Alnylam Highlights New Data From HELIOS-B Study of Vutrisiran for the Treatment of Transthyretin Amyloidosis With Cardiomyopathy at Heart Failure Society of America Annual Scientific Meeting 2024

− Echocardiographic and Cardiac Biomarker Data From the HELIOS-B Study Presented Today Support the Potential of Vutrisiran in ATTR-CM –

− Vutrisiran Significantly Improved Echocardiographic Assessments of Cardiac Structure, Systolic Function and Diastolic Function Relative to Placebo Over 30 Months –

− Vutrisiran Demonstrated Relative Stability of Cardiac Biomarkers NT-proBNP and Troponin-I Relative to Placebo Over 30 Months –

Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, today announced that two new data sets 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), were presented in the Late Breaking Clinical Research Session 1 at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2024, which was held virtually. An open access recording of Alnylam presentations will be available on the HFSA website following the session.

Progression in ATTR-CM is associated with cardiac wall thickening, deterioration in systolic and diastolic function and increases in biomarkers of cardiac stress and injury, NT-pro-BNP and Troponin I.

"Consistent with demonstrated improvements in outcomes and health status, these new data show that vutrisiran attenuated measures of disease progression across multiple domains of cardiac structure and function, NT-proBNP and troponin I, in a contemporary ATTR-CM patient population," said Pushkal Garg, M.D., Chief Medical Officer, Alnylam. "These data demonstrate that rapid knockdown of TTR leads to an early impact on cardiac biomarkers and echocardiographic parameters, indicative of a potential disease-modifying effect, and underscores the benefit of treating patients with an RNAi therapeutic earlier in the course of disease. We remain confident that, with approval, vutrisiran has the potential to become a first-line therapy for ATTR amyloidosis with cardiomyopathy and are on track to complete multiple global regulatory submissions before the end of the year."

Analysis results

New echocardiographic data demonstrated that treatment with vutrisiran slowed disease progression in a contemporary population of patients with ATTR-CM across multiple domains of cardiac structure and diastolic and systolic function at Month 30 as compared to placebo. The magnitude of the treatment effects with vutrisiran compared to placebo were similar or greater in the monotherapy population. Significant improvements in both diastolic and systolic function were observed as early as 12 months and 18 months, respectively, in the overall population. The Month 30 results in the overall population are detailed in the table below.*

*All p-values included within the table are nominal p-values.

In addition, analyses of cardiac biomarkers NT-proBNP and troponin I were also presented. At Month 30, the relative reduction in the fold change in NT-proBNP in patients treated with vutrisiran compared to placebo was 32% in the overall population and 43% in the monotherapy population (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.68; nominal p-value 3.440E-12 and 0.57; nominal p-value 4.339E-12, respectively). At Month 30, relative reduction in the fold change of troponin I was 32% in the overall population and 45% in the monotherapy population (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.68; nominal p-value 1.566E-14 and 0.55; nominal p-value 9.684E-17, respectively).

In the subgroup of patients receiving tafamidis at baseline, a relative reduction in the fold change of 18% was observed in NT-proBNP and 10% in troponin I (adjusted geometric mean fold change ratio [vutrisiran/placebo]: 0.82; nominal p-value 0.0045 and 0.90; nominal p-value 0.0849, respectively) at Month 30. For both NTproBNP and troponin I, patients treated with vutrisiran demonstrated nominally significant reductions relative to placebo at 6 months. These results were consistent across all pre-specified subgroups, with a larger treatment effect observed in the monotherapy population.

Detailed results from the HELIOS-B study were presented at the European Society of Cardiology annual congress on August 30, 2024, and simultaneously published in The New England Journal of Medicine.

Alnylam plans to include a discussion of these data at its upcoming TTR Investor Day on Wednesday, October 9, 2024, at 8:30 am ET in New York City. The event will be webcast on the Investors section of the Company's website, www.alnylam.com. A replay will be available on the Alnylam website within 48 hours after the event.

HELIOS-B Study Design

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 to were able receive vutrisiran in an open-label extension period of HELIOS-B.

IMPORTANT SAFETY INFORMATION

Reduced Serum Vitamin A Levels and Recommended Supplementation

AMVUTTRA® (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 AMVUTTRA. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, 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).

Adverse Reactions

The most common adverse reactions that occurred in patients treated with AMVUTTRA for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) were arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%).

For additional information about AMVUTTRA, please see the full Prescribing Information.

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, AMVUTTRA is approved and marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. 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. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com.

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. 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, Alnylam's expectations regarding the safety and efficacy of vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy, including its potential to become a first-line therapy for patients with ATTR amyloidosis with cardiomyopathy, and the timing of Alnylam's global regulatory submissions for vutrisiran 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.

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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