Roche, Alnylam to initiate Phase III cardiovascular outcomes trial for zilebesiran.

Roche and Alnylam have announced the decision to initiate a Phase III cardiovascular outcomes trial to evaluate the potential of zilebesiran, a RNAi therapeutic, in reducing major adverse cardiovascular events in patients with uncontrolled hypertension. The decision is based on encouraging safety and efficacy results from the Phase II KARDIA-3 study, which demonstrated clinically meaningful reductions in systolic blood pressure at month three with continuous control through month six. The Phase III trial is expected to be initiated by the end of the year.

Roche and Alnylam Pharmaceuticals have announced plans to initiate a Phase III cardiovascular outcomes trial (CVOT) to evaluate the potential of zilebesiran, an investigational RNAi therapeutic, in reducing major adverse cardiovascular events in patients with uncontrolled hypertension. The decision is based on encouraging safety and efficacy results from the Phase II KARDIA-3 study, which demonstrated clinically meaningful reductions in systolic blood pressure at month three with continuous control through month six [1].

The KARDIA-3 study, presented as a late-breaking abstract at the European Society of Cardiology Congress 2025, showed that a single 300 mg dose of zilebesiran resulted in a placebo-adjusted reduction of office systolic blood pressure (SBP) of -5.0 mmHg at month three (p=0.0431) and -3.9 mmHg at month six (95% CI: -8.5, 0.7). The study also indicated that zilebesiran was safe when combined with two or more antihypertensives, with no additional benefits observed for the 600 mg dose. The results support a biannual dosing regimen and inform the design of the global Phase III trial, ZENITH [1].

The ZENITH trial is expected to initiate by the end of 2025 and will enroll approximately 11,000 patients in over 30 countries. It will evaluate zilebesiran 300 mg every six months compared to placebo 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), and stroke [1].

Pushkal Garg, M.D., Chief Research and Development Officer of Alnylam, stated, "Cardiovascular disease, largely driven by uncontrolled hypertension, is a global health crisis and remains the leading addressable cause of cardiovascular morbidity and mortality. 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" [1].

Neha Pagidipati, M.D., MPH, FACC, Associate Professor of Medicine, Cardiology, Duke Clinical Research Institute, and KARDIA-3 Lead Investigator, added, "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. Therefore, I’m excited by the KARDIA-3 results, which together with the additional Phase 2 data from the KARDIA program, support zilebesiran’s potential to achieve clinically meaningful, sustained blood pressure reductions in high-risk patients" [1].

The KARDIA-3 study included two cohorts, with Cohort A assessing zilebesiran in patients with eGFR ≥ 45 mL/min/1.73m2 and Cohort B including patients with advanced kidney dysfunction (i.e., eGFR between 30 and 45 mL/min/1.73m2). The study demonstrated that zilebesiran 300 mg produced greater SBP reductions at month three and six in patients receiving at least two or more antihypertensives, one being a diuretic, and with office SBP ≥140 mmHg at baseline [1].

The ZENITH trial will provide valuable insights into the long-term cardiovascular benefits of zilebesiran in patients with uncontrolled hypertension. The results of this trial are expected to inform regulatory decisions and guide clinical practice, potentially offering a new treatment option for patients with hypertension and high cardiovascular risk.

References:
[1] https://www.businesswire.com/news/home/20250830851819/en/Alnylam-to-Advance-Zilebesiran-into-Global-Phase-3-Cardiovascular-Outcomes-Trial