Kardia-3 Study Design: Zilebesiran as Add-on Therapy in Patients With High Cardiovascular Risk and Hypertension Inadequately Controlled by Standard of Care Antihypertensives

Objective: Zilebesiran is an investigational subcutaneous (SC) RNA interference therapeutic that targets synthesis of hepatic angiotensinogen, the most upstream precursor of the renin-angiotensin system. In the phase 2 KARDIA-1 (NCT04936035) study, a single dose of zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to 3 and 6 months versus placebo in patients with mild to moderate hypertension. KARDIA-3, a phase 2 randomized, double-blind, placebo-controlled study (NCT06272487) will evaluate the efficacy and safety of zilebesiran as add-on therapy in patients with established cardiovascular (CV) disease or at high CV risk, with uncontrolled hypertension despite treatment with at least 2 standard-of-care antihypertensives. Design and method: KARDIA-3 will enroll adults with seated automated mean office SBP 140-170 mmHg on stable therapy with 2-4 antihypertensives and prior documented CV history or 10-year atherosclerotic CV disease risk >15% or estimated glomerular filtration rate (eGFR) 30-60 mL/min/1.73m 2 at screening in 2 cohorts: Cohort A (∼270 patients, eGFR at least 45 mL/min/1.73m 2 ) and Cohort B (up to 120 patients, eGFR 30 to <45 mL/min/1.73m 2 ). Patients will be randomized 1:1:1 to receive a single SC dose of zilebesiran 300 or 600 mg or placebo in Cohort A, or 1:1:1:1 to receive a single SC dose of zilebesiran 150, 300, or 600 mg or placebo in Cohort B. The primary endpoint is change in mean seated office SBP from baseline to month 3, assessed as the mean difference between each zilebesiran dose and placebo separately for Cohorts A and B. Secondary and exploratory endpoints include other measures of blood pressure response, pharmacodynamics, and safety and tolerability through month 6. Results: KARDIA-3 will initiate enrollment in early 2024. Conclusions: There remains a substantial unmet need to treat uncontrolled hypertension in patients at high CV risk, including those with advanced chronic kidney disease. This novel phase 2 KARDIA-3 study will evaluate efficacy and safety of zilebesiran in patients with or at high risk for CV disease, building on previous phase 1 and 2 studies of this innovative therapeutic.