– FDA Cites Insufficient Evidence of Clinical
Meaningfulness –
– No Clinical Safety, Study Conduct, Drug
Quality or Manufacturing Issues Identified –
– CRL Does Not Pertain to, nor Impact
Commercial Availability of, ONPATTRO® (patisiran) for Existing
Indication for the Treatment of the Polyneuropathy of Hereditary
ATTR Amyloidosis in Adults –
– Alnylam to Host Investor Conference Call
Today, Monday, October 9, 2023 at 8:30 a.m. ET –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced that the U.S. Food and Drug
Administration (FDA) has issued a Complete Response Letter (CRL) in
response to the Company’s supplemental New Drug Application (sNDA)
for patisiran for the treatment of the cardiomyopathy of
transthyretin-mediated (ATTR) amyloidosis.
Patisiran is the established name for ONPATTRO®, which is
approved by the FDA for the treatment of the polyneuropathy of
hereditary ATTR amyloidosis in adults. The CRL does not pertain to,
nor does it impact commercial availability of, ONPATTRO for this
existing indication.
The CRL indicated that the clinical meaningfulness of
patisiran’s treatment effects for the cardiomyopathy of ATTR
amyloidosis had not been established, and therefore, the sNDA for
patisiran could not be approved in its present form. The CRL did
not identify any issues with respect to clinical safety, study
conduct, drug quality or manufacturing.
As a result of the CRL, the Company will no longer pursue an
expanded indication for patisiran in the U.S. The Company remains
dedicated to the ATTR amyloidosis community and will continue to
focus on the HELIOS-B Phase 3 study of vutrisiran, an
investigational RNAi therapeutic subcutaneously administered once
every three months in development for the treatment of the
cardiomyopathy of ATTR amyloidosis, and ALN-TTRsc04, which utilizes
the Company’s IKARIA technology, with the potential for greater
than 90% TTR knockdown with once annual dosing.
“First and foremost, our hearts go out to patients with the
cardiomyopathy of ATTR amyloidosis who are living with a rapidly
progressive, debilitating and fatal disease and face significant
unmet need. While we are disappointed by this decision, we are
committed to supporting them and are well positioned to address
their needs with continued innovation that can potentially help
improve their outcomes and treatment experience,” said Yvonne
Greenstreet, MBChB, Chief Executive Officer of Alnylam
Pharmaceuticals. “We remain confident in the HELIOS-B Phase 3 study
of vutrisiran and look forward to sharing topline results in early
2024. If successful, we believe vutrisiran will offer convenient,
quarterly subcutaneous dosing with a therapeutic profile that may
potentially include cardiovascular outcome benefits. Beyond
vutrisiran, we are excited about the potential for ALN-TTRsc04,
which may allow for greater TTR knockdown and less frequent dosing,
providing patients with ATTR amyloidosis an optimized treatment
regimen.”
The sNDA for patisiran was supported by positive results from
the APOLLO-B Phase 3 study. In APOLLO-B, patisiran met the primary
endpoint as well as the first secondary endpoint at Month 12,
demonstrating a significant difference compared to placebo in
functional capacity, as measured by the 6-Minute Walk Test (6-MWT),
and health status and quality of life, as measured by the Kansas
City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score,
respectively.
New results from an interim analysis of the ongoing open-label
extension (OLE) period of the APOLLO-B Phase 3 study were presented
at the Heart Failure Society of America (HFSA) Annual Scientific
Meeting (ASM) 2023, which demonstrate the sustained treatment
effect of patisiran on functional status, health status and quality
of life and cardiac biomarkers over 24 months. These findings
reinforce the long-term treatment effect of TTR silencing by an
RNAi therapeutic in patients with ATTR amyloidosis and provide
strong support for the Company’s continued evaluation of vutrisiran
and ALN-TTRsc04.
As previously announced, the FDA’s Cardiovascular and Renal
Drugs Advisory Committee met on September 13, 2023 to discuss the
sNDA for patisiran and voted 9:3 that the benefits of patisiran
outweigh its risks for the treatment of the cardiomyopathy of ATTR
amyloidosis.
The Company intends to maintain availability of patisiran for
patients with the cardiomyopathy of ATTR amyloidosis who are
enrolled in the OLE period of the APOLLO-B Phase 3 study and
patisiran U.S. expanded access protocol (EAP).
Conference Call Information Alnylam management will
discuss the CRL via conference call on Monday, October 9, 2023 at
8:30 a.m. ET. To access the call, please register online at
https://register.vevent.com/register/BI8567d631e94e4c1eaa8da3a1ae2fcf69.
Participants are requested to register a minimum of 15 minutes
before the start of the call. A replay of the call will be
available two hours after the call and archived on the same webpage
for six months.
A live audio webcast of the call will be available on the
Investors section of the Company’s website at
www.alnylam.com/events. An archived webcast will be available on
the Company’s website approximately two hours after the event.
ONPATTRO® (patisiran) Indication and Important Safety
Information Indication ONPATTRO is indicated for the
treatment of the polyneuropathy of hereditary
transthyretin-mediated amyloidosis in adults.
Important Safety Information Infusion-Related Reactions
Infusion-related reactions (IRRs) have been observed in patients
treated with ONPATTRO. In a controlled clinical study, 19% of
ONPATTRO-treated patients experienced IRRs, compared to 9% 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, acetaminophen, 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 upper respiratory
tract infections (29%) and infusion-related reactions (19%).
For additional information about ONPATTRO, please see the full
U.S. Prescribing Information.
About ONPATTRO® (patisiran) ONPATTRO is an RNAi
therapeutic that is approved in the United States and Canada for
the treatment of the polyneuropathy of hereditary ATTR (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 reducing the production of
TTR protein before it is made. Reducing the pathogenic protein
leads to a reduction in amyloid deposits in tissues.
About ATTR Amyloidosis Transthyretin-mediated (ATTR)
amyloidosis is an underdiagnosed, rapidly progressive, debilitating
and fatal disease caused by misfolded transthyretin (TTR) proteins,
which accumulate as amyloid deposits in various parts of the body,
including the nerves, heart and gastrointestinal tract. Patients
may present with polyneuropathy, cardiomyopathy, or both
manifestations of disease. There are two different forms of ATTR
amyloidosis – hereditary ATTR (hATTR) amyloidosis, which is caused
by a TTR gene variant and affects approximately 50,000 people
worldwide, and wild-type ATTR (wtATTR) amyloidosis, which occurs
without a TTR gene variant and impacts an estimated 200,000 –
300,000 people worldwide.
About the APOLLO-B Phase 3 Study APOLLO-B is a Phase 3,
randomized, double-blind, placebo-controlled multicenter global
study designed and powered to evaluate the effects of patisiran on
functional capacity and quality of life in patients with ATTR
amyloidosis with cardiomyopathy. The study enrolled 360 adult
patients with ATTR amyloidosis (hereditary or wild-type) with
cardiomyopathy at 69 sites in 21 countries. Patients were
randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo
intravenously administered every three weeks over a 12-month
treatment period. After 12 months, all patients received patisiran
in a 36-month open-label extension period.
About IKARIA™ Platform Alnylam’s IKARIA platform takes
advantage of more than two decades of experience in developing RNAi
therapeutics. IKARIA enables an extended duration of activity in
preclinical studies, with potential for annual dosing in humans,
and has design features which provide exquisite specificity,
further widening the potential therapeutic index, with enhanced
target reduction levels.
About LNP Technology Alnylam has licenses to Arbutus
Biopharma LNP intellectual property for use in RNAi therapeutic
products using LNP technology.
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 or disease pathway 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 Pharmaceuticals
(Nasdaq: ALNY) has led 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 and prevalent
diseases with unmet need. Based on Nobel Prize-winning science,
RNAi therapeutics represent a powerful, clinically validated
approach yielding transformative medicines. Since its founding in
2002, Alnylam has led the RNAi Revolution and continues to deliver
on a bold vision to turn scientific possibility into reality.
Alnylam’s commercial RNAi therapeutic products are ONPATTRO®
(patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO®
(lumasiran), and Leqvio® (inclisiran), which is being developed and
commercialized by Alnylam’s partner, Novartis. Alnylam has a deep
pipeline of investigational medicines, including multiple 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 X (formerly Twitter) at @Alnylam, or on LinkedIn,
Facebook, or Instagram.
Alnylam Forward Looking Statements This press release
contains forward-looking statements within the meaning of Section
27A of the Securities Act of 1933 and Section 21E of the Securities
Exchange Act of 1934. All statements other than historical
statements of fact regarding Alnylam’s expectations, beliefs,
goals, plans or prospects including, without limitation,
expectations regarding Alnylam’s aspiration to become a leading
biotech company and the planned achievement of its “Alnylam P5x25”
strategy, the potential for Alnylam to identify new potential drug
development candidates and advance its research and development
programs, Alnylam’s ability to obtain approval for new commercial
products or additional indications for its existing products,
Alnylam’s projected commercial and financial performance, should be
considered forward-looking statements. 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; Alnylam’s ability to successfully execute on
its “Alnylam P5x25” strategy; 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 Alnylam’s
product candidates, including vutrisiran; actions or advice of
regulatory agencies and Alnylam’s ability to obtain and maintain
regulatory approval for its product candidates, including
vutrisiran, as well as favorable pricing and reimbursement;
successfully launching, marketing and selling Alnylam’s approved
products globally; delays, interruptions or failures in the
manufacture and supply of Alnylam’s product candidates or its
marketed products; delays or interruptions in the supply of
resources needed to advance Alnylam’s research and development
programs, including as may arise from recent disruptions in the
supply of non-human primates; obtaining, maintaining and protecting
intellectual property; Alnylam’s ability to successfully expand the
indication AMVUTTRA 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 Roche, Novartis,
Sanofi, Regeneron and Vir; the outcome of litigation; the risks of
future government investigations; and unexpected expenditures; as
well as those risks more fully discussed in the “Risk Factors”
filed with Alnylam's 2022 Annual Report on Form 10-K filed with the
Securities and Exchange Commission (SEC), as may be updated from
time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q
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 discusses investigational RNAi therapeutics and
uses of previously approved RNAi therapeutics in development and is
not intended to convey conclusions about efficacy or safety as to
those investigational therapeutics or uses. Patisiran has not been
approved by any regulatory agency for the treatment of ATTR
amyloidosis with cardiomyopathy. No conclusions can or should be
drawn regarding its safety or effectiveness in treating
cardiomyopathy in this population. There is no guarantee that any
investigational therapeutics or expanded uses of commercial
products will successfully complete clinical development or gain
health authority approval.
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version on businesswire.com: https://www.businesswire.com/news/home/20231009982660/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media) +1-617-682-4340 Josh Brodsky (Investors)
+1-617-551-8276
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