Alnylam Advances Zilebesiran Toward Twice-Yearly Blood Pressure Control in 11,000-Patient ZENITH Outcomes Trial
Key Insights
Alnylam outlined Phase III plans for zilebesiran, an RNAi therapy targeting angiotensinogen (search) to deliver blood pressure control with twice-yearly 300 mg injections.
The event-driven ZENITH trial, run with Roche, began last September and aims to enroll 11,000 patients across 35 countries with at least two years of follow-up.
Phase II KARDIA data showed a placebo-adjusted systolic blood pressure reduction of 10 mmHg with monotherapy and sustained 24-hour control for one year.
Alnylam Pharmaceuticals is advancing zilebesiran, an investigational RNA interference therapy designed to control blood pressure with dosing every six months, into a Phase III cardiovascular outcomes trial in patients whose hypertension (search) remains uncontrolled despite multiple oral medicines. The company detailed the program during an RNAi Roundtable, where executives and clinical speakers described the Phase II KARDIA data supporting the twice-yearly 300 mg injection dose selected for Phase III.
Zilebesiran targets angiotensinogen (search), or AGT, the upstream precursor to the renin-angiotensin system that regulates blood pressure. Ishir Bhan, Alnylam's executive director of clinical research and clinical lead for zilebesiran's Phase III study, said that by suppressing AGT production the therapy is intended to act upstream of ACE inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists.
Phase II KARDIA Data Support Six-Month Dosing
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. Patients receiving one dose every six months in KARDIA-1 achieved sustained 24-hour blood pressure control for a year.
Across the Phase II program, which involved 889 patients treated with zilebesiran, Alnylam observed low rates of adverse events including hyperkalemia and hypotension, with most events resolving without intervention or treatment discontinuation.
In KARDIA-3, which enrolled patients taking at least two antihypertensive medicines who had high cardiovascular risk or established cardiovascular disease, Alnylam reported an enhanced blood pressure-lowering response of about 9 mmHg among patients receiving a background diuretic, particularly when baseline systolic blood pressure was at least 140 mmHg. Bhan said KARDIA-3 also showed reductions in biomarkers including NT-proBNP and urine albumin-to-creatinine ratio among patients with modest baseline elevations.
ZENITH Compares Zilebesiran With Standard Care
Simon Fox, Alnylam's vice president and program lead for zilebesiran, said the event-driven ZENITH study compares zilebesiran with standard care in patients with uncontrolled hypertension (search) despite multiple oral antihypertensive medicines who either have established cardiovascular disease or are at high cardiovascular risk. The trial's primary outcome includes cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure (search) or urgent heart-failure visits.
ZENITH began last September and is intended to enroll 11,000 patients across 35 countries, with a minimum follow-up of two years. Fox said the trial is Alnylam's largest to date and that the company is actively screening and randomizing patients in all target countries, with enrollment on track. The program has received Fast Track designation from the U.S. Food and Drug Administration (search) and Breakthrough Therapy designation in China.
During the question-and-answer session, Bhan said Alnylam expects a potential 15% to 20% reduction in major adverse cardiovascular events based on blood pressure reductions observed in the Phase II target population. He said ZENITH was conservatively powered to assess an effect of that magnitude, though the study allows background medications to be adjusted.
The Treatment Gap in Hypertension
Pushkal Garg, Alnylam's chief research and development officer, said hypertension (search) 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.
Akshay Desai, professor of medicine at Harvard Medical School, said hypertension (search) prevalence has increased steadily, reaching nearly 1 billion people globally under the historical threshold of blood pressure above 140 mmHg, and that the disease contributes to ischemic heart disease, stroke, chronic kidney disease (search) and heart failure (search). 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 (search) and visit-to-visit blood pressure variability are associated with higher cardiovascular risk.
Commercial and Development Planning
Fox said Alnylam and Roche are also building manufacturing capacity, generating real-world evidence and preparing commercial infrastructure should the program succeed. The companies are assessing potential future development opportunities in heart failure (search) and chronic kidney disease (search).
Victoria Silva, Alnylam's vice president and head of U.S. TTR marketing, said the company views zilebesiran as a potential cardiovascular-protection therapy rather than simply another blood pressure-lowering treatment. She said cardiovascular outcomes data would be important for physician adoption, payer access and potential positioning in a market dominated by generic oral medicines. Alnylam's executives said the company believes outcomes data from ZENITH will be necessary to differentiate zilebesiran from existing therapies and to test whether continuous blood pressure control can translate into reduced cardiovascular events.