– At 9 Months, Vutrisiran Met Primary and All
Secondary Endpoints, with Statistically Significant Improvements in
Neuropathy, Quality of Life (QoL), and Gait Speed, Relative to
Placebo –
– In Majority of Patients, Vutrisiran Showed
Reversal of Polyneuropathy Manifestations with Improvements in
Neuropathy and QoL, Relative to Baseline –
– Vutrisiran Also Met Key Exploratory Endpoints
Including Measures of Nutritional Status, Overall Disability, and
Cardiac Biomarker (NT-proBNP), Relative to Placebo –
– Vutrisiran Demonstrated Encouraging Safety
and Tolerability Profile –
– In Addition, Alnylam Submits New Drug
Application (NDA) with U.S. Food and Drug Administration (FDA) for
Vutrisiran for the Treatment of the Polyneuropathy of Hereditary
ATTR (hATTR) Amyloidosis in Adults –
– Company to Host Conference Call Today at 4:00
pm ET –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced full positive results from
the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi
therapeutic in development for the treatment of
transthyretin-mediated (ATTR) amyloidosis, which met its primary
and both secondary endpoints at nine months in patients with
hereditary ATTR (hATTR) amyloidosis with polyneuropathy. The
results were presented today in an oral session at the 2021
American Academy of Neurology (AAN) Virtual Annual Meeting.
The 9-month results achieved the study’s primary endpoint, with
vutrisiran showing improvement in the mean change from baseline in
the modified Neuropathy Impairment Score (mNIS+7) as compared to
external placebo data from the APOLLO Phase 3 study of patisiran.
At 9 months vutrisiran also met all secondary endpoints,
demonstrating improvement in quality of life as assessed by the
Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk
QoL-DN) instrument and improvement in gait speed as assessed by the
timed 10-meter walk test (10-MWT), both compared to the external
placebo group. The majority of patients experienced improvement in
neuropathy and in quality of life, both relative to baseline,
showing the potential for vutrisiran to reverse polyneuropathy
manifestations of hATTR amyloidosis. Vutrisiran also demonstrated
an encouraging safety profile with no drug-related discontinuations
or deaths. Based on these positive data, Alnylam has submitted a
New Drug Application (NDA) with the U.S. Food and Drug
Administration (FDA) for the approval of vutrisiran for the
treatment of the polyneuropathy of hATTR amyloidosis in adults.
“The HELIOS-A study results demonstrate that vutrisiran improves
neuropathy, quality of life and gait speed as soon as 9 months –
compared to the external placebo arm of APOLLO – in patients with
hATTR amyloidosis with polyneuropathy, with an encouraging safety
and tolerability profile. The reversal of polyneuropathy
manifestations of disease demonstrated in patients treated with
vutrisiran in the study, the encouraging safety profile, and the
totality of data from the trial, reinforce our belief in the
promise of our RNAi therapeutics’ mechanism of action, as first
established with ONPATTRO® (patisiran). Further, we are encouraged
by the exploratory endpoint results showing the impact of
vutrisiran on NT-proBNP, a marker of cardiac stress, and look
forward to additional data on exploratory cardiac endpoints at the
18-month readout, expected in late 2021,” said Akshay Vaishnaw,
M.D., Ph.D., President of R&D at Alnylam. “With our NDA filing
now completed, we look forward to potentially bringing vutrisiran
to patients as a new treatment option for the polyneuropathy of
hATTR amyloidosis with subcutaneous administration and quarterly
dosing. The positive HELIOS-A study and our NDA filing are key
milestones as we continue our progress towards building an
industry-leading franchise of medicines for the treatment of ATTR
amyloidosis and towards our goal of expanding in the future the
population of patients who may benefit from treatment with an RNAi
therapeutic.”
HELIOS-A Study Results
At 9 months, vutrisiran met the primary and all secondary
endpoints in HELIOS-A, specifically:
- Vutrisiran achieved a rapid and sustained reduction in serum
TTR levels with an 83 percent mean steady-state serum TTR reduction
from baseline.
- Consistent results in serum TTR level reduction were observed
between the vutrisiran and patisiran arms of HELIOS-A, aligned with
the therapeutic hypothesis.
- Vutrisiran treatment (N=122) resulted in a 2.24 point mean
decrease (improvement) in mNIS+7 score from baseline at 9 months as
compared to a 14.76 point mean increase (worsening) reported for
the external placebo group (N=77), resulting in a 17.0 point mean
difference relative to placebo (p equal to 3.54x10-12).
- Improvement in mNIS+7 from vutrisiran treatment was also
consistently observed across all pre-specified patient subgroups,
including age, sex, race, geographic region, baseline neuropathy
impairment, genotype, prior TTR stabilizer use, baseline Familial
Amyloid Polyneuropathy (FAP) stage, and inclusion in the
pre-specified cardiac subpopulation.
- Patients randomized to the patisiran reference arm in HELIOS-A
showed results consistent with the vutrisiran arm.
- Vutrisiran treatment resulted in a 3.3 point mean decrease
(improvement) in Norfolk QoL-DN score from baseline at 9 months as
compared to a 12.9 point mean increase (worsening) reported for the
external placebo group, resulting in a mean 16.2 point difference
relative to placebo (p equal to 5.43x10-9).
- Patients treated with vutrisiran remained stable in gait speed
(mean decrease of 0.001 meters/second in 10-MWT), while patients in
the external placebo group demonstrated worsening (mean decrease of
0.133 meters/second in 10-MWT) (p equal to 3.10x10-5).
- Improvement in the exploratory cardiac endpoint, NT-proBNP, a
measure of cardiac stress, was observed in the vutrisiran arm in
both the pre-specified cardiac sub-population and the modified
intent-to-treat (mITT) population, relative to the external placebo
group.
- The cardiac subpopulation was defined as patients who had
pre-existing evidence of cardiac amyloid involvement (baseline left
ventricular wall thickness ≥1.3 cm and no aortic valve disease or
hypertension in medical history). NT-proBNP adjusted geometric fold
change from baseline was 0.95 for the vutrisiran cardiac
subpopulation group (N=35) and 1.60 for the external placebo
cardiac subpopulation (N=34) group, with an adjusted geometric fold
change ratio of 0.60 (p equal to 0.0016) in favor of
vutrisiran.
- Similar results from baseline were seen in the mITT population
in favor of vutrisiran relative to the external placebo group (p
equal to 9.20x10-7).
- In addition, vutrisiran demonstrated improvements in other
exploratory endpoints measured at 9 months, including change from
baseline in modified body mass index (mBMI) and the Rasch-built
overall disability scale (R-ODS), relative to external
placebo.
In the study and as previously reported with topline results
from the HELIOS-A study, vutrisiran demonstrated an encouraging
safety and tolerability profile relative to placebo with 9 months
of dosing and there were no drug-related discontinuations or
deaths. There were two study discontinuations (1.6 percent) due to
adverse events in the vutrisiran arm by Month 9, both due to death,
neither of which was considered related to study drug. There were
two serious adverse events (SAEs) considered related to vutrisiran
by the study investigator, consisting of dyslipidemia and urinary
tract infection. Treatment emergent adverse events (AEs) occurring
in 10 percent or more patients included diarrhea, pain in
extremity, fall, and urinary tract infections, with each of these
events occurring at a similar or lower rate as compared with
external placebo arm. Injection site reactions (ISRs) were reported
in five patients (4.1 percent) and were all mild and transient.
There were no safety signals regarding hematology, renal function
or liver function tests (LFTs).
“The results of the HELIOS-A Phase 3 study underscore the
potential of vutrisiran as an attractive new treatment option that
can be administered subcutaneously once every three months,
considerably simplifying the treatment for patients with hATTR
amyloidosis with polyneuropathy, a progressive, life-threatening,
multi-system disease,” said David Adams, M.D., Ph.D., Department of
Neurology, Bicetre hospital, Greater Paris University Hospitals,
AP-HP, University Paris Saclay and Principal Investigator for the
HELIOS-A trial. “The data released today are encouraging for the
amyloidosis community who suffer from this devastating disease as
we continue to see exciting progress from ongoing research focused
on meeting the needs of this diverse group of patients.”
Regulatory Submissions
Alnylam also announced that it has submitted an NDA to the U.S.
FDA for the approval of vutrisiran for the treatment of the
polyneuropathy of hATTR amyloidosis in adults. Vutrisiran has been
granted Orphan Drug Designation in the U.S. and the European Union
(EU) for the treatment of ATTR amyloidosis. Vutrisiran has also
been granted a Fast-Track designation in the U.S. for the treatment
of the polyneuropathy of hATTR amyloidosis in adults. The Company
plans to follow the FDA submission with regulatory filings in
Brazil and Japan. The Company also plans to submit a Marketing
Authorisation Application (MAA) in the EU upon obtaining the
results of the 18-month analysis from the HELIOS-A Phase 3 Study,
as previously aligned with the European Medicines Agency (EMA).
Conference Call
Alnylam management will discuss the full 9-month results from
the HELIOS-A Phase 3 clinical trial via conference call on Monday,
April 19th at 4:00 pm ET. A webcast presentation will also be
available on the Investors page of the Company’s website,
www.alnylam.com. To access the call, please dial 877-312-7507
(domestic) or +1-631-813-4828 (international) five minutes prior to
the start time and refer to conference ID 9580096. A replay of the
call will be available beginning at 7:00 pm ET on the day of the
call. To access the replay, please dial 855-859-2056 (domestic) or
+1-404-537-3406 (international) and refer to conference ID
9580096.
About Vutrisiran
Vutrisiran is an investigational, subcutaneously administered
RNAi therapeutic in development for the treatment of ATTR
amyloidosis, which encompasses both hereditary (hATTR) and
wild-type (wtATTR) amyloidosis. It is designed to target and
silence specific messenger RNA, blocking the production of
wild-type and variant transthyretin (TTR) protein before it is
made. Quarterly administration of vutrisiran may help to reduce
deposition and facilitate the clearance of TTR amyloid deposits in
tissues and potentially restore function to these tissues.
Vutrisiran utilizes Alnylam’s Enhanced Stabilization Chemistry
(ESC)-GalNAc-conjugate delivery platform, designed for increased
potency and high metabolic stability that allows for infrequent
subcutaneous injections. The safety and efficacy of vutrisiran have
not been evaluated by the U.S. Food and Drug Administration,
European Medicines Agency or any other health authority.
About HELIOS-A Phase 3 Study
HELIOS-A (NCT03759379) is a Phase 3 global, randomized,
open-label study to evaluate the efficacy and safety of vutrisiran.
The study enrolled 164 patients with hATTR amyloidosis with
polyneuropathy at 57 sites in 22 countries. Patients were
randomized 3:1 to receive either 25mg of vutrisiran (N=122) via
subcutaneous injection once every three months or 0.3 mg/kg of
patisiran (N=42) via intravenous infusion once every three weeks
(as a reference comparator) for 18 months. The primary endpoint is
the change from baseline in mNIS+7 score at 9 months, relative to
an external placebo group (APOLLO). Secondary endpoints at 9 months
are the change from baseline in the Norfolk QoL-DN score and the
timed 10-MWT, relative to an external placebo group. Changes from
baseline in NT-proBNP were evaluated as an exploratory endpoint at
9 months. The efficacy results of vutrisiran in HELIOS-A are
compared to the placebo group from the landmark APOLLO Phase 3
study, which evaluated the efficacy and safety of patisiran in a
patient population similar to that studied in HELIOS-A. Additional
secondary endpoints at 18 months will be evaluated in the HELIOS-A
study, including change from baseline in mNIS+7, Norfolk QoL-DN,
10-MWT, modified body mass index (mBMI), Rasch-built Overall
Disability Scale (R-ODS), and serum transthyretin (TTR) levels.
Additional exploratory cardiac endpoint data at the 18-month time
point will be evaluated, including NT-proBNP, echocardiographic
measures and cardiac amyloid assessments with technetium
scintigraphy imaging. Following the 18-month study period, all
patients are eligible to receive vutrisiran for an additional 18
months as part of an open-label extension study.
About hATTR Amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is
an inherited, progressively debilitating, and fatal disease caused
by variants (i.e., mutations) in the TTR gene. TTR protein is
primarily produced in the liver and is normally a carrier of
vitamin A. Variants in the TTR gene cause abnormal amyloid proteins
to accumulate and damage body organs and tissue, such as the
peripheral nerves and heart, resulting in intractable peripheral
sensory-motor neuropathy, autonomic neuropathy, and/or
cardiomyopathy, as well as other disease manifestations. hATTR
amyloidosis, represents a major unmet medical need with significant
morbidity and mortality affecting approximately 50,000 people
worldwide. The median survival is 4.7 years following diagnosis,
with a reduced survival (3.4 years) for patients presenting with
cardiomyopathy.
About RNAi
RNAi (RNA interference) is a natural cellular process of gene
silencing that represents one of the most promising and rapidly
advancing frontiers in biology and drug development today. Its
discovery has been heralded as “a major scientific breakthrough
that happens once every decade or so,” and was recognized with the
award of the 2006 Nobel Prize for Physiology or Medicine. By
harnessing the natural biological process of RNAi occurring in our
cells, a new class of medicines, known as RNAi therapeutics, is now
a reality. Small interfering RNA (siRNA), the molecules that
mediate RNAi and comprise Alnylam’s RNAi therapeutic platform,
function upstream of today’s medicines by potently silencing
messenger RNA (mRNA) – the genetic precursors – that encode for
disease-causing proteins, thus preventing them from being made.
This is a revolutionary approach with the potential to transform
the care of patients with genetic and other diseases.
About Alnylam Pharmaceuticals
Alnylam (Nasdaq: ALNY) is leading the translation of RNA
interference (RNAi) into a whole new class of innovative medicines
with the potential to transform the lives of people afflicted with
rare genetic, cardio-metabolic, hepatic infectious, and central
nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning
science, RNAi therapeutics represent a powerful, clinically
validated approach for the treatment of a wide range of severe and
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust RNAi therapeutics platform. Alnylam’s commercial RNAi
therapeutic products are ONPATTRO® (patisiran), GIVLAARI®
(givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being
developed and commercialized by Alnylam’s partner Novartis. Alnylam
has a deep pipeline of investigational medicines, including six
product candidates that are in late-stage development. Alnylam is
executing on its “Alnylam P5x25” strategy to deliver transformative
medicines in both rare and common diseases benefiting patients
around the world through sustainable innovation and exceptional
financial performance, resulting in a leading biotech profile.
Alnylam is headquartered in Cambridge, MA. For more information
about our people, science and pipeline, please visit
www.alnylam.com and engage with us on Twitter at @Alnylam, on
LinkedIn, or on Instagram.
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam’s
expectations, plans, aspirations, and goals, including those
related to vutrisiran and its potential as a low-dose, once
quarterly, subcutaneously administered treatment option with an
encouraging safety profile for patients with hATTR amyloidosis with
polyneuropathy, encouraging exploratory cardiac endpoint results,
the expected timing of regulatory filings for vutrisiran outside
the U.S., building an industry-leading franchise in medicines for
the treatment of ATTR amyloidosis and further growing the
population of hATTR amyloidosis patients with polyneuropathy who
may potentially benefit from treatment with an RNAi therapeutic,
becoming a leading biotech company, and the achievement of its
“Alnylam P5x25” strategy, constitute forward-looking statements for
the purposes of the safe harbor provisions under The Private
Securities Litigation Reform Act of 1995. Actual results and future
plans may differ materially from those indicated by these
forward-looking statements as a result of various important risks,
uncertainties and other factors, including, without limitation: the
direct or indirect impact of the COVID-19 global pandemic or any
future pandemic on Alnylam’s business, results of operations and
financial condition and the effectiveness or timeliness of
Alnylam’s efforts to mitigate the impact of the pandemic; Alnylam's
ability to discover and develop novel drug candidates and delivery
approaches and successfully demonstrate the efficacy and safety of
its product candidates; the pre-clinical and clinical results for
its product candidates; actions or advice of regulatory agencies
and Alnylam’s ability to obtain and maintain regulatory approval
for its product candidates, as well as favorable pricing and
reimbursement; successfully launching, marketing and selling its
approved products globally; delays, interruptions or failures in
the manufacture and supply of its product candidates or its
marketed products; obtaining, maintaining and protecting
intellectual property; Alnylam’s ability to successfully expand the
indication for ONPATTRO in the future; Alnylam's ability to manage
its growth and operating expenses through disciplined investment in
operations and its ability to achieve a self-sustainable financial
profile in the future without the need for future equity financing;
Alnylam’s ability to maintain strategic business collaborations;
Alnylam's dependence on third parties for the development and
commercialization of certain products, including Novartis,
Regeneron and Vir; the outcome of litigation; the risk of
government investigations; and unexpected expenditures; as well as
those risks more fully discussed in the “Risk Factors” filed with
Alnylam's most recent Annual Report on Form 10-K filed with the
Securities and Exchange Commission (SEC) and in its other SEC
filings. In addition, any forward-looking statements represent
Alnylam's views only as of today and should not be relied upon as
representing its views as of any subsequent date. Alnylam
explicitly disclaims any obligation, except to the extent required
by law, to update any forward-looking statements.
This release is not intended to convey conclusions about
efficacy or safety as to any investigational RNAi therapeutics or
investigational uses of previously approved therapeutics. There is
no guarantee that any investigational therapeutics or expanded uses
of commercial products will successfully complete clinical
development or gain health authority approval.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20210419005552/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media)
617-682-4340
Josh Brodsky (Investors) 617-551-8276
Alnylam Pharmaceuticals (NASDAQ:ALNY)
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