Alnylam to Progress Heart Drug to Late-Stage Trial Despite Mid-Stage Setback

Alnylam Pharmaceuticals and partner Roche are advancing heart disease therapy zilebesiran to a late-stage trial despite a mid-stage trial setback. The late-stage trial is set to begin later this year. The injectable therapy is designed to treat heart disease, and the company remains committed to its development despite the setback.

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) has announced plans to initiate a global Phase 3 cardiovascular outcomes trial (CVOT) for zilebesiran, an investigational RNAi therapeutic, despite a mid-stage trial setback. The decision to move forward with the trial is informed by results from the comprehensive KARDIA Phase 2 program, including the KARDIA-3 Phase 2 study [1].

The KARDIA-3 study, presented as a late-breaking abstract at the European Society of Cardiology (ESC) Congress 2025 in Madrid, Spain, evaluated the efficacy and safety of zilebesiran in patients with uncontrolled hypertension and high cardiovascular risk on two or more background antihypertensives. The study met its primary objective, demonstrating clinically meaningful reductions in office systolic blood pressure (SBP) at Month 3 and sustained benefits through Month 6 with a single 300 mg dose of zilebesiran [1].

Zilebesiran, which targets liver-expressed angiotensinogen (AGT), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), showed reductions in blood pressure by targeting AGT. The study supported a biannual dosing regimen and informed the design of the global Phase 3 CVOT, ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension) [1].

Despite not meeting the pre-specified definition for statistical significance, the KARDIA-3 results underscored the potential of zilebesiran to address an area of significant unmet need. Zilebesiran demonstrated encouraging safety, with no additional benefits observed with the 600 mg dose [1].

Clinical trial applications for the ZENITH Phase 3 trial have been submitted to global regulators, and Alnylam and Roche expect the trial to initiate by the end of 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 [1].

Alnylam remains committed to the development of zilebesiran despite the setback in the mid-stage trial. The company aims to assess the impact of zilebesiran on reducing the risk of major adverse cardiovascular events in the late-stage trial [1].

References:
[1] https://www.morningstar.com/news/business-wire/20250830851819/alnylam-to-advance-zilebesiran-into-global-phase-3-cardiovascular-outcomes-trial