– Treatment with an RNAi Therapeutic Preserved
Functional Capacity and Health Status and Quality of Life Compared
with Placebo at 12 Months –
– Patisiran Demonstrated an Encouraging Safety
and Tolerability Profile in Patients with the Cardiomyopathy of
ATTR Amyloidosis –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today that results from the
APOLLO-B Phase 3 study of investigational patisiran in patients
with the cardiomyopathy of transthyretin-mediated (ATTR)
amyloidosis were published online in the New England Journal of
Medicine (NEJM). The data reported in the APOLLO-B Phase 3 study
publication demonstrate that patisiran, an RNAi therapeutic
targeting transthyretin (TTR), preserved functional capacity and
health status and quality of life compared with placebo at 12
months. In addition, treatment with patisiran demonstrated
favorable effects on biomarkers of cardiac stress and injury and on
measures of cardiac structure and function. The full manuscript,
titled “Patisiran Treatment in Patients with Transthyretin Cardiac
Amyloidosis,” will appear in the October 26, 2023 issue of
NEJM.
“ATTR amyloidosis is a rapidly progressive disease, with cardiac
manifestations that can have a devastating impact on patients’
lives, and include arrhythmias, conduction disease, and heart
failure. Current treatment options are limited, with many patients
still experiencing declines in their functional capacity and
quality of life, underscoring the need for additional therapeutic
approaches,” said Mathew Maurer, M.D., Arnold and Arlene Goldstein
Professor of Cardiology at Columbia University Irving Medical
Center, principal investigator of the APOLLO-B Phase 3 study, and
lead author of the manuscript. “The results of the APOLLO-B Phase 3
study published in the New England Journal of Medicine support the
hypothesis that a reduction in circulating TTR protein can provide
benefit in patients with the cardiomyopathy of ATTR amyloidosis,
warranting further evaluation of investigational RNAi therapeutics
to treat this devastating disease.”
The APOLLO-B Phase 3 study achieved its primary endpoint at 12
months, with patisiran demonstrating a significant difference in
the change from baseline in functional capacity compared with
placebo, as measured by the 6-Minute Walk Test (6-MWT). The study
also met its first secondary endpoint, with patisiran demonstrating
a significant difference in the change from baseline in health
status and quality of life compared with placebo, as measured by
the Kansas City Cardiomyopathy Questionnaire Overall Summary
(KCCQ-OS) score. For the composite endpoint of all-cause mortality,
frequency of cardiovascular events, and change from baseline in
6-MWT over 12 months compared with placebo, the win ratio favored
patisiran but did not reach statistical significance.
“The APOLLO-B Phase 3 study results published in the New England
Journal of Medicine further our conviction that TTR silencing with
an RNAi therapeutic can have a positive therapeutic impact on
patients with the cardiomyopathy of ATTR amyloidosis – a disease
characterized by unrelenting symptom progression due to ongoing
amyloid deposition in the heart,” said Pushkal Garg, M.D., Chief
Medical Officer at Alnylam. “While the supplemental New Drug
Application (sNDA) that would have expanded the indication for
patisiran in the U.S. to include the cardiomyopathy of ATTR
amyloidosis received a Complete Response Letter (CRL), we remain
dedicated to the ATTR amyloidosis community. We look forward to
early 2024, when we expect to share topline results from 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.”
Select exploratory endpoints in APOLLO-B included changes in
cardiac biomarkers NT-proBNP, a measure of cardiac stress, and
Troponin I, a measure of cardiac injury, as well as
echocardiographic measures of cardiac structure and function. At 12
months, the change from baseline in NT-proBNP and Troponin I levels
favored patisiran compared with placebo, and differences between
patisiran and placebo in the change from baseline in left
ventricular (LV) global longitudinal strain, a measure of systolic
function, LV mass, and LV stroke volume all favored patisiran.
Additional findings in the NEJM publication were from a post-hoc
analysis of the primary endpoint evaluating patients without
walking impairment due to neuropathy at baseline (polyneuropathy
disability score [PND] of 0; N=205). The results were consistent
with those of the primary analysis, suggesting that the treatment
effect of patisiran on 6-MWT was not a result of effects on
polyneuropathy.
Patisiran demonstrated an encouraging safety and tolerability
profile in the APOLLO-B Phase 3 study, including no cardiac safety
concerns relative to placebo, through 12 months. The majority of
adverse events (AEs) were mild or moderate in severity. AEs
occurring in 5% or more of patients in the patisiran group and
observed at least 3% more commonly in the patisiran group included
infusion-related reactions (12% vs. 9%), arthralgia (8% vs. 4%),
and muscle spasm (7% vs. 2%). In the safety analysis, 5 deaths (3%)
were observed in patisiran-treated patients, none of which were
considered related to study drug, and 8 deaths (4%) were observed
in the placebo group.
Upon completion of dosing in the 12-month double-blind period,
patients were eligible to enroll in a 36-month open-label extension
(OLE) period to receive patisiran on an ongoing basis. Results from
an interim analysis of the ongoing OLE period of the APOLLO-B Phase
3 study were recently presented at the Heart Failure Society of
America (HFSA) Annual Scientific Meeting (ASM) 2023, demonstrating
the sustained treatment effect of patisiran on functional status
and health status and quality of life, as well as cardiac
biomarkers, through 24 months.
Patisiran is the established name for ONPATTRO®, which is
currently approved by the U.S. FDA for the treatment of the
polyneuropathy of hereditary ATTR (hATTR) amyloidosis in
adults.
The Company recently announced that the U.S. Food and Drug
Administration (FDA) issued a CRL in response to the sNDA for
patisiran for the treatment of the cardiomyopathy of ATTR
amyloidosis, indicating 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 does
not pertain to, nor impact commercial availability of, ONPATTRO in
the U.S. or in other countries where it has previously been
approved for the treatment of the polyneuropathy of hATTR
amyloidosis in adults.
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 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,
and Alnylam’s belief that TTR silencing with an RNAi therapeutic
could have a positive therapeutic impact on patients with the
cardiomyopathy of ATTR amyloidosis, 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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Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom (Investors and Media)
+1-617-682-4340
Josh Brodsky (Investors) +1-617-551-8276
Alnylam Pharmaceuticals (NASDAQ:ALNY)
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