− In the Overall Population, Achieved 28%
Reduction in Primary Composite of All-Cause Mortality and Recurrent
Cardiovascular Events, and 31% and 36% Reductions in All-Cause
Mortality During the 33-36-Month Double-Blind Period and up to
Month 42, Respectively –
− In the Monotherapy Population, Reduced
Composite Primary Endpoint by 33% and All-Cause Mortality up to
Month 42 by 35% –
− Strong Trends of Additive Efficacy on Top of
Tafamidis Across Primary and Secondary Endpoints –
− Demonstrated Statistically Significant
Benefits on Multiple Measures of Disease Progression –
− Encouraging Safety and Tolerability Profile,
Consistent with Established Profile –
− Results from HELIOS-B Simultaneously
Published in The New England Journal of Medicine –
− Alnylam to Host Conference Call Today at 1:00
p.m. BST (8:00 a.m. ET) –
−For Investors and Media –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced detailed results from the
HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi
therapeutic in development for the treatment of ATTR amyloidosis
with cardiomyopathy (ATTR-CM).
The data were presented today in a Hot Line session at the
European Society of Cardiology (ESC) Congress 2024, taking place
August 30-September 2 in London, United Kingdom. Results from the
HELIOS-B study were also simultaneously published in The New
England Journal of Medicine.
As previously reported, the HELIOS-B study met all 10 of its
primary and secondary endpoints, across both the overall and
monotherapy populations, with statistical significance.
Enrolled patients were predominantly New York Heart Association
(NYHA) Class I or II with wild-type disease and had been diagnosed
by non-invasive methods, with substantial concurrent treatment with
available standard of care treatments such as tafamidis and SGLT2
inhibitors – reflecting the contemporary ATTR-CM patient
population.
In the study, treatment with vutrisiran substantially reduced
the risk of death and cardiovascular events relative to placebo
(see table below for further details). In the overall population,
vutrisiran reduced the risk of all-cause mortality and recurrent
cardiovascular events by 28%, with similar reductions in both the
mortality and cardiovascular events components of the endpoint.
Mortality in this population was significantly reduced by 31%
during the double-blind period and by 36% up to 42 months. In the
monotherapy population, vutrisiran significantly reduced the risk
of all-cause mortality and recurrent cardiovascular events by 33%
and significantly reduced the risk of mortality by 35% up to 42
months. As a component of the primary endpoint, a non-significant
reduction of 30% in mortality was observed (nominal p-value 0.1179)
in the monotherapy population during the double-blind period.
Vutrisiran treatment was also associated with benefits versus
placebo across multiple well-established clinical measures of
disease progression, including 6-Minute Walk Test, Kansas City
Cardiovascular Questionnaire, and NYHA Class, as well as the
cardiac biomarker NT-proBNP.
Subgroup analyses demonstrated consistent benefits across all
key patient segments, including patients receiving background
tafamidis. Trends toward greater efficacy were seen in patients
with earlier disease (i.e., younger patients and those with lower
baseline NT-proBNP).
In HELIOS-B, the safety and tolerability profiles of vutrisiran
were consistent with what had been established in the currently
approved patient population, as well as earlier clinical
studies.
“Results from the HELIOS-B study demonstrate a significant
advance in the treatment of ATTR amyloidosis with cardiomyopathy,
suggesting that knockdown of TTR production with vutrisiran can
dramatically reduce all-cause mortality and cardiovascular events,”
said Marianna Fontana, M.D., Ph.D., HELIOS-B investigator,
Professor of Cardiology, University College London, National
Amyloidosis Center, Royal Free Hospital, London. “Over the past
decade, advances in ATTR-CM have led to more patients being
diagnosed earlier in their disease, often with less severe symptoms
and better prognosis, as well as receiving more robust background
standards of care. In this contemporary setting, the bar was high
to demonstrate benefit. These HELIOS-B data also suggest that,
within this current patient population, vutrisiran may provide
greater benefit to patients in earlier stages of the disease where,
due to the progressive nature of ATTR-CM, early treatment can more
effectively preserve functional capacity and quality of life.”
“We’re proud to share the detailed HELIOS-B data with the
cardiology community at the ESC Congress 2024. With this study, we
have demonstrated that the rapid knockdown of toxic TTR seen with
vutrisiran improves survival, and reduces cardiovascular
hospitalizations and disease progression versus placebo, with
benefits consistently observed across populations and regardless of
background stabilizer use,” said Pushkal Garg, M.D., Chief Medical
Officer of Alnylam. “While the results have not yet been reviewed
by a regulatory authority, the data we have shared today suggest
that vutrisiran has the potential to become a new standard of care
treatment for ATTR-CM, a progressive and ultimately fatal disease
with limited treatment options. We want to thank everyone who
contributed to the success of this study, including the patients,
caregivers, investigators, study staff and my Alnylam colleagues.
In light of these data, we are working with urgency to file these
data with regulators and bring this medicine to patients around the
world.”
Primary and Secondary Endpoints
The results of the prespecified primary and secondary endpoints
in both the overall and monotherapy populations are detailed in the
table below.
Overall
Population
(n=654)
Monotherapy
Population
(n=395)
Primary Endpoint
Composite of all-cause mortality
and recurrent CV events up to Month 36 [1]
HR=0.718
p=0.0118
HR=0.672
p=0.0162
Hazard Ratio
RRR=28%, ARR=9.9
RRR=33%, ARR=12.5
Component Analyses
All-cause mortality up to Month
36 [2]
HR=0.694
p=0.0389
HR=0.705
p=0.1179
Hazard Ratio
RRR=31%, ARR=7.9
RRR=30%, ARR=11.0
Recurrent CV events up to Month
36 [3]
Relative Rate Ratio =0.733
p=0.0010
Relative Rate Ratio =0.676
p=0.0012
Relative Rate Ratio
RRR=27%, ARR=7.7
RRR=32%, ARR=9.9
Secondary Endpoints
6-minute walk test (6-MWT)
Change from baseline at Month
30
LS mean difference
26.46 meters
p=7.976E-05
32.09 meters
p=0.0005
Kansas City Cardiomyopathy
Questionnaire (KCCQ)
Change from baseline at Month
30
LS mean difference
5.80 points
p=0.0008
8.69 points
p=0.0003
All-cause mortality Up to 42
months [4]
HR=0.645
p=0.0098
HR=0.655
p=0.0454
Hazard Ratio
RRR=36%, ARR=11.8
RRR=35%, ARR=19.5
New York Heart Association (NYHA)
Class
Percent stable or improved at
Month 30
Adjusted % difference
8.7%
p=0.0217
12.5%
p=0.0121
RRR=Relative Risk Reduction; ARR=Absolute
Risk Reduction
[1] ARR: difference in composite event
rate per 100 patient-years (placebo-vutrisiran)
[2] ARR: difference in mortality rate at
Month 36 (placebo-vutrisiran)
[3] ARR: difference in CV event rate per
100 patient-years (placebo-vutrisiran)
[4] ARR: difference in mortality rate at
Month 42 (placebo-vutrisiran)
Subgroup analyses of the primary and secondary endpoints, which
were not powered to show statistical significance, demonstrated
generally consistent results across all key patient segments,
including patients receiving tafamidis at baseline. In patients
receiving baseline tafamidis, vutrisiran demonstrated a 22%
reduction (HR 0.785, nominal p-value 0.2701, ARR 6.7) in the
composite primary endpoint of ACM and recurrent CV events and a 41%
reduction (HR 0.588, nominal p-value 0.0983, ARR 6.5) in ACM at 42
months versus placebo.
Trends toward greater than average benefit were seen in patients
with baseline characteristics indicative of early disease. Patients
with baseline NT-proBNP of ≤2000 experienced a 48% reduction (HR
0.525, nominal p-value 0.0019) in the composite primary endpoint,
as well as a 65% reduction (HR 0.348, nominal p-value 0.0012) in
ACM up to 42 months when treated with vutrisiran versus placebo. In
patients younger than 75 years old, vutrisiran demonstrated a 46%
reduction (HR 0.545, nominal p-value 0.0081) in the composite
primary endpoint and a 45% reduction (HR 0.552, nominal p-value
0.0661) in ACM up to 42 months versus placebo.
Additionally, the study demonstrated evidence of benefit on
NT-proBNP, an established cardiac biomarker that is prognostic of
mortality in ATTR-CM. At Month 30, vutrisiran led to a 32% relative
reduction in the fold change in NT-proBNP compared to placebo in
the overall population (adjusted geometric mean fold change ratio
[vutrisiran/placebo]: 0.68; nominal p-value 3.440E-12) and a 43%
relative reduction in the fold change in NT-proBNP compared to
placebo in the vutrisiran monotherapy subgroup (adjusted geometric
mean fold change ratio [vutrisiran/placebo]: 0.57; nominal p-value
4.339E-12).
Safety
In the HELIOS-B study, vutrisiran demonstrated an encouraging
safety and tolerability profile consistent with the established
profile of the drug. Rates of adverse events (AEs), serious AEs,
severe AEs and AEs leading to study drug discontinuation were
similar between the vutrisiran and placebo arms. Cardiac AEs were
similar or lower in the vutrisiran arm compared to placebo. AEs
occurring in more than 15% of patients overall were similar or
lower in the vutrisiran arm compared to placebo (cardiac failure,
Covid-19, atrial fibrillation, gout, dypnoea and fall). No AEs were
seen ≥3% more frequently in the vutrisiran arm compared to the
placebo arm.
Safety
Vutrisiran
n=326 (%)
Placebo
n=328 (%)
Adverse Events
322 (98.8%)
323 (98.5%)
Serious Adverse Events
201 (61.7%)
220 (67.1%)
Severe Adverse Events
158 (48.5%)
194 (59.1%)
Adverse Events Leading to Study
Drug Discontinuation
10 (3.1%)
13 (4.0%)
Deaths
49 (15.0%)
63 (19.2%)
HELIOS-B (NCT: NCT04153149) was a Phase 3, randomized,
double-blind, placebo-controlled multicenter global study designed
and powered to evaluate the efficacy and safety of vutrisiran on
the reduction of all-cause mortality and recurrent cardiovascular
events as a primary composite endpoint in patients with ATTR
amyloidosis with cardiomyopathy. The study randomized 655 adult
patients with ATTR amyloidosis (hereditary or wild-type) with
cardiomyopathy. Patients were randomized 1:1 to receive vutrisiran
25mg or placebo subcutaneously once every three months during a
double-blind treatment period of up to 36 months. After the
double-blind period, all eligible patients remaining on the study
were able receive vutrisiran in an open-label extension period of
HELIOS-B.
The Company remains on track to proceed with global regulatory
submissions for vutrisiran starting later this year, including
filing a supplemental New Drug Application with the U.S. Food and
Drug Administration using a Priority Review Voucher.
For U.S. Investors: To review the HELIOS-B study results
presented at ESC Congress 2024, please visit Capella.
Investor Webcast Information
Alnylam Management will discuss the HELIOS-B results via webcast
today at 1:00 p.m. BST (8:00 a.m. ET).
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.
AMVUTTRA® (vutrisiran) INDICATION AND IMPORTANT SAFETY
INFORMATION
Indication
In the US, vutrisiran is indicated for the treatment of the
polyneuropathy of hereditary transthyretin mediated amyloidosis
(hATTR amyloidosis) in adults. In Europe and the UK, vutrisiran is
indicated for the treatment of hATTR amyloidosis in adult patients
with stage 1 or stage 2 polyneuropathy.
Important Safety Information
Reduced Serum Vitamin A Levels and Recommended
Supplementation
Vutrisiran 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 vutrisiran (In Europe,
patients receiving vutrisiran should take oral supplementation of
approximately, but not exceeding, 2500 IU to 3000 IU vitamin A per
day.). Higher doses than the RDA should not be given to try to
achieve normal serum vitamin A levels during treatment with
vutrisiran, as serum vitamin A 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). See Summary of Product Characteristics for
further information on Vitamin A levels, including information on
the warnings and impact in pregnancy.
Adverse Reactions
The most common adverse reactions that occurred in patients
treated with vutrisiran for polyneuropathy of hereditary
transthyretin-mediated amyloidosis (hATTR-PN) were arthralgia
(11%), dyspnea (7%), and vitamin A decreased (7%).
For additional information about vutrisiran, please see the
full Prescribing Information / Summary of Product
Characteristics.
About AMVUTTRA® (vutrisiran)
AMVUTTRA® (vutrisiran) is an RNAi therapeutic that delivers
rapid knockdown of mutant and wild‑type transthyretin (TTR),
addressing the underlying cause of transthyretin (ATTR)
amyloidosis. Administered quarterly via subcutaneous injection,
vutrisiran is approved and marketed in more than 15 countries for
the treatment of the polyneuropathy of hereditary
transthyretin-mediated amyloidosis (hATTR-PN) in adults. In the UK,
vutrisiran is specifically indicated for the treatment of hATTR in
adult patients with stage 1 or stage 2 polyneuropathy. Vutrisiran
is also in development for the treatment of ATTR amyloidosis with
cardiomyopathy (ATTR-CM), which encompasses both wild-type and
hereditary forms of the disease.
About ATTR
Transthyretin amyloidosis (ATTR) 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 – hereditary ATTR (hATTR), which is caused
by a TTR gene variant and affects approximately 50,000 people
worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR
gene variant and impacts an estimated 200,000-300,000 people
worldwide.1-4
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.5 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.6 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.5
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) 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 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.
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, Alnylam’s expectations regarding the safety and
efficacy of vutrisiran for the treatment of ATTR amyloidosis with
cardiomyopathy, including its potential to be a transformative
medicine for patients with ATTR amyloidosis with cardiomyopathy;
the potential for vutrisiran to become the new standard of care for
the treatment of ATTR amyloidosis with cardiomyopathy; the
potential for vutrisiran to obtain regulatory approval for the
treatment of ATTR amyloidosis with cardiomyopathy; the potential
for vutrisiran to drive Alnylam’s next era of substantial growth;
the expected timing of the presentation of full data from the
HELIOS-B clinical trial and the filing of a U.S. Supplemental New
Drug Application for vutrisiran; Alnylam’s plans to use a Priority
Review Voucher in connection with the Supplemental New Drug
Application for vutrisiran; the potential for vutrisiran’s clinical
profile to support first-line positioning in newly diagnosed
patients and in those patients whose treatment could be optimized
beyond what background treatments could provide; and the potential
for Alnylam to achieve its Alnylam P5x25 vision of becoming a
leading biopharma company 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, risks and uncertainties relating to:
Alnylam’s ability to successfully execute on its “Alnylam P5x25”
strategy; Alnylam’s ability to 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 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; and any delays, interruptions
or failures in the manufacture and supply of Alnylam’s product
candidates or its marketed products; as well as those risks more
fully discussed in the “Risk Factors” filed with Alnylam’s 2023
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.
AMV-INTX-00050 - August 2024
1 Hawkins PN, Ando Y, Dispenzeri A, et al.
Ann Med. 2015;47(8):625-638.
2 Gertz MA. Am J Manag Care.
2017;23(7):S107-S112.
3 Conceicao I, Gonzalez-Duarte A, Obici L,
et al. J Peripher Nerv Syst. 2016;21:5-9.
4 Ando Y, Coelho T, Berk JL, et al.
Orphanet J Rare Dis. 2013;8:31.
5 Elbashir SM, Harborth J, Lendeckel W, et
al. Nature. 2001;411(6836):494-498.
6 Zamore P. Cell.
2006;127(5):1083-1086.
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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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