Alnylam's Zilebesiran Targets Twice-Yearly Blood Pressure Control in ZENITH Trial

Alnylam is developing zilebesiran, an investigational RNAi therapy designed to suppress angiotensinogen and provide sustained blood-pressure control with a twice-yearly injection. Phase II KARDIA results showed approximately 9–10 mmHg reductions in systolic blood pressure, sustained 24-hour control and generally low rates of adverse events, supporting a 300 mg dose for Phase III. The event-driven ZENITH Phase III trial is enrolling 11,000 high-risk patients across 35 countries to determine whether zilebesiran reduces cardiovascular events compared with standard care; Alnylam is targeting a potential 15%–20% reduction in major adverse cardiovascular events.

Alnylam Pharmaceuticals NASDAQ: ALNY outlined its strategy for advancing zilebesiran, an investigational RNA interference, or RNAi, therapy designed to provide sustained blood-pressure control with twice-yearly dosing for people with uncontrolled hypertension and elevated cardiovascular risk. During an RNAi Roundtable, executives and clinical speakers emphasized the global burden of hypertension, challenges with adherence to daily oral therapies and the company’s ongoing Phase III ZENITH cardiovascular outcomes trial, which is being conducted with Roche.

Alnylam’s chief research and development officer, Pushkal Garg, said hypertension remains one of the largest contributors to cardiovascular risk despite the availability of multiple medicines. He cited projections that annual global cardiovascular deaths could rise from 20.5 million in 2025 to 35.6 million by 2050, with deaths attributable to hypertension rising from 11 million to nearly 19 million.

Professor of medicine at Harvard Medical School, Akshay Desai, said hypertension prevalence has increased steadily, reaching nearly 1 billion people globally under the historical threshold of blood pressure above 140 mmHg. He said the disease contributes to ischemic heart disease, stroke, chronic kidney disease and heart failure.

Desai noted that while effective antihypertensive medicines are available, treatment gaps remain substantial. According to his presentation, only 40% of people with hypertension are identified and treated, and only one in five treated patients reaches guideline-recommended blood-pressure targets. He also highlighted poor adherence to oral regimens as a central issue, saying nearly half of patients discontinue prescribed antihypertensive medicines within one year.

In addition to office blood-pressure measurements, Desai said nighttime hypertension and visit-to-visit blood-pressure variability are associated with higher cardiovascular risk.

Alnylam’s executive director of clinical research and clinical lead for zilebesiran’s Phase III study, Ishir Bhan, said zilebesiran targets angiotensinogen, or AGT, the upstream precursor to the renin-angiotensin system that regulates blood pressure. By suppressing AGT production, the therapy is intended to act upstream of ACE inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists.

Bhan said Phase II results from the KARDIA program supported the company’s hypothesis that zilebesiran could deliver continuous blood-pressure control with dosing every six months. In KARDIA-1, patients receiving zilebesiran monotherapy had an average placebo-adjusted systolic blood-pressure reduction of 10 mmHg, according to the presentation.