− Analyses Presented at the American Heart Association Scientific Sessions 2025 Underscore Vutrisiran’s Differentiated Profile –

− Cardiovascular Magnetic Resonance (CMR) and Echocardiographic Analyses Demonstrate that Treatment with Vutrisiran Resulted in Significant Changes on Multiple Functional and Structural Cardiac Parameters –

– In a Cohort of HELIOS-B Patients, CMR Imaging Showed Amyloid Regression in 22% of Vutrisiran Treated Patients with No Regression Found in Patients Who Received Placebo –

– Treatment with Vutrisiran Preserved Kidney Function in HELIOS-B Patients, and Reduced Risk of Death and Cardiovascular Events in Patients with Advanced Chronic Kidney Disease –

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced results from new post hoc analyses of the HELIOS-B Phase 3 study of AMVUTTRA^® (vutrisiran), an RNAi therapeutic approved for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. Data from cardiovascular magnetic resonance (CMR) and echocardiographic imaging as well as renal function analyses were presented at the American Heart Association (AHA) Scientific Sessions 2025 in New Orleans, Louisiana.

As a multisystem disease, ATTR-CM can impact the health and function of organs throughout the body. These analyses evaluated the effect of vutrisiran on critical measures of heart function and structure as well as kidney health, providing deeper insight into its potential impact on key organs affected by the disease.

HELIOS-B Analyses: Cardiac Structure, Function, and Amyloid Burden

In ATTR-CM, amyloid deposits in the heart lead to thickening and stiffening of the ventricles, affecting how well the heart functions and increasing the risk of heart failure and death. Advanced imaging techniques offer insights into structural and functional changes, capturing the overall burden of amyloid deposits and their impact on cardiac function.

• A CMR analysis evaluated a retrospectively identified cohort of HELIOS-B patients from the National Amyloidosis Centre in London who underwent serial CMR scans as part of their routine clinical care at baseline (N=43), Year 1 (N=39), Year 2 (N=26), and Year 3 (N=17).
  • A mixed model analysis that pooled 24- and 36-month data found that treatment with vutrisiran monotherapy was associated with nominally statistically significant and directionally favorable changes in multiple measures of cardiac structure, function, and amyloid burden, including improvements in left and right ventricular ejection fractions as well as stroke volumes and left ventricular mass, compared to placebo.
  • Treatment with vutrisiran also reduced extracellular volume (ECV), which is thought to reflect amyloid buildup in the heart. At Year 3, amyloid regression, as assessed by ECV, was observed in 22% of patients treated with vutrisiran, while no patients who received placebo showed regression; conversely, progression occurred in 63% of patients who received placebo compared to 11% of patients treated with vutrisiran.
  • At Year 3, patients treated with vutrisiran exhibited an absolute mean (standard deviation) reduction in ECV of -0.10% (± 4.72) versus an increase of 7.86% (± 5.67) in the placebo group (p=0.006).
• To further assess cardiac function in patients with ATTR-CM, echocardiographic parameters including left atrial strain (LAS) and right ventricular free wall strain (RVFWS) were evaluated in analyses of the overall HELIOS-B population.
  • The LAS analysis demonstrated that measures of LAS were associated with baseline disease severity, mortality, and cardiovascular (CV) events, and that patients treated with vutrisiran experienced less worsening in LAS at 30 months, compared to those receiving placebo.
  • The RVFWS analysis showed that worse RVFWS was associated with higher risk of adverse outcomes and that treatment with vutrisiran stabilized RVFWS at 30 months, compared to placebo.

“As ATTR-CM progressively damages the heart muscle, making it thicker, stiffer, and less capable of pumping blood effectively, patients experience worsening symptoms, quality of life, and outcomes,” said Marianna Fontana, M.D., Ph.D., HELIOS-B investigator, Professor of Cardiology, University College London, National Amyloidosis Center, Royal Free Hospital, London. “The HELIOS-B CMR analysis provides compelling initial evidence that treatment with vutrisiran can counteract these changes in some patients, as shown by favorable impacts on measures of cardiac structure and function as well as regression of amyloid burden. These results suggest that vutrisiran has the potential not only to slow disease progression, but to reverse some of the structural damage caused by amyloid deposition in the heart in some patients.”

HELIOS-B Analysis: Renal Function and CV Outcomes in Patients with Severe Chronic Kidney Disease (CKD)

Kidney involvement is common in patients with ATTR-CM and is associated with disease progression along with worse patient outcomes as amyloid deposits in the kidneys can lead to a decline in kidney function, indicated by a decreasing estimated glomerular filtration rate (eGFR).

• A post hoc analysis of the HELIOS-B study evaluated the impact of vutrisiran on renal function and assessed the efficacy and safety of vutrisiran in patients who advanced to severe CKD during the double-blind period. Outcomes, including the composite endpoint of all-cause mortality (ACM) and recurrent CV events, as well as safety, were assessed in patients who advanced to CKD Stage 4 or greater (eGFR < 30 mL/min/1.73 m²) in the overall population, vutrisiran monotherapy population, and baseline tafamidis treatment group.
  • In the overall population, treatment with vutrisiran resulted in fewer patients experiencing ≥40% decreases in eGFR from baseline during the double-blind period, compared to placebo (12.7% vs 21.2%).
  • In patients in the overall population who progressed to CKD Stage 4 or greater during the double-blind period, treatment with vutrisiran reduced the risk of ACM and CV events (hazard ratio [HR] 0.47; 95% confidence interval [CI]: 0.26–0.85), compared to placebo.
  • In both analyses, results observed in patients who progressed to CKD Stage 4 or greater were consistent across the overall population, vutrisiran monotherapy, and baseline tafamidis treatment groups, and were also consistent with vutrisiran’s established efficacy profile from the primary HELIOS-B analysis.
  • The safety profile of vutrisiran in patients who advanced to CKD Stage 4 or greater was comparable with that established in the overall population of the HELIOS-B study.

“The new HELIOS-B analyses add depth to the growing body of evidence supporting AMVUTTRA’s first-line potential in ATTR-CM treatment,” said John Vest, M.D., Senior Vice President, TTR Global Clinical Lead, Alnylam. “From heart structure and function to renal health, the benefits observed are consistent across a wide range of measures and analyses, underscoring the potential for protection of the multiple organs impacted by this systemic disease. These findings build on the broadening dataset from HELIOS-B and continue to support the potential of AMVUTTRA to provide meaningful clinical benefit for patients living with this rapidly progressive multisystem disease.”

Data from the HELIOS-B study supported the approvals of AMVUTTRA for the treatment of the cardiomyopathy of wild-type or hereditary ATTR-CM in adults in the United States (US), Brazil, European Union (EU), Japan, United Arab Emirates (UAE), United Kingdom (UK), and Switzerland. AMVUTTRA is an RNAi therapeutic that works upstream to deliver rapid knockdown of transthyretin, addressing the disease at its source, with four subcutaneous doses per year. Collectively, AMVUTTRA has more than 8,000 patient-years of experience worldwide and is the first RNAi therapeutic approved for the treatment of both ATTR-CM and hATTR-PN in adults.

For additional information on Alnylam’s presentations in ATTR-CM at the AHA 2025 Scientific Sessions, please visit Capella.

Indications and Important Safety Information

Indications Approved by the U.S. FDA

AMVUTTRA^® (vutrisiran) is indicated for the treatment of the:

• cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.
• polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.

Important Safety Information

Reduced Serum Vitamin A Levels and Recommended Supplementation

AMVUTTRA 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

In a study of patients with hATTR-PN, the most common adverse reactions that occurred in patients treated with AMVUTTRA were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%).

In a study of patients with ATTR-CM, no new safety issues were identified.

For additional information about AMVUTTRA, please see the full U.S. Prescribing Information (revised March 2025)

About AMVUTTRA

AMVUTTRA^® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. It is marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults and it is also approved for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults in the US, EU, UK, Brazil, Japan, Switzerland, and UAE. In a clinical study, AMVUTTRA rapidly knocked down TTR in as early as six weeks and decreased TTR levels by 87% with two and a half years of treatment. Administered quarterly via subcutaneous injection, AMVUTTRA is the first and only RNAi therapeutic approved for the treatment of both the cardiomyopathy manifestations of ATTR amyloidosis and the polyneuropathy manifestations of hereditary transthyretin-mediated amyloidosis (hATTR).

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’s commercial RNAi therapeutic products include AMVUTTRA^® (vutrisiran), ONPATTRO^® (patisiran), GIVLAARI^® (givosiran), and OXLUMO^® (lumasiran), which are being developed and commercialized by Alnylam, and Leqvio^® (inclisiran) and Qfitlia^™ (fitusiran), which are being developed and commercialized by Alnylam’s partners, Novartis and Sanofi, respectively. 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 as a treatment for ATTR-CM, including vutrisiran’s impact on measures of cardiac structure and function; the potential for treatment with AMVUTTRA to result in regression of amyloid burden in some patients; the potential of AMVUTTRA to slow disease progression and to reverse some of the structural damage caused by amyloid deposition in the heart in some patients; the potential impact of vutrisiran on key organs affected by ATTR-CM; AMVUTTRA’s potential to be a first-line treatment for ATTR-CM; AMVUTTRA’s potential to protect multiple organs impacted by ATTR-CM and to deliver meaningful clinical benefit for patients living with ATTR-CM; and Alnylam’s ability to execute 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 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 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; the possibility of unfavorable new clinical data and further analyses of existing clinical data; interim and preliminary data; the possibility that clinical data are subject to differing interpretations and assessments by regulatory agencies; actions or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, 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; obtaining, maintaining and protecting intellectual property; 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; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products; the outcome of litigation; the potential risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2024 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 other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing Alnylam’s views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

References

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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