Zilebesiran, an RNA Interference Agent, Shows Promise for Hypertension in Phase 1 Trial

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A multipart, phase 1 trial provides evidence demonstrating the safety of zilebesiran, an RNA interference agent, which appeared to have a favorable safety profile among adult patients with hypertension.

Data from a phase 1 first-in-human, dose-escalation trial suggest use of zilebesiran, an investigational RNA interference therapeutic agent from Alnylam Pharmaceuticals Inc., could prove useful as a treatment for hypertension.1

Just 4 days after publication of the phase 1 trial in the New England Journal of Medicine, on July 24, 2023, Alnylam Pharmaceuticals announced it had entered into a strategic agreement with Roche to develop and commercialize zilebesiran, which is currently in the phase 2 stage of development.2

“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 optimizing 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 lead investigator Akshay Desai, MD, director of the Cardiomyopathy and Heart Failure Program in the Advanced Heart Disease Section of the Cardiovascular Division at Brigham and Women’s Hospital.3 “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.”

Despite advances in technology and management practices, treatment-resistant hypertension, the most recent data from the American Heart Association suggests nearly half of all US adults having elevated blood pressure.4 Designed to achieve specific reduction in hepatic angiotensinogen messenger RNA (mRNA) levels to reduce production of angiotensinogen, the phase 1 trial of zilebesiran was a 4-part, multicenter trial and conducted in 4 sites in the United Kingdom from May 30, 2019, through January 26, 2022.1

In part A, patients with hypertension were randomized in a 2:1 ratio to a single subcutaneous dose of zilebesiran or placebo therapy for 24 weeks. Of note, zilebesiran doses included in the study were 10, 25, 50, 100, 200, 400, or 800 mg. In part B, investigators assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions. In part E, investigators evaluated the effect of the aforementioned 800 mg dose when administered with irbesartan. Investigators noted part D of the trial is ongoing at the time of publication and part C was a multidose phase, but was removed during a protocol amendment.1

For inclusion in the trial, patients needed to be 18 to 65 years of age with treated or untreated hypertension with a mean seated systolic blood pressure more than 130 to 165 mmHg for parts A and B or more than 135 to 165 mmHg for part E and a mean systolic blood pressure of 130 mmHg or more as assessed by 24-hour ambulatory blood-pressure monitoring after washout of antihypertensive medications for at least 2 weeks. Participants were excluded based on a diagnosis of secondary hypertension, postural hypotension, diabetes, previous cardiovascular events, and current or anticipated treatment with a beta-blocker.1

Endpoints of interest for the phase 2 trial included safety, pharmacokinetic, and pharmacodynamic characteristics as well as the change from baseline in systolic and diastolic blood pressure, which was measured by 24-hour ambulatory blood-pressure monitoring.1

A total of 107 patients were enrolled in the trial. Of these, 84 were enrolled in part A, 12 were enrolled in part B, and 16 were enrolled in part E. Of note, part A included 56 randomized to zilebesiran and 12 randomized to placebo. Part B included 8 randomized to zilebesiran and 4 randomized to placebo. Part E included 5 patients who had participated in part A and received only placebo therapy.1

The overall trial population had a mean age of 53.5 (Range, 35 to 65) years, 62% were men, 25% were Black, and the mean 24-hour systolic blood pressure was 140.3 (Standard deviation, 9.0) mmHg. Investigators pointed out the study population was generally representative of the broader population of people with hypertension in the United Kingdom with regard to sex and race but was younger as a result of patients older than 65 years of age being excluded.1

Upon analysis, there were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention among the study cohort, with 5 mild, transient injection-site reactions observed.1

During part A, use of zilebesiran was associated with decreases in serum angiotensinogen levels correlated with the administered dose (r=−0.56 at week 8; 95% confidence interval [CI], −0.69 to −0.39). Further analysis suggested single doses of zilebesiran at doses of 200 mg or greater were associated with decreases in systolic blood pressure of 10 mmHg or greater and diastolic blood pressure of 5 mmHg or greater by week 8, with these apparent changes consistent throughout the diurnal cycle and sustained to 24 weeks. Analysis of parts B and E of the trial demonstrated results were consistent, with the attenuation effects on blood pressure from a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.1

“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, PhD, vice president and zilebesiran program lead at Alnylam Pharmaceuticals.3 “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.”


  1. Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. New England Journal of Medicine. 2023;389(3):228-238. doi:10.1056/nejmoa2208391
  2. Alnylam announces partnership with Roche to co-develop and co-commercialize zilebesiran, an investigational RN. Investor Relations | Alnylam Pharmaceuticals, Inc. July 24, 2023. Accessed July 24, 2023.
  3. Alnylam announces publication of phase 1 study results for Zilebesiran in the New England Journal of Medicine. Investor Relations | Alnylam Pharmaceuticals, Inc. July 19, 2023. Accessed July 24, 2023.
  4. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association [published correction appears in Circulation. 2023 Feb 21;147(8):e622]. Circulation. 2023;147(8):e93-e621. doi:10.1161/CIR.0000000000001123