Zilebesiran
Zilebesiran is an investigational RNA interference therapeutic agent being developed by Roche and Alnylam Pharmaceuticals for the treatment of hypertension.
It is small interfering RNA that is administered subcutaneously twice annually to lower blood pressure in people already taking other antihypertensive drugs. The drug is designed to inhibit hepatic angiotensinogen synthesis through targeted silencing of the angiotensinogen gene, offering the potential for prolonged blood pressure control with infrequent dosing.
Mechanism of action
Zilebesiran works by targeting the hepatic production of angiotensinogen, which is the sole precursor of angiotensin peptides and plays a key role in the pathogenesis of hypertension. The drug utilizes small interfering RNA technology to post-transcriptionally silence the angiotensinogen gene in liver cells.The mechanism involves several steps: zilebesiran, conjugated with GalNAc, binds to the asialoglycoprotein receptor on hepatocytes, enters endosomes, and releases the siRNA component which then binds to the RNA-induced silencing complex. The siRNA guide strand hybridizes with AGT mRNA, leading to its degradation and ultimately reducing angiotensinogen protein synthesis.
Clinical studies have shown that zilebesiran reduces serum angiotensinogen levels by more than 90%, leading to downstream reductions in the vasoconstrictor angiotensin II. This approach targets the renin-angiotensin-aldosterone system at its most upstream point, potentially offering more comprehensive blockade than traditional ACE inhibitors or ARBs.
Clinical development
Phase 1 studies
The first-in-human Phase 1 study of zilebesiran was a randomized, double-blind, placebo-controlled trial conducted in 107 patients with mild-to-moderate hypertension. Results published in the New England Journal of Medicine in July 2023 demonstrated that single subcutaneous doses of zilebesiran led to dose-dependent decreases in both serum angiotensinogen levels and 24-hour ambulatory blood pressure that were maintained for up to 24 weeks.The study showed that doses of 200 mg or higher achieved sustained blood pressure reductions, with the 800 mg dose producing mean reductions in 24-hour systolic blood pressure of greater than 20 mmHg at six months. Patients experienced consistent and sustained lowering of both daytime and nighttime systolic blood pressure throughout the six-month observation period.
Phase 2 studies
KARDIA-1 trial
The KARDIA-1 Phase 2 trial was a randomized, double-blind, placebo-controlled, multicenter global dose-ranging study designed to evaluate the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. The study enrolled 394 adults representing a diverse population and evaluated multiple dose levels of zilebesiran compared to placebo.KARDIA-2 trial
The KARDIA-2 study evaluated zilebesiran as an add-on therapy to standard of care antihypertensive medications. Results announced in March 2024 demonstrated clinically significant blood pressure reductions when zilebesiran was added to existing antihypertensive regimens.KARDIA-3 trial
The KARDIA-3 Phase 2 study is a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of zilebesiran used as an add-on therapy in adult patients with high cardiovascular risk. Enrollment was completed in 2025, with the study evaluating zilebesiran in combination with at least two antihypertensives in patients with uncontrolled hypertension.Phase 3 studies
In September 2025, Roche and Alnylam advanced zilebesiran into a global phase III cardiovascular outcomes trial for people with uncontrolled hypertension.Clinical efficacy
Clinical trials have demonstrated that zilebesiran provides dose-dependent and sustained blood pressure reductions lasting up to 24 weeks after a single subcutaneous injection. The KARDIA clinical program has enrolled more than 600 patients across Phase 2 trials, demonstrating clinically significant blood pressure reductions with encouraging safety profiles both as monotherapy and as add-on therapy.The drug achieves tonic blood pressure control with consistent and durable blood pressure reduction throughout a 24-hour period, sustained for months after a single dose. This prolonged duration of action represents a potential paradigm shift in hypertension management, offering the possibility of infrequent dosing schedules compared to daily oral medications.
Safety profile
Clinical trials have reported that zilebesiran has a satisfactory safety profile and is well tolerated by patients. The most commonly observed adverse events were mild injection-site reactions at the subcutaneous injection site. No serious adverse events directly attributable to zilebesiran have been reported in published studies.The safety profile appears favorable across the dose ranges studied, with higher doses showing proportionally greater efficacy without significant increases in adverse events. The infrequent dosing schedule may also contribute to improved patient tolerability and adherence compared to daily oral antihypertensive medications.
Technology platform
Zilebesiran utilizes Alnylam's Enhanced Stabilization Chemistry Plus GalNAc-conjugate technology, which enables targeted delivery to liver cells and enhanced stability of the siRNA molecule. The GalNAc conjugation allows for specific uptake by hepatocytes through the asialoglycoprotein receptor, ensuring targeted delivery to the site of angiotensinogen synthesis.This technology platform represents an advancement in RNAi therapeutics, providing prolonged duration of action that distinguishes zilebesiran from traditional small molecule drugs targeting the renin-angiotensin-aldosterone system.