- Question
- Can zilebesiran, an RNA interference agent that lowers hepatic angiotensinogen synthesis, reduce blood pressure in adults with mild to moderate hypertension, and at which dosing regimens?
- Design
- Phase 2, randomized, double-blind, placebo-controlled dose-ranging study conducted at 78 sites in 4 countries. A total of 394 patients were randomized (377 in the full analysis set: 302 on zilebesiran and 75 on placebo) with 6 months of follow-up.
- Population
- Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP of 135 to 160 mm Hg after antihypertensive washout. Mean age was 57 years, 44.3% were women and 24.7% were Black patients.
- Intervention
- Subcutaneous zilebesiran in one of four regimens: 150, 300 or 600 mg every 6 months, or 300 mg every 3 months.
- Control
- Subcutaneous placebo given every 3 months.
- Primary outcome
- Between-group difference in least-squares mean change in 24-hour mean ambulatory systolic BP from baseline to month 3.
- Results
- Differences vs placebo in 24-hour systolic BP change at month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with 150 mg every 6 months, -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with 300 mg and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with 600 mg every 6 months. Systolic BP rose by 6.8 mm Hg with placebo.
- Safety
- Adverse events occurred in 60.9% of zilebesiran-treated patients vs 50.7% with placebo; serious adverse events occurred in 3.6% vs 6.7%, respectively. Nonserious drug-related adverse events (mainly injection site reactions and mild hyperkalemia) occurred in 16.9% with zilebesiran and 8.0% with placebo.
- Conclusion
- Zilebesiran, across a range of doses at 3-month or 6-month intervals, significantly reduced 24-hour ambulatory systolic BP at month 3 in adults with mild to moderate hypertension.
- Why it matters
- It provided the first randomized evidence that silencing hepatic angiotensinogen with an infrequent injection can lower blood pressure, opening a novel therapeutic avenue that could improve adherence; as a phase 2 study, it requires confirmation in larger trials with clinical outcomes.
Card generated automatically with AI from the abstract of the original publication and the trial registry; every figure was checked against those sources. It may contain errors: verify the data at the source before using it for clinical decisions.
Generated on October 18, 2026