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

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 TheNew 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 AlnylamP⁵x25 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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