Physicians' Academy for Cardiovascular Education

Phase 1 study with siRNA targeting hepatic angiotensinogen synthesis in patients with hypertension

Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension

Literature - Desai AS, Webb DJ, Taubel J, et al. - N Engl J Med. 2023 Jul 20;389(3):228-238. doi: 10.1056/NEJMoa2208391

Introduction and methods


Management of hypertension remains suboptimal [1-3]. The siRNA zilebesiran has been designed to specifically inhibit the production of hepatic angiotensinogen. Angiotensinogen is the sole precursor of angiotensin peptides. Zilebesiran may provide sustained reductions in blood pressure (BP) over a longer period of time, requiring only twice-yearly or quarterly subcutaneous injections.

Aim of the study

In this phase 1 study, the authors assessed the safety, pharmacokinetic, and pharmacodynamic profiles of zilebesiran in patients with hypertension. In addition, the effects of zilebesiran on BP under low- or high-salt diet conditions were evaluated, as well as the effects of zilebesiran in combination with irbesartan on safety outcomes and BP.


This phase 1 study with subcutaneous administration of zilebesiran was comprised of 4 parts, of which 3 parts were reported. Part A and B of the study were double-blind, randomized, placebo-controlled studies of a single ascending dose (Part A) and a single fixed dose during low- and high-salt diet conditions (Part B). Part E was an open-label study of a single dose of zilebesiran with daily irbesartan coadministration. A total of 107 patients (18 to 65 years old) with treated or untreated hypertension were included who had a mean seated systolic BP (SBP) as assessed by automated cuff of >130-165 mmHg (Parts A and B) or >135-165 mmHg (Part E) and a mean SBP of >130 mmHg as assessed by 24-h ambulatory BP monitoring after washout of antihypertensive medication. Key exclusion criteria were secondary hypertension, postural hypotension, diabetes, previous CV events, and current and anticipated treatment with betablockers.

In Part A, patients (n=84, 12 per cohort) were randomly assigned in a 2:1 ratio to receive a single dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo. In Part B, patients (n=12) followed a low-salt diet (0.23 g per day) for 1 week (days -21 through -8) followed by a high-salt diet (5.75 g per day) for 1 week, and subsequently randomly assigned in a 2:1 ratio to a single dose of 800 mg zilebesiran or placebo. Patients were rechallenged with the same dietary protocol at days 43 through 56. In Part E, all patients (n=16) received a single 800 mg dose of zilebesiran. Patients with SBP of ≥120 mmHg at week 6 as assessed by 24-h ambulatory BP monitoring received additional treatment with 300 mg irbesartan once daily for 2 weeks. All patients received instructions to limit their salt intake to 2.0 g/day, except during other diet instructions in part B. The treatment period was concluded at week 12, after which patients entered an extended safety follow-up period.


The primary outcome was the frequency of adverse events. Secondary outcomes were pharmacokinetic and pharmacodynamic characteristics, and changes in systolic and diastolic blood pressure, as measured by 24-h ambulatory BP monitoring.

Main results

Safety and adverse events

Pharmacokinetic and pharmacodynamic measurements

Exploratory outcomes


This phase 1 study showed that a single dose of zilebesiran significantly reduces serum angiotensinogen levels and 24-h ambulatory BP in patients with hypertension up to 24 weeks. There were reports of mild injection-site reactions after treatment with zilebesiran, but no reports of hypotension, hyperkalemia, and renal adverse events.


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Find this article online at N Engl J Med.

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