Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic
medicines company committed to delivering life-changing treatments
for people battling devastating diseases, today announced data from
the Phase 1b/2a PRECISION-HD2 and PRECISION-HD1 trials evaluating
investigational treatments WVE-120102 and WVE-120101, respectively,
in Huntington’s disease (HD).
In the PRECISION-HD2 core trial, results from all participants
(n=88) showed no statistically significant change in mutant
huntingtin protein (mHTT) versus placebo after single or multiple
doses of WVE-120102 up to and including 32 mg monthly. There was no
evidence of a dose response across the dose levels tested.
In the PRECISION-HD2 open label extension (OLE) trial, results
from all participants (n=28) showed modest reductions in mHTT after
a mean of 8.1 monthly doses (range: 1-17), but effects were
inconsistent over the course of the trial. While there was a
correlation between WVE-120102 cerebrospinal fluid (CSF)
concentrations and mHTT lowering, pharmacokinetic (PK) modeling
suggests that additional dose escalation is unlikely to achieve
drug concentrations needed for robust mHTT knockdown. Given the
lack of consistent and significant reductions in mHTT and the PK
modeling projections, Wave will stop clinical development of
WVE-120102. Trial participants will have a final follow-up visit
but receive no further doses.
Results in all participants through 16 mg (n=51) from the
PRECISION-HD1 core trial are similar to those in PRECISION-HD2 at
those dose levels. Given these and results from Wave’s previous
clinical trials, as well as current understanding of the
limitations of the company’s first-generation candidates, Wave will
also stop clinical development of WVE-120101. Dosing in the 32 mg
cohort of the PRECISION-HD1 core trial is complete, and core and
OLE trial participants will have a final follow-up visit but
receive no further doses. Wave expects to complete analysis of the
32 mg cohort in the second quarter of 2021.
“We are disappointed not to have better news to share with the
HD community and would like to extend our gratitude to the trial
participants and their families for their commitment to these
programs,” said Michael Panzara, MD, MPH, Chief Medical Officer and
Head of Therapeutics Discovery and Development at Wave Life
Sciences. “However, we have learned an enormous amount from
these trials and are encouraged by data that suggest our SNP
targeting approach may achieve allele-selectivity. We look forward
to continuing our collaboration with our research partners to
advance our first HD clinical candidate that incorporates our
next-generation PN backbone chemistry, WVE-003, and remain
committed to the science of HD and, in particular, selective mutant
huntingtin lowering.”
WVE-003 is an investigational drug designed to selectively lower
mHTT by targeting a specific single nucleotide polymorphism (SNP3)
that is commonly found on the expanded CAG allele. This
allele-selective approach is guided by the recognition that, in
addition to a gain of function of mHTT, people with HD have lost
one copy of the wild-type HTT allele, leaving them with a smaller
protective reservoir of healthy, wild-type HTT protein (wtHTT) than
unaffected individuals. A growing body of scientific evidence
suggests that preserving as much of this essential protein as
possible is important for favorable health outcomes.
Wave expects to initiate dosing in a Phase 1b/2a clinical trial
for WVE-003 in 2021. As people with HD can carry multiple SNPs,
participants from the PRECISON-HD trials will be offered the
opportunity to undergo screening for potential enrollment in the
WVE-003 trial. It is estimated that approximately 40% of adults
with HD carry SNP3 in association with the HD mutation.
“Everyone at Wave wishes our PRECISION-HD programs had yielded
different results, but we believe our WVE-003 program will enable
us to address deficiencies with our first-generation candidates
while maintaining our commitment to developing wild-type sparing
therapies for HD,” said Paul Bolno, MD, MBA, President and Chief
Executive Officer of Wave Life Sciences. “Our next generation of
investigational clinical candidates, which also includes WVE-004
for amyotrophic lateral sclerosis and frontotemporal dementia and
WVE-N531 for Duchenne, as well as our current preclinical and
discovery programs, all use novel PN chemistry, which has been
shown to increase potency, exposure, and durability across our
silencing, splicing, and editing modalities in preclinical studies.
Our clinical candidates have also been optimized with
pharmacodynamic and pharmacokinetic insights from in vivo models,
which were not available for our first-generation compounds. For
example, we selected WVE-003 as our next HD candidate after years
of optimization and demonstrated target engagement in vivo.
Moreover, we are implementing innovative, adaptive designs across
our new clinical programs to speed development and help us make
data-driven decisions more quickly. These collective advances and
learnings will improve our ability to deliver transformative
genetic medicines.”
Additional Results from the PRECISION-HD
Trials
mHTT Assessments
- PRECISION-HD2 core trial participants who received three or
four 32 mg doses of WVE-120102 had a non-statistically significant
median reduction of 9.9% in mHTT in the CSF (p=0.74) as compared to
a pooled placebo group who had a median decrease in mHTT of
0.8%.
- PRECISION-HD1 core trial participants who received three or
four 16 mg doses of WVE-120101 had a non-statistically significant
median reduction of 11.6% in mHTT in the CSF (p=0.56) as compared
to a pooled placebo group who had a median decrease in mHTT of
10.0%.
wtHTT and Neurofilament Light Chain (NfL) Assessments
- Observations from PRECISION-HD2 OLE participants with >20%
reduction in mHTT were used to determine whether wtHTT was
similarly affected by treatment. There was no correlation between
mHTT reduction and wtHTT change, suggesting allele-selectivity.
- This analysis was not performed for the PRECISION-HD2 or the
PRECISION-HD1 core trials given insufficient mHTT reduction.
- In the PRECISION-HD trials (core and OLE), there were no
changes in CSF NfL over time. NfL is a protein component of the
neuronal cytoskeleton, which has been shown to increase in the CSF
with disease severity in HD.
- In the PRECISION-HD trials (core and OLE), there was no
worsening of disease progression in treated participants versus
progression expected based upon natural history studies.
Safety and TolerabilityOverall, adverse events (AEs) were
balanced across treatment groups in the PRECISION-HD2 core trial
(83% of WVE-120102-treated participants versus 90% on placebo) and
most events were mild to moderate in intensity. The most common AEs
(those occurring in at least 10% of participants receiving
WVE-120102) were headache, procedural pain, back pain, falls, viral
upper respiratory tract infection, dizziness, and post-lumbar
puncture syndrome. There was an increase in serious adverse events
(SAEs) in the 32 mg group as compared to lower doses. Seven of 13
participants in the 32 mg group were reported with an SAE related
to treatment and six participants discontinued treatment due to an
AE. SAEs were transient and included disorientation, delirium,
ataxia, slurred speech, amnesia, meningitis, fever, and
vertigo.
Adverse events were similar in the PRECISION-HD2 OLE to those
that occurred in the core trial. Thirty-six participants reported
with an event over 327 person/months of exposure. The incidence of
SAEs related to treatment with 32 mg WVE-120102 was lower than in
the core trial. Three participants discontinued treatment due to
AEs (two receiving 16 mg, one receiving 32 mg).
In the PRECISION-HD1 core trial, 91% of participants who
received up to 16 mg of WVE-120101 were reported with an AE
compared with 75% who received placebo, most of which were mild to
moderate in intensity. The most common AEs were headache,
procedural pain, dizziness, back pain, falls and viral upper
respiratory infection. There were no participants with SAEs related
to WVE-120101 up through 16 mg. Two participants discontinued
treatment due to AEs, one participant each in the 2 mg and 4 mg
groups.
Adverse events were similar in the PRECISION-HD1 OLE as in the
core trial, with 25 participants experiencing an event over 95
person/months of exposure. There were no discontinuations due to
AEs. One participant experienced a related SAE of gait
disturbance.
Across both PRECISION-HD programs (core and OLE), there were no
clinically meaningful trends in clinical laboratory values
including no CSF white blood cell and protein elevations.
WVE-003 Targeting SNP3 in HD To Begin Dosing in
2021Site activation and enrollment in the Phase 1b/2a
clinical trial of WVE-003 for adults with HD that carry SNP3 are
currently underway and Wave expects to begin dosing in 2021.
Preclinical models that have established pharmacologic activity
have informed the starting dose for this trial. Additionally, Wave
will incorporate an adaptive design, intended to support
data-driven decisions regarding dosing and to potentially
accelerate time to proof-of-concept.
In preclinical studies, WVE-003 showed dose-dependent and
selective reduction of mHTT mRNA in vitro, and potent and durable
knockdown of mHTT mRNA and protein in vivo. Based on the modeling
of the pharmacokinetic-pharmacodynamic (PK-PD) relationship for
WVE-003, the model predicts that WVE-003 will attain sufficient
concentrations to engage mHTT transcript in both the cortex and
striatum and decrease expression of mHTT protein.
Additional Clinical Trials Initiating in 2021
Wave also expects to initiate dosing in two other clinical trials
this year, which will assess target engagement, impact on key
disease biomarkers, and initial safety of WVE-004 (targeting
C9orf72) for amyotrophic lateral sclerosis (ALS) and frontotemporal
dementia (FTD) and WVE-N531 (targeting exon 53) for Duchenne
muscular dystrophy (DMD). Wave submitted a clinical trial
application (CTA) for WVE-N531 in March 2021. These clinical
candidates also utilize PN backbone chemistry modifications and
have been optimized based on the evolution of Wave’s
PRISM™ discovery and drug development platform.
Cash GuidanceWave expects that its existing
cash and cash equivalents, together with expected and committed
cash from its existing collaboration, will enable the company to
fund its operating and capital expenditure requirements into the
second quarter of 2023.
Investor Conference Call and WebcastWave
management will host an investor conference call today at 4:30 p.m.
ET to discuss these results and provide a business update. The
conference call may be accessed by dialing (866) 220-8068 for
participants based in the United States, or +1 (470) 495-9153 for
participants based outside the United States, and entering
conference ID 9608737. The live webcast may be accessed by visiting
the investor relations section of the Wave Life Sciences corporate
website at www.ir.wavelifesciences.com. Following the webcast, a
replay will be available on the website.
About the PRECISION-HD Clinical
TrialsPRECISION-HD1 and PRECISION-HD2 were Phase 1b/2a
multicenter, randomized, double-blind, placebo-controlled trials,
which evaluated the safety, tolerability, pharmacokinetics, and
pharmacodynamics of single and multiple doses of WVE-120101 and
WVE-120102 in adults with early manifest HD who carried a targeted
single nucleotide polymorphism (SNP) rs362307 (SNP1) and rs362331
(SNP2), respectively. The trials included both single and
multi-dose portions where participants were randomized to either
active drug or placebo, with five cohorts in the multi-dose
portion, ranging from 2-32 mg dosed intrathecally every four weeks.
Upon completing the core trials, eligible participants were
transitioned to OLE trials and dose escalated to the highest doses
tested. The primary objective of both the core and OLE trials was
to evaluate safety and tolerability, and secondary objectives
included evaluation of PK and PD to assess plasma concentration and
disease biomarkers (respectively).
About Huntington’s Disease Huntington’s disease
(HD) is a debilitating and ultimately fatal autosomal dominant
neurological disorder, characterized by cognitive decline,
psychiatric illness, and chorea. HD causes nerve cells in the brain
to deteriorate over time, affecting thinking ability, emotions, and
movement. HD is caused by an expanded cytosine-adenine-guanine
(CAG) triplet repeat in the huntingtin (HTT) gene that results in
production of mutant HTT protein (mHTT). Accumulation of mHTT
causes progressive loss of neurons in the brain. Wild-type, or
healthy, HTT protein (wtHTT) is critical for neuronal function and
suppression may have detrimental long-term consequences.
Approximately 30,000 people in the United States have symptomatic
HD and more than 200,000 others are at risk for inheriting the
disease. There are currently no approved disease-modifying
therapies available. Wave’s allele-selective approach may also
enable treatment in the premanifest setting, before onset of
clinical disease.
About PRISM™PRISM is Wave Life Sciences’
proprietary discovery and drug development platform that enables
genetically defined diseases to be targeted with stereopure
oligonucleotides across multiple therapeutic modalities, including
silencing, splicing, and editing. PRISM combines the company’s
unique ability to construct stereopure oligonucleotides with a deep
understanding of how the interplay among oligonucleotide sequence,
chemistry, and backbone stereochemistry impacts key pharmacological
properties. By exploring these interactions through iterative
analysis of in vitro and in vivo outcomes and machine
learning-driven predictive modeling, the company continues to
define design principles that are deployed across programs to
rapidly develop and manufacture clinical candidates that meet
pre-defined product profiles.
About Wave Life Sciences Wave Life Sciences
(Nasdaq: WVE) is a clinical-stage genetic medicines company
committed to delivering life-changing treatments for people
battling devastating diseases. Wave aspires to develop
best-in-class medicines across multiple therapeutic modalities
using PRISM, the company’s proprietary discovery and drug
development platform that enables the precise design, optimization,
and production of stereopure oligonucleotides. Driven by a resolute
sense of urgency, the Wave team is targeting a broad range of
genetically defined diseases so that patients and families may
realize a brighter future. To find out more, please visit
www.wavelifesciences.com and follow Wave on Twitter
@WaveLifeSci.
Forward-Looking StatementsThis press release
contains forward-looking statements concerning our goals, beliefs,
expectations, strategies, objectives and plans, and other
statements that are not necessarily based on historical facts,
including statements regarding the following, among others: our
commitment to developing wild-type sparing therapies for people
living with HD; our plans to stop clinical development of
WVE-120102 and WVE-120101 following the results received from our
PRECISION-HD trials; our encouragement by PRECISION-HD trial data
that suggest our SNP targeting approach may achieve
allele-selectivity; the anticipated benefits of our
allele-selective approach to lowering mutant huntingtin while
sparing wild-type huntingtin; our understanding of the growing body
of scientific evidence suggesting that preserving as much wild-type
huntingtin protein as possible is important for favorable health
outcomes; our plans to advance development of and begin dosing in
2021 for WVE-003, our first HD clinical candidate that incorporates
our next-generation PN backbone chemistry modifications; our belief
that additional preclinical modeling for and optimization of
WVE-003 and our plans to use adaptive clinical trial designs to
support data-driven decisions regarding dosing may assist in
potentially accelerating time to proof-of-concept; our expectations
regarding dosing for two other PN-containing clinical candidates,
including WVE-004 for ALS and FTD and WVE-N531 targeting exon 53
for DMD; our ability to deliver on the promise of our current and
future pipeline; the future performance and results of our programs
in clinical trials and in preclinical development; the potential
benefits of PRISM and our stereopure oligonucleotides compared with
stereorandom oligonucleotides; the benefit of nucleic acid
therapeutics generally; and the anticipated duration of our cash
runway. Actual results may differ materially from those indicated
by these forward-looking statements as a result of various
important factors, including the following: our ability to finance
our drug discovery and development efforts and to raise additional
capital when needed; the ability of our preclinical programs to
produce data sufficient to support our clinical trial applications
and the timing thereof; our ability to maintain the company
infrastructure and personnel needed to achieve our goals; the
clinical results of our programs, which may not support further
development of product candidates; actions of regulatory agencies,
which may affect the initiation, timing and progress of clinical
trials; our effectiveness in managing future clinical trials and
regulatory interactions; the effectiveness of PRISM and our next
generation therapeutic candidates, including our novel PN backbone
chemistry modifications; the effectiveness of our novel
ADAR-mediated RNA editing platform capability; the continued
development and acceptance of oligonucleotides as a class of
medicines; our ability to demonstrate the therapeutic benefits of
our candidates in clinical trials, including our ability to develop
candidates across multiple therapeutic modalities; our dependence
on third parties, including contract research organizations,
contract manufacturing organizations, collaborators and partners;
our ability to manufacture or contract with third parties to
manufacture drug material to support our programs and growth; our
ability to obtain, maintain and protect our intellectual property;
our ability to enforce our patents against infringers and defend
our patent portfolio against challenges from third parties;
competition from others developing therapies for similar
indications; the severity and duration of the COVID-19 pandemic and
its negative impact on the conduct of, and the timing of
enrollment, completion and reporting with respect to, our clinical
trials; and any other impacts on our business as a result of or
related to the COVID-19 pandemic, as well as the information under
the caption “Risk Factors” contained in our most recent Annual
Report on Form 10-K filed with the Securities and Exchange
Commission (SEC) and in other filings we make with the SEC from
time to time. We undertake no obligation to update the information
contained in this press release to reflect subsequently occurring
events or circumstances.
Investor Contact:Kate
Rausch617-949-4827krausch@wavelifesci.com
Media Contact:Alicia
Suter617-949-4817asuter@wavelifesci.com
Patient Advocacy Contact:Jeff Smith
617-949-4773jsmith@wavelifesci.com
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