BACKGROUND AND PURPOSE:

• Angiotensinogen is an upstream precursor involved in a key blood pressure regulation pathway
• Zilebesiran is an investigational RNA interference therapeutic that targets hepatic angiotensinogen synthesis
• Bakris et al. (JAMA, 2024) evaluated the antihypertensive efficacy and safety of different zilebesiran dosing regimens

METHODS:

• Phase 2, randomized, double-blind, dose-ranging study
  • Conducted in 78 sites
  • Canada, Ukraine, the UK, and the US
  • Between July 2021 and June 2023
• Participants
  • Mild to moderate hypertension
    • Daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg
• Intervention
  • Zilebesiran, 1 of 4 subcutaneous regimens, for 6 months
    • 150 mg once every 6 months
    • 300 mg once every 6 months
    • 600 mg once every 6 months
    • 300 mg once every 3 months
  • Placebo, once every 3 months, for 6 months
• Study design
  • Between-group difference in least-squares mean (LSM) was used to assess the primary outcome
• Primary outcome
  • Change from baseline to month 3 in 24-hour mean ambulatory SBP

RESULTS:

• Zilebesiran: 302 participants | Placebo: 75 participants
  • Mean age: 57 (SD, 11) years| Black: 24.7% | Women: 44.3%
• 24-hour mean ambulatory SBP was improved from baseline for all doses of zilebesiran
  • 150 mg zilebesiran every 6 months
    • Mean change: −7.3 mm Hg (95% CI, −10.3 to −4.4)
    • LSM vs placebo: −14.1 mm Hg (95% CI, −19.2 to −9.0) | P<0.001
  • 300 mg zilebesiran every 3 or 6 months
    • Mean change: −10.0 mm Hg (95% CI, −12.0 to −7.9)
    • LSM: −16.7 mm Hg (95% CI, −21.2 to −12.3) | P<0.001
  • 600 mg zilebesiran every 6 months
    • Mean change: −8.9 mm Hg (95% CI, −11.9 to −6.0)
    • LSM: −15.7 mm Hg (95% CI, −20.8 to −10.6) | P<0.001
  • Placebo
    • Mean change: 6.8 mm Hg (95% CI, 3.6 to 9.9)
• Adverse events over 6 months
  • Zilebesiran: 60.9% | Placebo: 50.7%
  • Serious events
    • Zilebesarin: 3.6% | Placebo: 6.7%
  • Nonserious drug-related adverse events
    • Zilebesiran: 16.9% | Placebo: 8.0%
    • Primary injection site reactions and mild hyperkalemia

CONCLUSION:

• Treatment for mild to moderate hypertension with zilbesarin once a quarter or every 6 months, was associated with improvements in 24-hour mean ambulatory SBP at 3 months
• The authors state

These data support the potential for quarterly or biannual dosing of subcutaneous zilebesiran in achieving a consistent pharmacodynamic effect and effective BP reduction through 6 months

Learn More – Primary Sources:

RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial