Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• RNA Therapeutics

Background:

• Angiotensinogen is a key mediator in hypertension pathogenesis.
• Zilebesiran is an RNA interference therapeutic targeting hepatic angiotensinogen synthesis.
• Hypertension remains a significant global health concern requiring novel therapeutic strategies.

Purpose of the Study:

• To evaluate the safety and efficacy of zilebesiran in patients with hypertension.
• To assess the dose-dependent effects of zilebesiran on angiotensinogen levels and blood pressure.
• To investigate the duration of action and effects of zilebesiran under varying dietary salt conditions and with coadministration of irbesartan.

Main Methods:

• Phase 1 study with ascending subcutaneous doses of zilebesiran or placebo.
• Randomized 2:1 assignment, followed for 24 weeks.
• 24-hour ambulatory blood pressure monitoring and serum angiotensinogen level assessment.

Main Results:

• Zilebesiran demonstrated dose-dependent reductions in serum angiotensinogen levels.
• Single doses (≥200 mg) of zilebesiran led to sustained decreases in systolic and diastolic blood pressure for 24 weeks.
• Mild, transient injection-site reactions were the primary adverse events; no significant safety concerns like hypotension or hyperkalemia were reported.

Conclusions:

• A single subcutaneous dose of zilebesiran (≥200 mg) provides sustained reduction in blood pressure and angiotensinogen levels for up to 24 weeks.
• Zilebesiran exhibits a favorable safety profile, with mild injection-site reactions being the main adverse event.
• These findings support zilebesiran as a promising long-acting therapeutic agent for hypertension management.