Aug 30, 2024 Press Release for Alnylam
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Alnylam Presents Detailed Results from the Positive HELIOS-B Phase 3 Study of Vutrisiran▼ in Patients with ATTR Amyloidosis with Cardiomyopathy at the European Society of Cardiology Congress
Aug 30, 2024
− 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
−
−For Investors and Media –
The data were presented today in a Hot Line session at the
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
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
“We’re proud to share the detailed HELIOS-B data with the cardiology community at the
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 |
|
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 |
|
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 |
|
RRR=36%, ARR=11.8 |
RRR=35%, ARR=19.5 |
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
For U.S. Investors: To review the HELIOS-B study results presented at
Investor Webcast Information
Alnylam Management will discuss the HELIOS-B results via webcast today at
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
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
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 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
AMV-INTX-00050 -
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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