The New England Journal of MedicineZilebesiran, an RNA Interference Therapeutic Agent for Hypertension

Angiotensinogen is the sole precursor of angiotensin peptides and plays an important role in hypertension development.

Zilebesiran is an investigational RNA interference therapeutic agent that targets hepatic angiotensinogen synthesis and has potential implications in treating hypertension. A phase 1 study was conducted to assess the effects of zilebesiran on hypertension, with special focus on dosage, safety, pharmacodynamics, and the influence of dietary conditions.

Study Design:

• Participants: 107 patients with hypertension.
• Method: Randomized 2:1 to receive single ascending subcutaneous doses of zilebesiran (10 to 800 mg) or placebo, followed for 24 weeks.
  • Part A: Assessed different dosages of zilebesiran.
  • Part B: Studied the effect of an 800-mg dose on blood pressure under low- or high-salt diet conditions.
  • Part E: Examined the effect of an 800-mg dose when coadministered with irbesartan.
• End Points: Safety, pharmacokinetic and pharmacodynamic characteristics, changes in systolic and diastolic blood pressure.

Key Findings

• Side Effects: 5 mild, transient injection-site reactions; no hypotension, hyperkalemia, or worsening renal function.
• Efficacy in Part A: Dose-correlated decreases in serum angiotensinogen levels; ≥200 mg doses associated with decreases in systolic (>10 mm Hg) and diastolic (>5 mm Hg) blood pressure by week 8, sustained at 24 weeks.
• Results in Parts B & E: Attenuation of effect with high-salt diet; augmented effect with coadministration of irbesartan.

Conclusion

• Zilebesiran demonstrated dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure for up to 24 weeks with a single subcutaneous dose of 200 mg or more; mild injection-site reactions were observed.

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Did You Know?
Approximately 1 in 3 adults, or 33% of the adult population globally, is affected by hypertension.