Zilebesiran: an RNA interference agent-its need and potential to transform hypertension treatment

Hypertension remains the leading modifiable risk factor for cardiovascular morbidity and mortality worldwide, yet nearly half of patients fail to achieve target blood pressure (BP) despite the availability of multiple antihypertensive agents. Non-adherence, therapeutic inertia, and complex dosing regimens continue to undermine treatment effectiveness. The renin-angiotensin-aldosterone system (RAAS) is central to BP regulation, and long-term blockade of its components reduces cardiovascular risk. However, current therapies require daily adherence. Zilebesiran, a novel RNA interference (RNAi) therapeutic, represents an innovative approach by silencing hepatic angiotensinogen (AGT) synthesis, offering sustained RAAS suppression with infrequent dosing.

Zilebesiran is a GalNAc-conjugated small interfering RNA (siRNA) that targets AGT mRNA in hepatocytes via asialoglycoprotein receptor-mediated delivery. This mechanism leads to durable reductions in circulating AGT and downstream angiotensin II, providing consistent BP lowering for up to 6 months after a single subcutaneous injection. Phase I and II trials demonstrated > 90% AGT suppression and clinically significant reductions in 24-h systolic BP (- 10 to - 27 mmHg), with favorable safety and tolerability. The KARDIA-1 and KARDIA-2 studies confirmed zilebesiran's sustained efficacy as monotherapy and as an adjunct to standard antihypertensive agents, without major renal or electrolyte disturbances.

Zilebesiran may redefine therapy in hypertension management through twice-yearly dosing that enhances adherence, ensures sustained BP control, and may reduce cardiovascular risk. Ongoing Phase III trials (ZENITH and KARDIA-3) will clarify its long-term efficacy, safety, and applicability across diverse populations, potentially establishing RNAi therapeutics as a new frontier in chronic hypertension treatment.