On October 1, 2025, Alnylam Pharmaceuticals announced that the first patient has been dosed in the ZENITH global Phase 3 cardiovascular outcomes trial for its investigational RNAi therapeutic zilebesiran. The announcement, released via BusinessWire, confirms the initiation of the study, which is co‑developed with Roche and will enroll approximately 11,000 patients across 35 countries.
The ZENITH trial will evaluate a 300‑mg subcutaneous dose of zilebesiran administered every six months in patients with uncontrolled hypertension who have either established cardiovascular disease or are at high risk despite use of at least two antihypertensives. The primary endpoint is the reduction in the composite of cardiovascular death, non‑fatal myocardial infarction, non‑fatal stroke, or heart‑failure events, compared with placebo.
Zilebesiran targets liver‑expressed angiotensinogen, the upstream precursor of the renin‑angiotensin‑aldosterone system, and uses Alnylam’s Enhanced Stabilization Chemistry Plus GalNAc conjugate technology to enable biannual dosing. By inhibiting angiotensinogen synthesis, the drug aims to provide durable blood‑pressure control and reduce cardiovascular risk in a high‑unmet‑need population.
The first‑patient dose represents a critical operational milestone for Alnylam’s hypertension pipeline and strengthens its partnership with Roche. Successful outcomes from ZENITH could establish a new therapeutic indication for an RNAi platform, expanding the company’s product portfolio beyond its current transthyretin franchise.
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