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Alnylam Announces Publication of Phase 1 Study Results for Zilebesiran

Key highlights:

Alnylam Pharmaceuticals, Inc. announces that results from its Phase 1 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension, were published in the New England Journal of Medicine (NEJM). The full manuscript is titled, “Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension,” and will appear in the July 20, 2023 issue of NEJM. The key data reported in the publication showed that in the Phase 1 study, compared to placebo, zilebesiran was associated with dose-dependent reductions in serum AGT, achieving tonic blood pressure control with consistent and durable blood pressure reduction throughout a 24-hour period, sustained up to six months after single doses of ≥200 mg of zilebesiran. Zilebesiran also demonstrated an acceptable safety profile supporting continued clinical development; the most frequent treatment-related adverse events were mild, transient injection-site reactions.

“Hypertension is the leading cause of premature death, cardiovascular disease, and chronic kidney disease worldwide, and the global prevalence is steadily increasing in parallel with population aging and secular trends in the prevalence of risk factors including obesity, physical inactivity, and unhealthy diet. Despite the availability of effective antihypertensive treatments, nearly half of patients with hypertension fail to achieve guideline-recommended blood pressure targets, leaving them at residual risk for myocardial infarction, stroke, kidney disease progression, and mortality. For clinicians, the challenge in optimising treatment of hypertension is frequently compounded by poor adherence to prescribed medical therapy and substantial variability in blood pressure between office visits and over the 24-hour cycle,” said Akshay Desai, M.D., the lead author of the manuscript and Director of the Cardiomyopathy and Heart Failure Program in the Advanced Heart Disease Section of the Cardiovascular Division at Brigham and Women’s Hospital. “In this context, the data we have published in NEJM are exciting, suggesting the potential role for zilebesiran to treat hypertension in a novel way via a novel, subcutaneously administered gene silencing approach to hypertension. This novel approach may provide durable, tonic blood pressure control with infrequent, office-based dosing and a favorable safety profile. Additional clinical trials will provide further insights into the potential of this approach to improve clinical outcomes in the growing population of patients with hypertension.”

“The data published in NEJM suggest the potential for zilebesiran to be an effective and highly-differentiated treatment that may help people with hypertension achieve sustained blood pressure control,” said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam. “To that end, we are currently evaluating the safety and efficacy of zilebesiran in our KARDIA Phase 2 clinical program either as a monotherapy (KARDIA-1) or in combination with a standard-of-care antihypertensive medication (KARDIA-2), and we look forward to reporting results from these programs in mid- and late 2023, respectively.”

Summary of Published Results

The study was conducted in 107* patients (zilebesiran, N=80; placebo, N=32) with mild-to-moderate hypertension. In Part A, patients were randomised 2:1 to receive single ascending subcutaneous doses of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo. Part B of the study assessed the effects of zilebesiran (800 mg) on blood pressure under low- and high-salt diet conditions and Part E assessed the effects of zilebesiran (800 mg) coadministration with irbesartan (an angiotensin II receptor blocker). The study primary endpoint was the frequency of adverse events (AEs). AEs were reported for 58 patients receiving zilebesiran (72 percent) and 28 receiving placebo (88 percent). The most frequent treatment-related adverse events were mild, transient injection-site reactions reported in five (6 percent) patients who received zilebesiran. No events of hypotension, hyperkalemia, or worsening renal function requiring intervention were observed. Secondary and exploratory endpoints included change from baseline in serum AGT, pharmacokinetics, and change from baseline in blood pressure. In Part A, versus placebo, zilebesiran was associated with dose-dependent reductions in serum AGT that were sustained for up to six months. Single doses of zilebesiran (≥200 mg) resulted in reductions in systolic (>10 mm Hg) and diastolic (>5 mm Hg) blood pressure by Week 8, which were consistent throughout the diurnal cycle and sustained to six months. At the 800 mg dose, zilebesiran treatment resulted in mean (± standard error) systolic and diastolic reductions of 22.5 ± 5.1 mm Hg and 10.8 ± 2.7 mm Hg at Month 6, respectively. In Parts B and E of the study, blood pressure changes following zilebesiran treatment could be attenuated through high dietary salt intake and were augmented by irbesartan coadministration.

*Five patients receiving placebo in Part A of the study re-enrolled into Part E of the study and thus transitioned from placebo to zilebesiran.

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