Abstract Body (Do not enter title and authors here): Background:
Many patients do not reach blood pressure (BP) targets despite wide availability of oral antihypertensives. Zilebesiran is an RNA interference therapeutic that reduces hepatic angiotensinogen production and has potential to provide continuous control of BP with dosing every 6 months. KARDIA-3 aimed to evaluate zilebesiran in patients with uncontrolled hypertension at high cardiovascular (CV) risk, with or without chronic kidney disease (CKD), to inform a Phase 3 CV outcomes trial (CVOT) in this population.
Methods:
KARDIA-3 was a phase 2, randomized, double-blind, placebo-controlled trial to assess efficacy, safety, and dosing of zilebesiran (NCT06272487). Eligible patients had established CV disease (CVD) or high CV risk with uncontrolled hypertension (mean screening office systolic BP [SBP] 140–170 mmHg and 24-hour mean ambulatory SBP 130–170 mmHg) on 2–4 antihypertensives.
Patients in Cohort A (eGFR ≥45 mL/min/1.73 m²) were randomized 1:1:1 to a single subcutaneous dose of zilebesiran 300 mg, 600 mg, or placebo; those in Cohort B (eGFR 30 to <45 mL/min/1.73 m²) were randomized 1:1:1:1 to 150 mg, 300 mg, 600 mg, or placebo. Primary outcome was change from baseline in mean office SBP at Month 3. Secondary outcomes included change in 24-hour mean ambulatory SBP at Months 3 and 6, among other metrics. Cohort B and overall trial results will be reported here.
Results:
374 randomized patients from 6 countries were dosed (270 in Cohort A and 104 in Cohort B). Baseline data for Cohort B: median age was 71 yrs (interquartile range, 66–77), 22% were Black, and 44% were female. Approximately 15% had prior CVD, 85% were at high CV risk, and 60% had diabetes. At baseline, mean office and 24-hour mean ambulatory SBP were 147 mmHg (SD 14) and 143 mmHg (SD 10), respectively, with mean eGFR of 39 mL/min/1.73 m². Patients were on 2 (30%), 3 (43%), or 4 (26%) antihypertensives at baseline (65% on a thiazide, thiazide-like, or loop diuretic, 66% on a calcium channel blocker, and 85% on an angiotensin (Ang)-converting-enzyme inhibitor or Ang receptor blocker). Primary and secondary efficacy outcomes and safety data for Cohort B will be presented for the first time, along with overall trial results.
Conclusions:
Results of the KARDIA-3 trial, including patients with CKD, will characterize the efficacy and safety profile of zilebesiran in patients with uncontrolled hypertension despite standard care who are at high CV risk and will inform the design of a planned CVOT.