy in preclinical
development for SOD1 amyotrophic lateral sclerosis (ALS), which
combines a SOD1 RNAi transgene packaged in a second-generation
capsid, reduced SOD1 messenger RNA (mRNA) expression by up to 80%
in non-human primate (NHP) spinal cord motor neurons following a
single IV delivery at a clinically relevant dose of 3E13 vg/kg. The
potential translatability of these capsids is supported by data
across multiple species, including mice and multiple species of
NHP, as well as binding to Alkaline Phosphatase (ALPL, formerly
called Receptor X) in multiple species and in human cells. These
data are highlighted in the oral presentation, “Continued directed
evolution of VCAP-101 and VCAP-102 identifies second generation
capsids with increased brain tropism in non-human primates and mice
(#119)” on Wednesday, May 8, 2024, 4:30 p.m. – 4:45 p.m. ET, as
well as in multiple posters detailed below.
“Results across species, capsid generations, and disease models
provide the most extensive validation to date of the high
translational potential of our TRACER capsids for gene therapy in
the CNS,” said Todd Carter, Ph.D., Chief Scientific Officer of
Voyager Therapeutics. “The strong performance of our capsids has
enabled selection of three development candidates in Voyager’s
wholly-owned and partnered gene therapy programs for neurologic
diseases, which are currently advancing towards anticipated IND
filings in 2025.”
Additional data demonstrating the potential translatability,
activity against therapeutic targets, manufacturability and
performance of Voyager’s TRACER capsids are being presented across
12 oral and poster presentations throughout the ASGCT meeting as
follows:
Second-Generation CapsidsOral Presentation:
Continued directed evolution of VCAP-101 and VCAP-102 identifies
second generation capsids with increased brain tropism in non-human
primates and mice (#119)
- Applying its TRACER capsid discovery platform, Voyager has
evolved a second generation of capsids with further optimized
features, including central nervous system (CNS) tropism and liver
detargeting, compared to VCAP-101 or VCAP-102 capsids.
- With low doses (3E13 vg/kg) delivered IV in an NHP model,
Voyager’s second-generation capsids achieved transgene expression
in up to 65% of neurons and up to 97% of astrocytes across diverse
brain regions, including cortical and subcortical areas.
- A SOD1 RNAi transgene packaged in a second-generation capsid
and delivered IV reduced SOD1 mRNA expression by up to 80% in NHP
spinal cord motor neurons.
- The potential translatability of Voyager’s capsids is supported
by data across mice and multiple NHP models, as well as binding to
ALPL, a highly conserved cell surface receptor expressed at the BBB
that mediates enhanced brain tropism of Voyager’s capsids in
multiple species and in human cells.
Advancements in Wholly-Owned CNS Gene Therapy
ProgramsIntravenous administration of BBB-penetrant,
MAPT-Silencing, AAV gene therapy provides broad and robust CNS Tau
lowering in tauopathy mouse models (#1602)
- A single IV administration of a tau silencing gene therapy
candidate in a mouse model expressing human tau resulted in
dose-dependent increases in vector genomes and concomitant
reductions in tau mRNA levels of up to 90%, which were associated
with significant reductions (50-70%) in human tau protein levels
across the brain.
- Voyager anticipates filing an investigational new drug (IND)
application in this program in 2026.
Intravenous delivery of AAV gene therapy for the treatment of
SOD1-ALS provides broad SOD1 lowering in NHP (#1647)
- A potent SOD1 RNAi transgene packaged in a novel
TRACER™-evolved capsid and administered IV in NHPs led to a
favorable safety profile and significant reductions of SOD1 mRNA in
critical spinal cord and brain regions impacted in ALS, supporting
continued development and advancement into clinical testing.
- Voyager anticipates filing an IND application in this program
in mid-2025.
Mechanism of Action and Cross-Species
TranslationIdentification and characterization of a highly
conserved cell surface receptor utilized by engineered
BBB-penetrant AAV capsids with enhanced brain tropism in non-human
primates and mice (#975)
- Voyager identified a highly conserved cell surface receptor
that mediates enhanced brain tropism of the VCAP-101/102 engineered
capsid class. The discovery of a conserved cross-species receptor
facilitating BBB passage by a novel engineered AAV capsid class
represents a significant step forward in the development of
targeted CNS therapeutics and provides a foundation for the
rational design of next-generation AAV vectors.
Establishment of a predictive transcytosis model to recapitulate
capsid-receptor interaction and phenotype of BBB-penetrant AAV
variants (#976)
- To further characterize the mechanism underlying VCAP-102’s
enhanced brain tropism, Voyager developed a transcytosis model
expressing the VCAP-102 receptor in cultured cells and demonstrated
that VCAP-102 and second-generation capsids, but not the AAV9
capsid, exhibited efficient transcytosis.
Evaluation of cross-species expression across four species and
cellular tropism of VCAP-102, an engineered blood-brain
barrier-penetrating AAV derived capsid from TRACER Platform screens
(#1452)
- Across mice, marmosets, African Green Monkeys, and Cynomolgus
macaques, VCAP-102 demonstrated higher biodistribution and
widespread transgene expression in the CNS compared to AAV9,
supporting potential translatability into humans.
High-resolution quantitative analysis of multiple AAV capsids in
rodent and primate models using multiplexed reporter protein
tagging platform (#511)
- To solve the bottleneck in capsid variant characterization,
Voyager designed and optimized a cross-species platform to
simultaneously analyze up to 10 capsids in a single animal, while
providing transgene DNA and RNA quantitation and protein
detection.
Reduced Immunogenicity, Developability, and
ManufacturingDiscovery of TRACER AAV capsids escaping
pre-existing neutralizing antibodies (#973)
- A new generation of AAV capsids was bioengineered via the
TRACER™ platform to evade pre-existing neutralizing antibodies
while retaining improved CNS tropism, potentially increasing
patient eligibility to receive AAV gene therapies.
Oral Presentation: Developability assessment of novel AAV
capsids and payloads at early preclinical stage to enable
development of AAV gene therapies (#65)
- Developability refers to the likelihood that an AAV development
candidate can be advanced towards the clinic as a manufacturable,
safe, and efficacious drug. This study outlines analytical methods
that can be utilized early in assessing critical quality attributes
and may help enable efficient development of AAV gene
therapies.
Machine Learning for AAV production-fitness modeling (#974)
- Voyager has advanced machine learning to predict production
fitness of capsid variants with high accuracy, helping guide
development of high-production-fit libraries.
Comparing CsCl density gradient ultracentrifugation and anion
exchange chromatography for the enrichment of full adeno-associated
viral (AAV) vectors (#1037)
- Robust manufacturing processes are needed to remove empty and
partially filled capsids from recombinant AAV (rAAV) drug product.
This study compares performance of ultracentrifugation and
chromatographic separation methods.
Development of HEK293 cell line for optimal production of novel
capsids with enhanced brain tropism (#1035)
- Voyager has internally developed an HEK293 cell line
(VYGR-293). This cost-efficient cell line provides an AAV
expression platform to produce drug candidates for neurological
disorders.
About the TRACER™ Capsid Discovery
PlatformVoyager’s TRACER™ (Tropism Redirection of AAV by
Cell-type-specific Expression of RNA) capsid discovery platform is
a broadly applicable, RNA-based screening platform that enables
rapid discovery of novel AAV capsids to enable gene therapy.
Voyager has leveraged TRACER to create multiple families of novel
capsids that, following intravenous delivery in preclinical
studies, harness the extensive vasculature of the central nervous
system (CNS) to cross the blood-brain barrier and transduce a broad
range of CNS regions and cell types. In cross-species preclinical
studies (rodents and multiple non-human primate species),
intravenous delivery of TRACER-generated capsids resulted in
widespread payload expression across the CNS at relatively low
doses, enabling selection of multiple development candidates in
Voyager’s wholly-owned and partnered gene therapy programs for
neurologic diseases.
About Voyager TherapeuticsVoyager Therapeutics,
Inc. (Nasdaq: VYGR) is a biotechnology company dedicated to
leveraging the power of human genetics to modify the course of –
and ultimately cure – neurological diseases. Our pipeline includes
programs for Alzheimer’s disease, amyotrophic lateral sclerosis
(ALS), Parkinson’s disease, and multiple other diseases of the
central nervous system. Many of our programs are derived from our
TRACER™ AAV capsid discovery platform, which we have used to
generate novel capsids and identify associated receptors to
potentially enable high brain penetration with genetic medicines
following intravenous dosing. Some of our programs are wholly
owned, and some are advancing with partners including Alexion,
AstraZeneca Rare Disease; Novartis Pharma AG; Neurocrine
Biosciences, Inc.; and Sangamo Therapeutics, Inc. For more
information, visit www.voyagertherapeutics.com.
Voyager Therapeutics® is a registered trademark, and TRACER™ is
a trademark, of Voyager Therapeutics, Inc.
Forward-Looking StatementsThis 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 “potential,” “anticipate,” “expect,” “believe,” “could,”
“may,” and other similar expressions are intended to identify
forward-looking statements.
For example, all statements Voyager makes regarding Voyager’s
ability to advance its AAV-based gene therapy programs, including
expectations for Voyager’s achievement of preclinical and clinical
development milestones for its potential development candidates
such as the initiation of clinical trials; Voyager’s ability to
advance gene therapy product candidates under its partnered
programs; the potential for Voyager’s novel TRACER capsids to
achieve desired results in humans, including achievement of a
higher therapeutic index and increased patient eligibility to
receive AAV gene therapies; and the ability of Voyager’s analytical
methods to enable efficient development of AAV gene therapies are
forward looking.
All forward-looking statements are based on estimates and
assumptions by Voyager’s management that, although Voyager believes
such forward-looking statements 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, the continued development of Voyager’s
technology platforms, including Voyager’s TRACER platform and its
antibody screening technology; the ability to initiate and conduct
preclinical studies in animal models; the development by third
parties of capsid identification platforms that may be competitive
to Voyager’s TRACER capsid discovery platform; Voyager’s ability to
create and protect intellectual property rights associated with the
TRACER capsid discovery platform, the capsids identified by the
platform, and development candidates for Voyager’s pipeline
programs; the initiation, timing, conduct and outcomes of Voyager’s
preclinical and clinical studies; the possibility or the timing of
Voyager’s receipt of program reimbursement, development or
commercialization milestones, option exercise, and other payments
under Voyager’s existing licensing or collaboration agreements; the
ability of Voyager to negotiate and complete licensing or
collaboration agreements with other parties on terms acceptable to
Voyager and the third parties; the ability to attract and retain
talented directors, employees, and contractors; and the sufficiency
of cash resources to fund its operations and pursue its corporate
objectives.
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. All information in the press release is as of the date
of this press release, and any forward-looking statement speaks
only as of the date on which it was made. Voyager undertakes no
obligation to publicly update or revise this information or any
forward-looking statement, whether as a result of new information,
future events or otherwise, except as required by law.
ContactsTrista Morrison, NACD.DC,
tmorrison@vygr.com Investors: Adam Bero, Ph.D., abero@kendallir.com
Media: Brooke Shenkin, brooke@scientpr.com
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