Zilebesiran as Add-on Therapy in Patients With Hypertension Inadequately Controlled With a Standard Antihypertensive Medication: Efficacy and Safety Results From the Kardia-2 Study

Objective: Zilebesiran is an investigational RNA interference therapeutic that targets hepatic angiotensinogen, the most upstream precursor of the renin-angiotensin system. In the Phase 2 KARDIA-1 study, single subcutaneous (SC) doses of zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to Months 3 and 6 versus placebo. The objective of KARDIA-2, a Phase 2 randomized, double-blind, placebo-controlled study, was to assess efficacy, safety, and pharmacodynamics of zilebesiran in combination with a standard-of-care antihypertensive medication class in patients with uncontrolled hypertension. Design and method: KARDIA-2 enrolled adults with mild-to-moderate hypertension who were untreated or receiving stable therapy with up to two antihypertensives. Patients entered a run-in period, where previous antihypertensives were discontinued, and were subsequently randomized to open-label, once-daily oral olmesartan 20 or 40 mg, amlodipine 5 mg, or indapamide 2.5 mg as background antihypertensive therapy. After at least 4 weeks of run-in, patients with 24-hr mean ambulatory SBP of 130–160 mmHg were randomized 1:1 to single-dose SC zilebesiran 600 mg or placebo as add-on therapy. Escape antihypertensives could be initiated after Month 3 if a patient's SBP met pre-specified escape criteria. However, assessments while patients were on or within two weeks of stopping any escape medication were excluded in analyses. The primary endpoint was change in 24-hr mean ambulatory SBP from baseline to Month 3, assessed as the least-square mean difference between zilebesiran and placebo. Key secondary endpoints were change from baseline to Month 3 in office SBP, time-adjusted change from baseline to Month 6 in 24-hr mean ambulatory and office SBP, and proportion of patients with 24-hr mean ambulatory SBP less than 130 mmHg and/or a reduction of at least 20 mmHg without escape medication at Month 6. Results: KARDIA-2 enrolled 672 patients and is currently ongoing. Primary, secondary, safety, and pharmacodynamic endpoints will be presented at the meeting. Conclusions: KARDIA-2 will provide insights into the potential benefit of adding zilebesiran to patients with hypertension inadequately controlled with standard-of-care antihypertensive monotherapy, building on efficacy and safety learnings from previous Phase 1 and 2 studies of this novel therapeutic strategy.