Zilebesiran, RNAi for Hypertension, Heads to Phase 3 Cardiovascular Outcomes Trial

Alnylam Pharmaceuticals has announced plans to advance zilebesiran, their subcutaneously administered RNA-interfering therapeutic, into a phase 3 cardiovascular outcomes trial in patients with uncontrolled hypertension named the ZENITH trial.

According to the August 30, 2025 announcement, the ZENITH trial’s design is based on data from the KARDIA phase 2 program, including the KARDIA-3 trial, which missed its primary endpoint but met the objective of informing the design, patient population, and dose and was presented at the European Society of Cardiology (ESC) Congress 2025.

“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. This, in turn, may lead to more consistent long-term blood pressure control and improve cardiovascular outcomes,” explained KARDIA-3 principal investigator Neha Pagidipati, MD, MPH, associate professor of Medicine, Cardiology at Duke Clinical Research Institute. “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.”

According to Alnylam Pharmaceuticals, the company, along with partner Roche, expects the trial to initiate by the end of 2025 and to enroll approximately 11,000 patients. The trial will evaluate zilebesiran against placebo in patients with uncontrolled hypertension with either established cardiovascular disease or at high risk for cardiovascular disease on 2 or more antihypertensives, with at least 1 being a diuretic.

The ZENITH’s trial primary endpoint is risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure or urgent heart failure visit relative to placebo therapy.

“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, MD, chief research and development officer of Alnylam.

KARDIA-3 was a double-blind, placebo-controlled, randomized trial of 270 adult patients with established cardiovascular disease or at high cardiovascular risk with uncontrolled hypertension on 2 to 4 antihypertensives from 5 countries. The phase 2 study included 2 cohorts, referred to as cohort A and cohort B, which leveraged the same primary endpoint of change in office systolic blood pressure (SBP) at 3 months.

Investigators presented the results of Cohort A, which included patients with an eGFR of at least 45 mL/min/1.73 m² or more, during a Hot Line presentation at the ESC Congress 2025. Cohort B data, which includes a population with more advanced kidney dysfunction, will be presented at an upcoming medical conference, according to Alnylam Pharmaceuticals.

Cohort A included a total of 270 individuals. The cohort had a mean baseline office SBP of 143.6 mmHg and a 24-hour mean ambulatory SBP of 142.4 mmHg. These patients were randomized 1:1:1 to a single dose of zilebesiran 300 mg, zilebesiran 600 mg, or placebo therapy.

Among the 270 included patients, 53.3%, 35.6%, and 11.1% were on 2, 3, or more than 3 antihypertensives, respectively. Additionally, 90.7% of patients were taking ACE inhibitors or ARBs, 65.9% were taking a diuretic, and 57.7% were taking calcium channel blockers.

Primary results suggested zilebesiran 300 mg was placebo-adjusted reductions of office SBP at the month 3of -5.0 mmHg (95% Confidence Interval [CI], -9.9 to -2.2; P = .0431), with sustained benefits out to month 6 (-3.9 mmHg; 95% CI, -8.5 to 0.7), with no additional benefits observed with the 600 mg dose at month 3 (-3.3 mmHg; P = .1830) or month 6 (-3.6 mmHg; 95% CI, -8.2 to 1.0).

The trial missed its primary endpoint. As the release from Alnylam Pharmaceuticals notes, per the trial’s design, 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 <.05, or 1 dose to have a P-value of <.025, to be considered statistically significant.

Safety data through month 6 indicated adverse events occurred among 43.2%, 51.6%, and 50.5% of the placebo, zilebesiran 300 mg, and zilebesiran 600 mg groups, respectively. Serious events occurred among 4.5%, 1.1%, and 6.6% of the placebo, zilebesiran 300 mg, and zilebesiran 600 mg groups, respectively.

“The totality of the evidence from the phase II programme supports the conduct of a phase III outcomes trial to further assess the potential of zilebesiran for improving cardiovascular outcomes in patients with uncontrolled hypertension,” Pagidipati said.

References:

1. Pagidipati N, Weber M, Saxena M, et al. KARDIA-3: Zilebesiran as add-on therapy in adults with hypertension and established cardiovascular disease or at high cardiovascular risk. Presented at the European Society of Cardiology (ESC) Congress 2025. Madrid, Spain. August 29-September 1, 2025.

2. Alnylam Pharmaceuticals, Inc. Alnylam to Advance Zilebesiran into Global Phase 3 Cardiovascular Outcomes Trial. Investor Relations | Alnylam Pharmaceuticals, Inc. Published August 30, 2025. Accessed August 31, 2025. https://investors.alnylam.com/press-release?id=29246

3. European Society of Cardiology. KARDIA-3 trial examines blood-pressure lowering effects of zilebesiran in hypertensive patients at high cardiovascular risk. Escardio.org. Published August 30, 2025. Accessed August 31, 2025. https://www.escardio.org/The-ESC/Press-Office/Press-releases/KARDIA-3-trial-examines-blood-pressure-lowering-effects-of-zilebesiran-in-hypertensive-patients-at-high-cardiovascular-risk#