− Phase 3b Open-Label Study Showed Treatment
with Patisiran Achieved Rapid and Sustained Reduction in Serum TTR
Levels in hATTR Amyloidosis Patients with Polyneuropathy
Progression Following Orthotopic Liver Transplant –
− Additional Results from Pre-specified Patient
Subgroups Analysis Included with Encore Presentation of HELIOS-A
Phase 3 Study of Investigational Vutrisiran −
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced positive results from a Phase
3b open-label study conducted to evaluate the safety, efficacy and
pharmacokinetics (PK) of patisiran in hereditary ATTR (hATTR)
amyloidosis patients with polyneuropathy progression after
receiving an orthotopic liver transplant (OLT). In patients treated
with patisiran, the median reduction in serum TTR levels compared
to baseline was 91 percent, measured as an average of the month six
and month 12 reduction. In addition, the safety profile of
patisiran was consistent with the previously reported safety
results observed in the APOLLO Phase 3 study. Patisiran is the
established name for ONPATTRO®, which is approved in the United
States, Canada and Japan for the treatment of the polyneuropathy of
hATTR amyloidosis in adults, and in the European Union, Switzerland
and Brazil for the treatment of hATTR amyloidosis in adults with
Stage 1 or Stage 2 polyneuropathy. These data will form the basis
of post-approval supplements which have the potential to change
labeling for ONPATTRO where approved, including in the European
Union.
In addition, 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, were
presented today with additional data from pre-specified patient
subgroups. Improvement in the modified Neuropathy Impairment Score
(mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy score
(Norfolk QOL-DN) from vutrisiran treatment was 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 in a pre-specified cardiac
subpopulation. These data were presented as posters during the 2021
Peripheral Nerve Society’s Annual Meeting, and the HELIOS-A results
will also be featured during the Richard A.C. Hughes - Clinical
Science Highlights Presentation on Sunday, June 27th.
“We are excited to share new data from our TTR clinical program
at this year’s PNS virtual conference, which help demonstrate the
potential of patisiran and vutrisiran for a broad group of patients
with hATTR amyloidosis with polyneuropathy. Patients with hATTR
amyloidosis who experience polyneuropathy progression post-OLT have
a significant treatment need and the results of the Phase 3b study
of patisiran demonstrated robust TTR knockdown, improved
neuropathy, and quality of life after 12 months of treatment,” said
John Vest, M.D., Vice President of Clinical Research at Alnylam.
“In addition, results from our HELIOS-A study of investigational
vutrisiran underscore the potential of vutrisiran as an attractive
potential new treatment option for hATTR amyloidosis patients with
polyneuropathy with subcutaneous administration and quarterly
dosing.”
Results of Patisiran in Patients with hATTR Amyloidosis
Post-OLT
Historically, OLT has been used to slow disease progression in
patients with early stages of hATTR amyloidosis; however, some
patients experience disease progression after the transplant due to
continued amyloid deposition of wild-type TTR on top of existing
amyloid deposits in tissues. In the Phase 3b study conducted across
several European countries, 23 patients who showed polyneuropathy
progression post-OLT (based on an increase in polyneuropathy
disability [PND] score) received patisiran infusion (0.3 mg/kg)
every three weeks for 12 months.
Results from the study show that at month 12, patisiran
treatment resulted in an improvement in neuropathy, as demonstrated
by a 3.7 point decrease in the mean total neurological impairment
(NIS) score from baseline. Patisiran treatment also resulted in an
improvement in quality of life with a 6.5 decrease in mean total
Norfolk Quality of Life-Diabetic Neuropathy score (Norfolk QOL-DN)
and autonomic symptoms with treatment resulting in a 5.0 decrease
in the least squares (LS) mean total COMPASS-31 score from
baseline. Patisiran treatment also demonstrated stabilization in
other endpoints, including measures of disability like the
Rasch-built Overall Disability Scale (R-ODS) and nutritional status
with the modified body mass index (mBMI) which were both stable
relative to baseline at month 12.
Patisiran also demonstrated an encouraging safety and
tolerability profile after 12 months of treatment and there were no
drug-related study discontinuations or deaths. There was one
serious adverse event (SAE) considered related to patisiran by the
study investigator, consisting of an infusion reaction, which
resolved without intervention and without change in patisiran
treatment. Treatment emergent adverse events (AE) were consistent
with those seen in the Phase 3 APOLLO study. The most common
observed AE was diarrhea. There was one case of liver transplant
rejection observed during the study which was deemed unrelated to
patisiran by the study investigator. There were no safety signals
regarding hematology, renal function or liver function tests
(LFTs).
About ONPATTRO® (Patisiran)
ONPATTRO is an RNAi therapeutic that was approved in the United
States and Canada for the treatment of the polyneuropathy of hATTR
amyloidosis in adults. ONPATTRO is also approved in the European
Union, Switzerland and Brazil for the treatment of hATTR
amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and
in Japan for the treatment of hATTR amyloidosis with
polyneuropathy. ONPATTRO is an intravenously administered RNAi
therapeutic targeting transthyretin (TTR). It is designed to target
and silence TTR messenger RNA, thereby blocking the production of
TTR protein before it is made. ONPATTRO blocks the production of
TTR in the liver, reducing its accumulation in the body’s tissues
in order to halt or slow down the progression of the polyneuropathy
associated with the disease. For more information about ONPATTRO,
visit ONPATTRO.com.
ONPATTRO Important Safety Information
Infusion-Related Reactions
Infusion-related reactions (IRRs) have been observed in patients
treated with ONPATTRO. In a controlled clinical study, 19 percent
of ONPATTRO-treated patients experienced IRRs, compared to 9
percent of placebo-treated patients. The most common symptoms of
IRRs with ONPATTRO were flushing, back pain, nausea, abdominal
pain, dyspnea, and headache.
To reduce the risk of IRRs, patients should receive
premedication with a corticosteroid, paracetamol, and
antihistamines (H1 and H2 blockers) at least 60 minutes prior to
ONPATTRO infusion. Monitor patients during the infusion for signs
and symptoms of IRRs. If an IRR occurs, consider slowing or
interrupting the infusion and instituting medical management as
clinically indicated. If the infusion is interrupted, consider
resuming at a slower infusion rate only if symptoms have resolved.
In the case of a serious or life-threatening IRR, the infusion
should be discontinued and not resumed.
Reduced Serum Vitamin A Levels and Recommended
Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A
levels. Supplementation at the recommended daily allowance (RDA) of
vitamin A is advised for patients taking ONPATTRO. Higher doses
than the RDA should not be given to try to achieve normal serum
vitamin A levels during treatment with ONPATTRO, as serum levels do
not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they
develop ocular symptoms suggestive of vitamin A deficiency (e.g.
night blindness).
Adverse Reactions
The most common adverse reactions that occurred in patients
treated with ONPATTRO were respiratory-tract infection (29 percent)
and infusion-related reactions (19 percent).
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 may allow 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 the 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 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. The primary endpoint is the change from baseline in
mNIS+7 score at nine months. Secondary endpoints at 9 months are
the change from baseline in the Norfolk QoL-DN score and the timed
10-MWT. Changes from baseline in NT-proBNP were evaluated as an
exploratory endpoint at nine months. 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 treatment period, all patients are eligible
to receive vutrisiran for an additional 18 months as part of the
randomized treatment extension.
About hATTR Amyloidosis
Hereditary transthyretin-mediated (hATTR) amyloidosis 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 results from a Phase 3b open-label study of patisiran
and the potential benefit of patisiran treatment for patients with
polyneuropathy progression after receiving an OLT, the use of the
Phase 3b data to support post-approval supplements which have the
potential to change labeling for ONPATTRO where approved, including
in the European Union, vutrisiran and its potential as an
attractive new treatment option for hATTR amyloidosis patients with
polyneuropathy with subcutaneous administration and quarterly
dosing, 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 (or vutrisiran,
if approved) 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 Quarterly Report on Form 10-Q 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 uses or dosing
regimens of any investigational RNAi therapeutics. There is no
guarantee that any investigational therapeutics or dosing regimens
for such therapeutics will successfully complete clinical
development or gain health authority approval.
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version on businesswire.com: https://www.businesswire.com/news/home/20210607005208/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media)
617-682-4340
Josh Brodsky
(Investors) 617-551-8276
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