Kardia-3: Zilebesiran as Add-on Therapy in Adults with Hypertension and Established Cardiovascular Disease Or High Cardiovascular Risk with and without Chronic Kidney Disease

Abstract

Objective: - Zilebesiran is an investigational RNA interference therapeutic that reduces hepatic angiotensinogen production, with potential to improve continuous control of blood pressure (BP) with 6-monthly subcutaneous dosing. KARDIA-3 evaluated zilebesiran in patients with uncontrolled hypertension at high cardiovascular (CV) risk, with or without chronic kidney disease, to inform the design of a Phase 3 CV outcomes trial. Design and method: - KARDIA-3 was a Phase 2, randomized, double-blind, placebo-controlled trial (NCT06272487). Eligible patients had established CV disease or high CV risk, uncontrolled hypertension (mean office systolic BP 140-170 mmHg at screening, and 24-hour mean ambulatory systolic BP 130-170 mmHg within 7 days before randomization), while treated with 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 efficacy outcome, assessed in Cohort A, was change in mean office systolic BP from baseline to month 3. Result(s): - Overall, 373 patients (Cohort A: 270; Cohort B: 103) were randomized (median age [IQR] 68.0 [62-74] years; 44.5% female; 23.3% Black). At month 3 in Cohort A, least-squares mean differences (95% CI) between zilebesiran and placebo in office systolic BP were -5.0 (-9.9, -0.2, p=0.04) mmHg and -3.3 (-8.2, 1.6, p=0.18) mmHg for the 300 mg and 600 mg doses, respectively, p-values were not statistically significant after adjustment for multiplicity. Across Cohorts A and B, most adverse events were mild or moderate and transient. Rates of hyperkalemia, hypotension, and kidney dysfunction were low and most were not confirmed by subsequent measurements. There was no evidence of dose-dependent adverse events. Conclusion(s): - KARDIA-3 demonstrated an acceptable safety profile of zilebesiran in patients with uncontrolled hypertension at high CV risk, including in patients with low baseline eGFR. The totality of evidence from the Phase 2 zilebesiran program informed the design of ZENITH (NCT07181109), an ongoing global CV outcomes trial enrolling patients with hypertension and established CV disease or high CV risk. Copyright © 2026 Wolters Kluwer Health, Inc. All rights reserved.