Daily Pharmacy News

Get your free subscription started now. Just enter your email address below.

Zilebesiran for Hypertension

In a phase 1 study, patients with hypertension who received a single subcutaneous dose of the RNA interference agent zilebesiran had dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure for up to 24 weeks. The small interfering RNA product inhibits hepatic angiotensinogen synthesis with a prolonged duration of action.

Patients with hypertension were randomized to a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B looked at the effect of the highest dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E considered that dose when coadministered with irbesartan.

Based on endpoints of safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure during 24-hour ambulatory monitoring, the investigators found: “Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r=−0.56 at week 8; 95% confidence interval, −0.69 to −0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.”

Editorial: “Angiotensinogen suppression in the liver by [small interfering RNA] is a novel and exciting means of targeting the renin–angiotensin system: it offers specificity, long-term efficacy, and sustained blood-pressure lowering,” an editorialist writes. “Although zilebesiran offers new possibilities as an antihypertensive agent, it may also have therapeutic benefit in other conditions associated with activation of the renin–angiotensin system, such as kidney and heart disease.”

Source: New England Journal of Medicine