Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage
biotechnology company focused on unlocking the broad potential of
RNA medicines to transform human health, today announced positive
results from its Phase 1b/2a SELECT-HD clinical trial of WVE-003,
which is being developed as a potential disease modifying
therapeutic for Huntington’s disease (HD). WVE-003 is a
first-in-class, allele-selective antisense oligonucleotide (ASO)
designed to lower mutant huntingtin (mHTT) protein and preserve
healthy, wild-type huntingtin (wtHTT) protein.
In the multidose portion of the SELECT-HD study
(n=23), participants received either every-eight-week (Q8W)
intrathecal doses of 30 mg WVE-003 (n=16) or placebo (n=7), with 12
weeks of follow up (total study period of 28 weeks). Key results
are as follows:
- WVE-003 was generally safe and well-tolerated, with no Serious
Adverse Events (SAEs) reported; ventricular volume was in line with
natural history.
- Significant mHTT protein lowering was observed throughout the
28-week assessment period.
- At 24 weeks (8 weeks after last dose), mean mHTT lowering in
cerebrospinal fluid (CSF) was 46% versus placebo (p=0.0007).
- At 28 weeks (12 weeks after last dose), mean mHTT lowering in
CSF was 44% versus placebo (p=0.0002), which supports quarterly or
less frequent dosing.
- wtHTT protein was preserved throughout the 28-week assessment
period, validating allele-selective silencing. Additionally,
statistically significant increases were observed in wtHTT protein
versus placebo.
- wtHTT protein supports the health and function of neurons and
is crucial for CSF flow in the ventricles. mHTT also has a
detrimental effect on wtHTT at the protein level, which further
decreases wtHTT’s function. Only selective lowering of mHTT has
potential to relieve its negative impact on wtHTT protein
function.
- Most WVE-003-treated participants had neurofilament light
protein (NfL) levels that were in the range of placebo or had NfL
levels that increased and returned to the range of placebo.
- At 24 weeks (the last MRI assessment), mHTT reduction was
correlated with slowing of caudate atrophy (R=-0.50; p=0.047).
Caudate atrophy is an imaging biomarker that is predictive of
clinical outcomes, including clinically meaningful worsening of
Total Motor Score (TMS).
- While not powered for clinical outcomes, a slowing of decline
was observed for TMS for WVE-003 versus placebo (4.25 mean
difference at 24 weeks, p=not significant).
“We are very proud to have demonstrated mHTT
lowering of 46%, with preservation of wtHTT, and are encouraged to
see these reductions in mHTT significantly correlating with a
slowing in caudate atrophy after just 28 weeks. These results
represent a significant achievement for Wave, for the
oligonucleotide field, and most importantly, for the HD community,”
said Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, Chief
Development Officer at Wave Life Sciences. “Alongside the HD
community, we have been working diligently to establish caudate
volume as a biomarker for clinical development due to its
association with clinical outcomes. We believe these strong data
compel a case for accelerated approval for WVE-003, which we plan
to discuss with regulators. We would like to express our immense
gratitude to the HD community, the study participants, their
families, and study site staff for their trust, support, and
engagement that have helped us reach this important milestone.”
“Wild-type huntingtin plays such a critical role in
the central nervous system, and it’s very exciting to finally have
an opportunity to evaluate mHTT lowering in the context of
allele-selectivity and to see positive signals emerging,” said Ralf
Reilmann, MD, founder of the George-Huntington Institute, Muenster,
Germany, as well as the Primary Investigator and member of the
Advisory Committee for SELECT-HD. “Additionally, these data have
arrived at an opportune time when the HD community is coalescing
around rapid, efficient registrational trial design utilizing
sensitive clinical endpoints to detect early treatment effects, and
Wave is well positioned to take advantage of this momentum with
WVE-003. These data provide hope and a compelling path forward as
the community continues to drive toward a long-awaited therapy to
treat this devastating disease.”
HD is a debilitating and ultimately fatal autosomal
dominant neurological disorder. The HD population is significant –
in the United States alone, approximately 30,000 people have
clinical symptoms of HD and more than 200,000 are at risk of
inheriting HD. WVE-003 is expected to address approximately 40% of
individuals with HD, and up to 80% of HD may be addressed in the
future with other SNP-targeted candidates.
“With these results, we have delivered the
first-ever clinical demonstration of allele-selective silencing in
any disease target. This was only possible due to the specificity,
potency and durability enabled through our PRISM platform and it is
validating of more than 10 years of chemistry innovation pioneered
at Wave, including PN chemistry and stereochemistry,” said Paul
Bolno, MD, MBA, President and Chief Executive Officer at Wave Life
Sciences. “The translation of genetic insights and preclinical data
in the clinic is also highly encouraging and reinforces the broader
value of our pipeline. We are looking forward to our Duchenne
muscular dystrophy and Alpha-1 antitrypsin deficiency data this
year, the continued advancement of our INHBE program for obesity,
and new targets to be shared at R&D Day this Fall, which
together will open up a substantial total addressable market for
Wave. We are at a very exciting point in Wave’s history as we
advance our mission to unlock the broad potential of RNA
medicines.”
Cash RunwayWave continues to
expect that its current cash and cash equivalents will be
sufficient to fund operations into the fourth quarter of 2025.
Investor Conference Call and
WebcastWave will host an investor conference call today
at 8:30 a.m. ET to review the SELECT-HD clinical trial
results. A webcast of the conference call can be accessed by
visiting “Investor Events” on the investor relations section of
the Wave Life Sciences website:
https://ir.wavelifesciences.com/events-publications/events.
Analysts planning to participate during the Q&A portion of the
live call can join the conference call at the audio-conferencing
link available here. Once registered, participants will receive the
dial-in information. Following the live event, an archived version
of the webcast will be available on the Wave Life
Sciences website.
About SELECT-HDThe SELECT-HD trial
(NCT05032196) was a global, multicenter, randomized, double-blind,
placebo-controlled Phase 1b/2a clinical trial to assess the safety
and tolerability of single- and multiple-ascending intrathecal
doses of WVE-003 in people with a confirmed diagnosis of HD who are
in the early stages of the disease and carry SNP3 in association
with their cytosine-adenine-guanine (CAG) expansion. Additional
objectives include assessing pharmacokinetics and exploratory
pharmacodynamic and clinical endpoints.
About WVE-003 WVE-003 is a
first-in-class, allele-selective antisense oligonucleotide that
selectively lowers mutant huntingtin (mHTT) protein by targeting a
single nucleotide polymorphism (SNP3) located on the mHTT messenger
RNA that is not present on the wild-type huntingtin (wtHTT) mRNA.
Wave’s approach to Huntington’s disease (HD) is guided by the
recognition that, in addition to a gain of function of the mHTT
protein, people with HD have lost one copy of the healthy wtHTT
allele, leaving them with a smaller protective reservoir of wtHTT
protein than unaffected individuals. wtHTT protein is critical for
neuronal function, and suppression may have detrimental long-term
consequences. For more information, please refer to Wave’s
published manuscript of WVE-003 preclinical data here.
About Huntington’s
DiseaseHuntington’s disease (HD) is a debilitating and
ultimately fatal autosomal dominant neurological disorder, which is
passed down from generation to generation within affected families.
The symptoms of HD have been compared to having Alzheimer’s
disease, Amyotrophic lateral sclerosis, and Parkinson’s disease all
at once. HD is caused by an expanded cytosine-adenine-guanine (CAG)
triplet repeat in the huntingtin (HTT) gene that results in
production of mutant HTT (mHTT) protein. Accumulation of mHTT
causes progressive loss of neurons in the brain, affecting thinking
ability, emotions, and movement. Clinical symptom onset typically
occurs during adulthood, between the ages of 30 and 50. It is
characterized by cognitive decline, psychiatric illness, and
chorea, and patients ultimately succumb to pneumonia, heart failure
or other complications. There are no disease modifying treatments
for HD.
About Wave Life SciencesWave
Life Sciences (Nasdaq: WVE) is a biotechnology company focused on
unlocking the broad potential of RNA medicines to transform human
health. Wave’s RNA medicines platform, PRISM®, combines multiple
modalities, chemistry innovation and deep insights in human
genetics to deliver scientific breakthroughs that treat both rare
and prevalent disorders. Its toolkit of RNA-targeting modalities
includes editing, splicing, RNA interference and antisense
silencing, providing Wave with unmatched capabilities for designing
and sustainably delivering candidates that optimally address
disease biology. Wave’s diversified pipeline includes clinical
programs in Duchenne muscular dystrophy, Alpha-1 antitrypsin
deficiency and Huntington’s disease, as well as a preclinical
program in obesity. Driven by the calling to “Reimagine Possible”,
Wave is leading the charge toward a world in which human potential
is no longer hindered by the burden of disease. Wave is
headquartered in Cambridge, MA. For more information on Wave’s
science, pipeline and people, please visit www.wavelifesciences.com
and follow Wave on X (formerly Twitter) and LinkedIn.
Forward-Looking Statements This
press release contains forward-looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995, as
amended, including, without limitation, our beliefs as to what our
WVE-003 data evidencing allele-selective mutant huntingtin lowering
portend for our ability to deliver meaningful disease modifying
therapies for people living with HD and their families; our
understandings of the potential clinical efficacy of WVE-003,
evidenced by correlations in exploratory pharmacodynamic and
clinical endpoints and slowing of caudate atrophy, and our plans to
engage regulators on a clinical development path that would support
potential accelerated approval for WVE-003; our estimates of the HD
patient population that would benefit from WVE-003 and other
potential future SNP-targeted therapies; the potential benefits of
our RNA medicines platform, PRISM, including PN chemistry, and
pipeline; the benefits of RNA medicines generally for both rare and
common diseases; our expectations and timing to deliver 6-month
dystrophin data for WVE-N531 in DMD; our expectations and
anticipated timing for delivering proof-of-mechanism clinical data
in AATD patients treated with WVE-006; our expectations and
anticipated timing to initiate a clinical trial for its INHBE
GalNAc siRNA (WVE-007) for obesity; and our expectations on timing
for announcing new targets at our R&D Day this Fall. The words
“may,” “will,” “could,” “would,” “should,” “expect,” “plan,”
“anticipate,” “intend,” “believe,” “estimate,” “predict,”
“project,” “potential,” “continue,” “target” and similar
expressions are intended to identify forward-looking statements,
although not all forward-looking statements contain these
identifying words. Any forward-looking statements in this press
release are based on management's current expectations and beliefs
and are subject to a number of risks, uncertainties and important
factors that may cause actual events or results to differ
materially from those expressed or implied by any forward-looking
statements contained in this press release and actual results may
differ materially from those indicated by these forward-looking
statements as a result of these risks, uncertainties and important
factors, including, without limitation, the risks and uncertainties
described in the section entitled “Risk Factors” in Wave’s most
recent Annual Report on Form 10-K filed with the Securities and
Exchange Commission (SEC), as amended, and in other filings Wave
makes with the SEC from time to time. Wave undertakes no obligation
to update the information contained in this press release to
reflect subsequently occurring events or circumstances.
Investor Contact:Kate Rausch+1
617-949-4827krausch@wavelifesci.com
Media Contact:Alicia Suter+1
617-949-4817asuter@wavelifesci.com
HD Community Contact:Chelley
Casey+1 774-276-8738ccasey@wavelifesci.com
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