Oct 01, 2025 Press Release for Alnylam

Alnylam Announces First Patient Dosed in ZENITH Global Phase 3 Cardiovascular Outcomes Trial of Zilebesiran

Oct 01, 2025

- Global Cardiovascular Outcomes Trial will Enroll ~11,000 Patients Across 35 Countries to Evaluate Zilebesiran as a Novel Biannual Treatment -

- Trial to Assess Zilebesiran in Patients with Uncontrolled Hypertension with Either Established or at High Risk of Cardiovascular Disease -

- Milestone Payment of $300 Million Triggered Under Global Collaboration and License Agreement with Partner Roche -

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Oct. 1, 2025-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the first patient has been dosed in ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension), a global Phase 3 cardiovascular outcomes trial (CVOT) designed to evaluate the potential of zilebesiran, an investigational biannual subcutaneously administered RNAi therapeutic, to reduce the risk of major adverse cardiovascular (CV) events in patients with uncontrolled hypertension. Zilebesiran works by targeting liver-expressed angiotensinogen (AGT), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), which plays a key role in blood pressure regulation and impacts CV and renal health.

“The first patient dosed in our pivotal global Phase 3 cardiovascular outcomes trial, ZENITH, marks a major milestone in our commitment to exploring the ability of zilebesiran to reduce cardiovascular risk in patients with uncontrolled hypertension, a leading addressable cause of cardiovascular morbidity and mortality worldwide,” said Weinong Guo, MD, PhD, Senior Vice President, Clinical Research at Alnylam. “By targeting the most upstream precursor of the RAAS, zilebesiran offers the potential for sustained, 24-hour, continuous control of blood pressure with biannual dosing in patients with high unmet need. It is one of the many novel RNAi therapeutics in our pipeline that demonstrates our long-term commitment to transforming the treatment of cardiovascular disease and improving outcomes for patients.”

In this global multi-center Phase 3 ZENITH CVOT (NCT07181109), Alnylam and its partner Roche will enroll approximately 11,000 patients in 35 countries to evaluate zilebesiran (300 mg) administered every six months compared to placebo in patients with uncontrolled hypertension with either established CV disease or at high risk for CV disease despite the use of at least two or more antihypertensives. The primary objective will be to assess the impact of zilebesiran on reducing the risk of CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure (HF) events (hospitalization for HF or urgent HF visit), compared to placebo.

In August, Alnylam presented data from KARDIA-3 (Cohort A), the final study in the comprehensive KARDIA Phase 2 clinical program, as a late-breaking abstract at the European Society of Cardiology (ESC) Congress in Madrid, Spain. For additional details on the KARDIA-3 Cohort A presentation, please visit Capella. Results from KARDIA-3 Cohort B will be presented at the American Heart Association (AHA) Scientific Sessions 2025.

For more information on ZENITH, please visit www.clinicaltrials.gov (NCT07181109).

About Zilebesiran
Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of hypertension to reduce cardiovascular risk in high unmet need populations. Zilebesiran targets angiotensinogen (AGT), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), which plays a role in blood pressure (BP) regulation and impacts cardiovascular and renal health. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein, and ultimately, in the vasoconstrictor angiotensin (Ang) II. Zilebesiran utilizes Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables infrequent biannual subcutaneous dosing and increased selectivity. Zilebesiran has demonstrated the ability to provide continuous control of BP with biannual dosing in patients with mild-to-moderate hypertension as a monotherapy and in combination with standard-of-care antihypertensives, as well as in patients with high cardiovascular risk and uncontrolled hypertension despite the use of multiple background therapies. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche.

About Cardiovascular Disease and Hypertension
Cardiovascular disease (CVD) is a global health crisis and a leading cause of death worldwide, responsible for approximately 20 million deaths annually.^1,2 Hypertension is the primary cause of and number one modifiable risk factor for CVD.³ An estimated 1 in 3 adults worldwide have hypertension, and despite wide availability of antihypertensives, up to 80% of all patients, and up to a third of treated patients, do not reach and maintain blood pressure (BP) targets.⁴ Even when BP appears well-managed, continuous control of BP may remain suboptimal, leading to variability in BP during the 24-hour period and in the long-term, putting patients at greater risk of cardiovascular events and end organ damage.^5-11 These patients require novel approaches that not only reduce BP, but also lower overall cardiovascular risk.

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.¹² 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.¹³ 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.¹² 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, statements regarding the number of patients who will be enrolled in the ZENITH trial and the number of countries in which those patients will be located; the potential safety and efficacy of zilebesiran for the treatment of uncontrolled hypertension, including the ability of zilebesiran to reduce cardiovascular risk in patients with uncontrolled hypertension; the potential for zilebesiran to provide sustained, 24-hour, continuous control of blood pressure with biannual dosing in patients with high unmet need; Alnylam’s long-term commitment to transforming the treatment of cardiovascular disease and improving outcomes for patients; and Alnylam’s ability 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, including zilebesiran; 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; 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.

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² Lindstrom M, DeCleene N, Dorsey H, et al. J Am Coll Cardiol. 2022;80:2372-2425.
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⁷ Doumas M, Tsioufis C, Fletcher R, et al. J Am Heart Assoc. 2017;6(11).
⁸ Mezue K, Goyal A, Pressman GS, et al. J Clin Hypertens. 2018;20:1247-1252.
⁹ Rothwell PM, Howard SC, Dolan E, et al. Lancet. 2010;375:895-905.
¹⁰ Tatasciore A, Renda G, Zimarino M, et al. Hypertension. 2007;50:325-332.
¹¹ Mokadem ME, Boshra H, El Hady YA, et al. J Hum Hypertens. 2019;34:641-647.
¹² Elbashir SM, Harborth J, Lendeckel W, et al. Nature. 2001;411(6836):494-498.
¹³ Zamore P. Cell. 2006;127(5):1083-1086.

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Alnylam Pharmaceuticals, Inc.

Christine Akinc
(Investors and Media)
+1-617-682-4340

Josh Brodsky
(Investors)
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Source: Alnylam Pharmaceuticals, Inc.