Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension

This phase 1 multicenter trial evaluated zilebesiran, a hepatocyte-targeted small interfering RNA (siRNA) therapeutic designed to suppress hepatic angiotensinogen production, thereby lowering blood pressure. Patients with hypertension were randomized to receive single ascending subcutaneous doses of zilebesiran (10–800 mg) or placebo, with additional arms assessing high- vs. low-salt diets (Part B) and coadministration with irbesartan (Part E). Zilebesiran ≥200 mg produced dose-dependent reductions in serum angiotensinogen (≥90%) and sustained 24-hour ambulatory blood pressure reductions (≥10 mm Hg systolic, ≥5 mm Hg diastolic) through week 24. Blood pressure lowering was enhanced with irbesartan and blunted by high salt intake. Adverse events were mostly mild; transient injection-site reactions occurred in 6%. No drug-related hypotension, hyperkalemia, or renal injury was reported. Pharmacodynamic effects were consistent across dosing cohorts, and blood pressure improvements persisted throughout the diurnal cycle.

This phase 1 multicenter trial evaluated zilebesiran, a hepatocyte-targeted small interfering RNA (siRNA) therapeutic designed to suppress hepatic angiotensinogen production, thereby lowering blood pressure. Patients with hypertension were randomized to receive single ascending subcutaneous doses of zilebesiran (10–800 mg) or placebo, with additional arms assessing high- vs. low-salt diets (Part B) and coadministration with irbesartan (Part E). Zilebesiran ≥200 mg produced dose-dependent reductions in serum angiotensinogen (≥90%) and sustained 24-hour ambulatory blood pressure reductions (≥10 mm Hg systolic, ≥5 mm Hg diastolic) through week 24. Blood pressure lowering was enhanced with irbesartan and blunted by high salt intake. Adverse events were mostly mild; transient injection-site reactions occurred in 6%. No drug-related hypotension, hyperkalemia, or renal injury was reported. Pharmacodynamic effects were consistent across dosing cohorts, and blood pressure improvements persisted throughout the diurnal cycle.