Zilebesiran
From Wikipedia, the free encyclopedia
- Investigational
 | |
| Clinical data | |
|---|---|
| Other names | AD-85481, ALN-85481, ALN-AGT01 |
| Legal status | |
| Legal status |
|
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| UNII | |
| Chemical and physical data | |
| Formula | C89H152N16NaO36P |
| Molar mass | 2076.235 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Zilebesiran (development code ALN-AGT01) is an investigational RNA interference (RNAi) therapeutic agent being developed by Roche and Alnylam Pharmaceuticals for the treatment of hypertension.[1][2]
It is small interfering RNA that is administered subcutaneously twice annually to lower blood pressure in people already taking other antihypertensive drugs.[3][4][5] 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.[1][6][7]
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.[1] The drug utilizes small interfering RNA (siRNA) technology to post-transcriptionally silence the angiotensinogen (AGT) gene in liver cells.[8]
The mechanism involves several steps: zilebesiran, conjugated with GalNAc (N-acetylgalactosamine), binds to the asialoglycoprotein receptor (ASGPR) on hepatocytes, enters endosomes, and releases the siRNA component which then binds to the RNA-induced silencing complex (RISC).[9] The siRNA guide strand hybridizes with AGT mRNA, leading to its degradation and ultimately reducing angiotensinogen protein synthesis.[9]
Clinical studies have shown that zilebesiran reduces serum angiotensinogen levels by more than 90%, leading to downstream reductions in the vasoconstrictor angiotensin II.[2] This approach targets the renin-angiotensin-aldosterone system at its most upstream point, potentially offering more comprehensive blockade than traditional ACE inhibitors or ARBs.[10]
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.[1] 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.[1]
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.[11] Patients experienced consistent and sustained lowering of both daytime and nighttime systolic blood pressure throughout the six-month observation period.[11]
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.[12] The study enrolled 394 adults representing a diverse population and evaluated multiple dose levels of zilebesiran compared to placebo.[12][13]
KARDIA-2 trial
The KARDIA-2 study evaluated zilebesiran as an add-on therapy to standard of care antihypertensive medications.[10] Results announced in March 2024 demonstrated clinically significant blood pressure reductions when zilebesiran was added to existing antihypertensive regimens.[10][14]
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.[15][10][16] Enrollment was completed in 2025, with the study evaluating zilebesiran in combination with at least two antihypertensives in patients with uncontrolled hypertension.[16]
Phase 3 studies
In September 2025, Roche and Alnylam advanced zilebesiran into a global phase III cardiovascular outcomes trial for people with uncontrolled hypertension.[17]
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.[1] 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.[18]
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.[19] 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.[20]
Safety profile
Clinical trials have reported that zilebesiran has a satisfactory safety profile and is well tolerated by patients.[2] The most commonly observed adverse events were mild injection-site reactions at the subcutaneous injection site.[1] No serious adverse events directly attributable to zilebesiran have been reported in published studies.[1]
The safety profile appears favorable across the dose ranges studied, with higher doses showing proportionally greater efficacy without significant increases in adverse events.[18] The infrequent dosing schedule may also contribute to improved patient tolerability and adherence compared to daily oral antihypertensive medications.[20]
Technology platform
Zilebesiran utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables targeted delivery to liver cells and enhanced stability of the siRNA molecule.[10] The GalNAc conjugation allows for specific uptake by hepatocytes through the asialoglycoprotein receptor, ensuring targeted delivery to the site of angiotensinogen synthesis.[9]
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.[21]