Zilebesiran in combination with a diuretic in patients with uncontrolled hypertension: a subgroup analysis from the Phase 2 KARDIA-3 trial

Background Despite availability of oral antihypertensive therapies, most patients do not achieve hypertension (HTN) control. Zilebesiran is an investigational RNA interference therapeutic, dosed subcutaneously (SC) every 6 months to lower production of hepatic angiotensinogen (AGT), the most upstream precursor of the renin–angiotensin–aldosterone system (RAAS). Combining RAAS-targeting agents with a diuretic can enhance blood pressure (BP) lowering via complementary mechanisms. Therefore, the potential benefits of zilebesiran may be further enhanced in patients with confirmed HTN and use of a background diuretic. In the KARDIA-3 Phase 2 trial, 300 and 600 mg doses of zilebesiran plus standard of care antihypertensives led to 5.0 and 3.3 mmHg reductions, respectively, in office systolic BP at Month 3 vs placebo in primary analyses, although statistical significance was not reached after multiplicity adjustment. In a prespecified subgroup analysis in patients on background diuretics, reductions of 6.6 and 5.1 mmHg were observed. Purpose Post hoc analysis was conducted to assess BP lowering with zilebesiran in patients receiving a background diuretic and with baseline office systolic BP ≥140 mmHg. Methods KARDIA-3 is a randomized, placebo-controlled trial. Primary analyses were in a cohort of patients with estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 with uncontrolled HTN on 2–4 antihypertensives and high cardiovascular (CV) risk or CV disease (CVD). Patients received SC zilebesiran 300 or 600 mg or placebo. Mean office and 24-hr mean ambulatory BP was assessed over 6 months. Results In KARDIA-3, 178/270 (65.9%) patients were receiving a background diuretic and 166 (61.5%) had baseline office systolic BP ≥140 mmHg. Overall, 110 patients (41%) met both subgroup criteria (mean age: 66.0 years; female: 48.2%; Black: 16.4%, 24-hr mean ambulatory systolic BP: 144.8 mmHg [SD 8.9], mean office systolic BP: 151.7 mmHg [SD 10.1]). Least squares mean (95% CI) placebo-adjusted change from baseline to Month 3 for zilebesiran 300 and 600 mg were –9.2 (–17.3, –1.2) and –7.0 (–15.3, 1.3) mmHg, respectively, for office and –6.8 (–13.9, 0.2) and –6.0 (–13.5, 1.4) mmHg for ambulatory systolic BP; reductions were sustained to Month 6 (Fig). Adverse event (AE) rates were similar in zilebesiran and placebo groups (31 [43.7%] vs 17 [43.6%]). Incidences of eGFR decline from baseline and hyperkalemia were low and largely transient. There were no hypotension AEs with zilebesiran. Conclusions These post hoc results suggest complementary effects on BP reduction when combining zilebesiran with a diuretic-containing standard of care regimen in patients with uncontrolled HTN. This analysis informed the design of ZENITH (NCT07181109), an ongoing global Phase 3 CV outcomes trial of zilebesiran in patients with HTN receiving ≥2 antihypertensives, including a diuretic, systolic BP ≥140 mmHg at randomization, and CVD or high CV risk.