– Continued Treatment with Patisiran in
Open-Label Extension Period Showed Evidence of Sustained Benefit
across Measures of Functional Capacity and Health Status and
Quality of Life, as well as Cardiac Stress and Injury, through 18
Months –
– Safety Profile Consistent with that Observed
in 12-Month Double-Blind Period, with No New Safety Findings –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced new results from an interim
analysis of exploratory data from the open-label extension (OLE)
period of the APOLLO-B Phase 3 study of patisiran, an
investigational RNAi therapeutic in development for the treatment
of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy.
The results were presented at the Annual Congress of the Heart
Failure Association of the European Society of Cardiology (Heart
Failure 2023; May 20-23, 2023). The Company previously announced
that APOLLO-B achieved its primary endpoint and met its first
secondary endpoint during the 12-month double-blind (DB) period and
that it has submitted the 18-month data to the U.S. Food and Drug
Administration (FDA) as an amendment to the supplemental New Drug
Application (sNDA) for patisiran for the treatment of the
cardiomyopathy of ATTR amyloidosis.
The 18-month findings indicate that the favorable effects on
functional capacity and health status and quality of life, as
measured by the 6-Minute Walk Test (6-MWT) and the Kansas City
Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS),
respectively, observed during the DB period were sustained with
continued patisiran treatment during the OLE period. Patients
treated with patisiran through 18 months also appear to have
maintained relative stability of NT-proBNP and Troponin I levels,
measures of cardiac stress and injury, respectively. Patients who
crossed over from placebo in the DB period to patisiran during the
OLE period appear to show slowing of disease progression or
relative stabilization across these same endpoints at Month 18.
While the APOLLO-B study was not designed to show benefits in
cardiac outcomes between patisiran and placebo, evidence of
favorable, but non-statistically significant, trends were observed
for composite all-cause death and hospitalization, and mortality
analyses across the DB and OLE periods.
“We are pleased to share encouraging new data from our APOLLO-B
OLE study, which we believe continue to support the potential for
patisiran to be an important therapeutic option for patients with
ATTR amyloidosis with cardiomyopathy,” said Rena N. Denoncourt,
Vice President, TTR Franchise Lead. “The results demonstrate that
serum TTR reduction with an RNAi therapeutic has the potential to
provide sustained clinical benefit through 18 months of treatment.
These data, in conjunction with the observed decline in
placebo-treated patients during the DB period, reinforce the
importance of early treatment initiation in ATTR amyloidosis. We
remain steadfast in our commitment to bring patisiran to patients
with ATTR amyloidosis with cardiomyopathy who currently have
limited treatment options.”
APOLLO-B 18-Month Study Results
APOLLO-B is a Phase 3, randomized, DB, placebo-controlled
multicenter global study 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. Patients were randomized 1:1 to receive 0.3 mg/kg
of patisiran or placebo intravenously administered every three
weeks over a 12-month DB treatment period. After 12 months, all
patients were eligible to enter the OLE period of the trial to
receive patisiran. An analysis performed at Month 18 indicated:
- Favorable effects on functional capacity (6-MWT) and health
status and quality of life (KCCQ-OS) were sustained in patients
receiving patisiran through 18 months. In patients who received
placebo during the DB period, initiation of patisiran in the OLE
period was associated with a slower rate of worsening (6-MWT) or
relative stability (KCCQ-OS) at Month 18 compared with the DB
period.
- For 6-MWT, the mean change from baseline to Month 18 was -9.2
meters in patients initially randomized to patisiran, consistent
with the Month 12 assessment. For patients initially randomized to
placebo, the mean change from baseline to Month 12 was -25.4 meters
and to Month 18 was -31.1 meters.
- For KCCQ-OS, the mean change from baseline to Month 18 was +0.2
points in patients initially randomized to patisiran, and -4.0
points in patients initially randomized to placebo.
- Continued treatment with patisiran through 18 months was also
associated with relative stability in biomarker measures of cardiac
stress (NT-proBNP) and cardiac injury (Troponin I). Patients who
received placebo in the DB period showed steadily rising cardiac
biomarker levels up to Month 12, which then appeared to slow or
stabilize after initiating patisiran in the OLE period.
- The geometric mean fold-change from baseline at Month 18 in
NT-proBNP was 1.17 for patients who continued on patisiran, and
1.53 for placebo-crossover patients.
- The geometric mean fold-change from baseline at Month 18 in
Troponin I was 1.09 for patients who continued on patisiran, and
1.21 for placebo-crossover patients.
- Additionally, while the APOLLO-B study was not designed to show
a treatment difference in death and hospitalizations between
patisiran and placebo in the DB or OLE period, and no statistically
significant differences were achieved, evidence of favorable trends
were observed for these composite endpoints. The analyses of
outcomes included all available data from the DB and OLE periods at
the time of the Month 18 data-cut.
- The point estimate of hazard ratio (HR) for the composite of
all-cause mortality and frequency of all-cause hospitalization and
urgent heart failure visits was 0.801 (95% CI, 0.573–1.118).
- The HR for all-cause mortality was 0.554 (95% CI,
0.281–1.094).
Patisiran demonstrated an encouraging safety profile through 18
months of treatment, consistent with the underlying disease and the
known safety profile of patisiran, with no new safety concerns
identified. The majority of adverse events (AEs) were mild or
moderate in severity. The most common treatment-related AE was
infusion-related reactions (14.1 percent).
As previously announced, the U.S. FDA has set an action date of
October 8, 2023 under the Prescription Drug User Fee Act (PDUFA)
and noted that they are planning to convene a meeting of the
Cardiovascular and Renal Drugs Advisory Committee to discuss the
application. Patisiran is the established name for ONPATTRO®, which
is approved by the U.S. FDA for the treatment of the polyneuropathy
of hereditary ATTR amyloidosis in adults.
To view the APOLLO-B 18-month results presented at Heart Failure
2023, please visit Capella.
ONPATTRO 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 (patisiran) is an RNAi therapeutic that is 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 reducing the production of
TTR protein before it is made. Reducing the pathogenic protein
leads to a reduction in amyloid deposits in tissues. Patisiran is
also being evaluated for the treatment of the cardiomyopathy of
ATTR amyloidosis; the safety and efficacy of patisiran in this
indication have not been established or evaluated by the FDA, EMA
or any other health authority.
About ATTR Amyloidosis
Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly
progressive, debilitating disease caused by misfolded transthyretin
(TTR) proteins which accumulate as amyloid fibrils in multiple
tissues including the nerves, heart, and gastrointestinal (GI)
tract. There are two different types of ATTR amyloidosis –
Hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant,
and Wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR
gene variant. hATTR amyloidosis affects approximately 50,000 people
worldwide, while wtATTR amyloidosis is estimated to impact 200,000
– 300,000 people worldwide.
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 20 years ago, 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 Twitter at @Alnylam, on LinkedIn, or on
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, and 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 and the
effectiveness or timeliness of Alnylam’s efforts to mitigate the
impact of the pandemic; 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 patisiran and vutrisiran; actions or
advice of regulatory agencies and Alnylam’s ability to obtain and
maintain regulatory approval for its product candidates, including
patisiran and 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 for ONPATTRO or 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 Novartis, Sanofi,
Regeneron and Vir; the outcome of litigation; the potential impact
of a current government investigation and the risk 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/20230520005007/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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