Alnylam and its partner Roche will initiate a global Phase 3 cardiovascular outcomes trial for zilebesiran by the end of 2025, according to the company. The ZENITH trial will enroll about 11,000 patients across more than 30 countries to assess the efficacy of a 300 mg twice-yearly dose versus placebo in individuals with uncontrolled hypertension, despite treatment with at least two standard antihypertensives—including a diuretic—and who have established cardiovascular disease or are at high risk for it.
This Phase 3 decision is informed by results from the KARDIA-3 Phase 2 study. A single 300 mg dose of zilebesiran delivered clinically meaningful placebo-adjusted reductions in office systolic blood pressure (−5.0 mmHg at Month 3; sustained −3.9 mmHg at Month 6). The 600 mg dose did not show additional benefits.
KARDIA-3 met its intended goal of guiding trial design rather than demonstrating definitive statistical significance, according to the company. In patients taking a diuretic and with baseline systolic blood pressure above 140 mmHg, reductions were more pronounced (−9.2 mmHg at Month 3; −8.3 mmHg at Month 6).
The company said the favorable safety profile of zilebesiran, including when combined with multiple antihypertensives, supports its further evaluation in a multi-year cardiovascular outcomes trial.
