Alnylam to Advance Zilebesiran into Global Phase 3 Cardiovascular Outcomes Trial

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced plans to initiate a Phase 3 cardiovascular outcomes trial (CVOT) to evaluate the potential of zilebesiran to reduce the risk of major adverse cardiovascular events. This decision is informed by results from the comprehensive KARDIA Phase 2 program, including KARDIA-3 results presented today as a late-breaking abstract at the European Society of Cardiology (ESC) Congress in Madrid, Spain. Zilebesiran is an investigational subcutaneously administered RNAi therapeutic which, in the KARDIA Phase 2 program, has shown reductions in blood pressure 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 cardiovascular and renal health.

KARDIA-3, the third Phase 2 study in the KARDIA program, evaluated the efficacy and safety of zilebesiran in patients with uncontrolled hypertension and high cardiovascular (CV) risk on two or more background antihypertensives. The study met the objective of informing the design, patient population, and dose for the global Phase 3 CVOT, ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension).

Results of KARDIA-3 showed a single 300 mg dose of zilebesiran resulted in clinically meaningful, placebo-adjusted reductions of office systolic blood pressure (SBP) at the Month 3 primary endpoint (-5.0 mmHg; p=0.0431) with sustained benefits out to Month 6 (-3.9 mmHg; 95% CI: -8.5, 0.7). There were no additional benefits of the 600 mg dose at Month 3 (-3.3 mmHg; p=0.1830) or Month 6 (-3.6 mmHg; 95% CI: -8.2, 1.0). The statistical testing of change in office SBP at the Month 3 primary endpoint was controlled for multiplicity, which required both doses to have a p-value of <0.05, or one dose to have a p-value of <0.025, to be considered statistically significant. As such, the study did not meet the pre-specified definition for statistical significance.

As observed in the KARDIA-2 Phase 2 study, the KARDIA-3 results support the biologically based, synergistic effects of combining zilebesiran with a diuretic-containing regimen. In patients with uncontrolled hypertension with a baseline office SBP of ≥140, despite treatment with a diuretic and at least one other antihypertensive, zilebesiran produced an enhanced effect with observed SBP reductions of at least 8 mmHg sustained out to six months.

Zilebesiran demonstrated encouraging safety in patients with comorbidities on multiple background therapies – over 90% of whom were receiving treatment with an ACE inhibitor or an Angiotensin Receptor Blocker (ARB). These findings support zilebesiran's potential to be combined with any standard of care antihypertensive.

As a result, clinical trial applications for the ZENITH Phase 3 trial have been submitted to global regulators. Alnylam and its partner Roche expect the trial to initiate by the end of 2025. ZENITH will be a CVOT enrolling approximately 11,000 patients and evaluating zilebesiran (300 mg) every six months compared to placebo in patients with uncontrolled hypertension with either established cardiovascular disease or at high risk for cardiovascular disease on two or more antihypertensives, one being a diuretic.

“Cardiovascular disease, largely driven by uncontrolled hypertension, is a global health crisis and remains the leading addressable cause of cardiovascular morbidity and mortality,” said Pushkal Garg, M.D., Chief Research and Development Officer of Alnylam. “The KARDIA-3 results demonstrate that a single dose of zilebesiran provided continuous control of blood pressure over the 24-hour period, day and night, for up to six months, while also showing the potential to improve cardiac and renal biomarkers independent of blood pressure reduction. Taken together with the full KARDIA Phase 2 program data, these findings reinforce that targeting angiotensinogen – the most upstream precursor of the RAAS – with zilebesiran offers a differentiated approach that has the potential to improve blood pressure control and cardiovascular outcomes.”

These results add to the growing body of evidence from the KARDIA Phase 2 program, underscoring zilebesiran’s potential to address an area of significant unmet need.

“Patients with uncontrolled hypertension despite the use of multiple background therapies are at the highest risk of major adverse cardiovascular events. It is well known that reductions in systolic blood pressure of five mmHg or more can result in a reduction in cardiovascular risk,” said Neha Pagidipati, M.D., MPH, FACC, Associate Professor of Medicine, Cardiology, Duke Clinical Research Institute, and KARDIA-3 Lead Investigator. “Therefore, I’m excited by the KARDIA-3 results, which together with the additional Phase 2 data from the KARDIAprogram, support zilebesiran’s potential to achieve clinically meaningful, sustained blood pressure reductions in high-risk patients. This, in turn, may lead to more consistent long-term blood pressure control and improve cardiovascular outcomes. Zilebesiran’s emerging profile, now including the KARDIA-3 findings, underscores its ability to address the well-known challenges of managing patients with hypertension, and warrants further exploration in a multi-year Phase 3 cardiovascular outcomes trial.”

KARDIA-3 Cohort A Results:
The KARDIA-3 Phase 2 study included two Cohorts (A and B). Cohort A assessed zilebesiran in patients with eGFR ≥ 45 mL/min/1.73m2, while Cohort B included patients with advanced kidney dysfunction (i.e., eGFR between 30 and <45 mL/min/1.73m2). Cohort A enrolled 270 patients who were randomized to treatment with zilebesiran (300 mg or 600 mg) or placebo. Randomization was stratified by background diuretic use, baseline blood pressure, and race. The primary endpoint was change in office SBP at Month 3. Key secondary endpoints were changes in office SBP at Month 6 and change in 24-hour mean ambulatory SBP at Months 3 and 6.

At baseline, 144 (53.3%), 96 (35.6%), and 30 (11.1%) patients were on two, three, or more than three antihypertensives, respectively, with ~91% of patients taking ACE inhibitors/ARBs, ~66% of patients taking a diuretic, and ~58% of patients taking calcium channel blockers. The mean baseline office and 24-hour mean ambulatory SBP were 143.6 mmHg and 142.4 mmHg, respectively (N= 270).

Cohort A Study population	Endpoint	Month 3 Change (censored)* †	Month 6 Change (all collected) ** †
Overall study population	Office SBP (300 mg)	-5.0 (-9.9, -0.2) p=0.0431	-3.9 (-8.5, 0.7)
	24-Hour Mean Ambulatory SBP (300 mg)	-3.6 (-7.7, 0.4)	-5.5 (-9.4, -1.5)
Enhanced Response Subgroup (Diuretic use with SBP ≥ 140 mmHg at baseline) ***	Office SBP (300 mg)	-9.2 (-17.3, -1.2)	-8.3 (-16.4, -0.2)
	24-Hour Mean Ambulatory SBP (300 mg)	-6.8 (-13.9, 0.2)	-6.6 (-13.3, -0.0)
*** Post hoc Analysis	*Censored analysis excludes patients who intensified antihypertensive use within two weeks of visits at Month 3 **All Collected analysis includes all available patient data, regardless of medication changes, through visits at Month 6 The statistical testing procedure, The Hochberg Method, was used for multiplicity control, requiring both doses to have a p<0.05 or one dose to have a p<0.025 to be considered statistically significant. † The placebo-adjusted SBP changes are shown as LS mean (95% CI)

• In the Cohort A overall study population, zilebesiran 300 mg achieved clinically meaningful reductions in both office and 24-hour mean ambulatory SBP at Month 3, which persisted through Month 6, compared to placebo. No incremental SBP reductions were observed with zilebesiran 600 mg at Months 3 or 6.
• Treatment with zilebesiran 300 mg produced greater SBP reductions at Month 3 and 6 in patients receiving at least two or more antihypertensives, one being a diuretic, and with office SBP ≥140 mmHg at baseline (N=110), compared to placebo.
• Reductions in blood pressure were sustained over six months and the entire 24-hour period. Incremental reductions were also observed at nighttime, a period during which blood pressure elevation is a strong predictor of cardiovascular risk.
• Zilebesiran also led to early and sustained reductions in prognostic cardiovascular and renal biomarkers (NT-proBNP and UACR) in patients with elevated biomarkers at baseline, suggesting the potential to reduce cardiovascular and renal events in high-risk patients with longer term use.
• Consistent with prior studies, zilebesiran demonstrated an encouraging safety profile. Most adverse events were mild or moderate, non-serious, and transient with few requiring intervention; rates of hyperkalemia, kidney dysfunction, and hypotension were low. Across study arms, serious adverse events were observed in 3.8% and 4.5% in zilebesiran and placebo-treated patients, respectively. No deaths were reported during the six-month double-blind period.

Results from KARDIA-3 Cohort B are expected to be presented at an upcoming medical meeting.

Alnylam and its partner Roche will now advance zilebesiran into the global Phase 3 ZENITH CVOT, which is expected to initiate by year-end 2025. ZENITH will enroll approximately 11,000 patients in over 30 countries to evaluate zilebesiran 300 mg in patients with uncontrolled hypertension, despite the use of at least two standard of care antihypertensives (one being a diuretic), and with either established cardiovascular disease (CVD) or at high risk for CVD. The primary objective will be to assess the impact of zilebesiran on reducing the risk of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or heart failure (HF) events (hospitalization for HF or urgent HF visit), compared to placebo.

For additional information on Alnylam’s presentations at ESC Congress 2025, including a new exploratory analysis from the KARDIA-1 study highlighting zilebesiran’s mechanism of action in suppressing all downstream substrates of AGT, please visit Capella.

Investor Webcast Information
Alnylam management as well as Neha Pagidipati, M.D., MPH, FACC, Associate Professor of Medicine, Cardiology, Duke Clinical Research Institute, and Professor Bryan Williams, OBE, M.D., FMedSci, Chair of Medicine, University College London, will discuss the KARDIA-3 results in a live event which will be webcast on August 30, 2025, at 1:00 pm ET (7:00 pm CEST). The webcast 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.

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 Alnylam’s plans to advance zilebesiran into a global Phase 3 cardiovascular outcomes trial (ZENITH) by year-end 2025; the number of patients who will be enrolled in the ZENITH trial, the number of countries in which those patients will be located, and the specific design of the ZENITH trial; the potential safety and efficacy of zilebesiran for the treatment of hypertension, including the potential for a single dose of zilebesiran to provide continuous control of blood pressure over a 24-hour period for up to six months while also improving cardiac and renal biomarkers independent of blood pressure reduction, that targeting angiotensinogen with zilebesiran offers a differentiated approach that has the potential to improve blood pressure control and cardiovascular outcomes, zilebesiran’s ability to be combined with any standard of care antihypertensive, zilebesiran’s potential to address an area of significant unmet need, zilebesiran’s potential to achieve clinically meaningful, sustained blood pressure reductions in high-risk patients, which may in turn lead to more consistent long-term blood pressure control and improve cardiovascular outcomes, and zilebesiran’s ability to address the well-known challenges of managing patients with hypertension; and Alnylam’s expectations regarding its aspiration to become a leading biotech company and the planned achievement of its “Alnylam P⁵ x25” strategy, 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; 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.

¹ GBD 2021 Causes of Death Collaborators. Lancet. 2024;403:2100-2132.
² Lindstrom M, DeCleene N, Dorsey H, et al. J Am Coll Cardiol. 2022;80:2372-2425.
³ Yusuf S, Joseph P, Rangarajan S, et al. Lancet. 2020;395:795-808.
⁴ NCD Risk Factor Collaboration (NCD-RisC). Lancet. 2021;398:957-980.
⁵ Ebinger JE, Driver M, Ouyang D, et al. eClinicalMedicine. 2022;48:101442.
⁶ Kario K. Prog Cardiovasc Dis. 2016;59:262-281.
⁷ Doumas M, Tsioufis C, Fletcher R, et al. J Am Heart Assoc. 2017;6:e006093.
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.

View source version on businesswire.com: https://www.businesswire.com/news/home/20250830851819/en/