Investigational RNA Drug Zilebesiran Enters Phase 3 MACE Trial in 11,000 Patients With Uncontrolled Hypertension

The ZENITH trial, sponsored by Alnylam Pharmaceuticals, will test whether zilebesiran — a silencing RNA that targets the root of the blood-pressure cascade — reduces heart attacks, strokes, and cardiovascular death in high-risk patients already on standard therapy.

A Phase 3 trial is now recruiting patients to find out whether an investigational RNA-based medicine can cut the rate of major heart attacks, strokes, and cardiovascular deaths in people whose blood pressure remains too high despite standard drug therapy.

The study, known as ZENITH (NCT07181109), is sponsored by Alnylam Pharmaceuticals in collaboration with Hoffmann-La Roche and will enroll 11,000 participants across 856 sites worldwide — making it one of the largest cardiovascular outcomes trials currently underway.

What Is Zilebesiran?

Zilebesiran is an investigational small interfering RNA (siRNA) designed to silence the hepatic gene that produces angiotensinogen — the protein at the very top of the renin-angiotensin-aldosterone system (RAAS), the pathway that regulates blood pressure. By blocking angiotensinogen production in the liver, the drug aims to suppress the entire RAAS cascade at its source, a fundamentally different approach from existing antihypertensives such as ACE inhibitors or ARBs, which act further downstream.

Trial Design

ZENITH is a global, randomized, double-blind, placebo-controlled Phase 3 trial. Participants must be adults with established cardiovascular disease (age 18 or older) or high cardiovascular risk (age 55 or older), already taking at least two standard antihypertensive medications including a diuretic, yet still inadequately controlled. The study is event-driven, with follow-up of up to approximately five years.

The trial’s primary endpoint is the time to first occurrence of a composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, or a heart failure event (defined as hospitalization for heart failure or an urgent heart failure visit).

The trial began recruiting in September 2025, with an estimated completion date of September 2030. No efficacy or safety results have been posted to the registry.

Zilebesiran is an investigational drug that has not been approved by any regulatory authority. This article reports trial design only; no results are available.

Trials Today

Phase 3 ZENITH / zilebesiran (siRNA antihypertensive) — 11,000-patient CV outcomes trial; composite endpoint of CV death, MI, stroke, HF hospitalization over ~5 years; twice-yearly dosing investigational.

Phase 3 COMBINE 2 / IcoSema (insulin icodec + semaglutide) — 683-patient trial in T2DM inadequately controlled on GLP-1 RA; 52-week results posted with HbA1c change as primary endpoint.

Phase 3 CONVOKE / CT-155 digital therapeutic for schizophrenia — 464-patient trial for negative symptoms of schizophrenia (Click Therapeutics/Boehringer Ingelheim); primary endpoint completed June 2025, results pending.

Phase 3 PRIOH-1 / pritelivir for acyclovir-resistant HSV — 158-patient trial in immunocompromised patients; novel helicase-primase inhibitor; completed November 2025, results imminent.

Phase 3 PREGnant / elagolix pre-IVF in endometriosis — NIH/NICHD-funded, 103-patient trial at Yale; live birth rate primary endpoint; completed May 2025, results posted.

At the Agencies

BD ChloraPrep / FREPP — Nationwide Voluntary Recall — Aspergillus penicillioides contamination in specific lots of ChloraPrep 1 mL and FREPP 1.5 mL chlorhexidine skin-prep applicators; risk of sepsis and death in surgical patients; distributed to hospitals March-June 2024.

J&J Cerenovus CEREPAK — Class I Recall — Higher-than-expected failure-to-detach rate linked to four serious injuries and one death; risks include hemorrhagic/ischemic stroke; ~12,000 units across 11 product lines.

GE HealthCare MIM Contour ProtegéAI+ 2.0 — FDA 510(k) Clearance — First radiation oncology AI software cleared with a Predetermined Change Control Plan (PCCP), allowing model updates without new 510(k) submissions; cleared June 4, 2026.