Alnylam Pharmaceuticals, Inc. announced that the KARDIA-2 Phase 2 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension, met the primary endpoint showing that zilebesiran resulted in clinically and statistically significant additive, placebo-adjusted reductions in 24-hour mean systolic blood pressure (SBP) at Month 3 as measured by ambulatory blood pressure monitoring (ABPM) in each of three independent patient cohorts receiving the standardized background therapies of either a thiazide-like diuretic (indapamide), calcium channel blocker (amlodipine) or angiotensin receptor blocker (olmesartan). Zilebesiran demonstrated an encouraging safety and tolerability profile when added to these standard of care antihypertensives. The Company believes these findings support further development.

The KARDIA-2 Phase 2 study is a randomized, double-blind (DB), placebo-controlled study designed to evaluate the efficacy and safety of zilebesiran, when added to standard of care antihypertensive medications, in adults with mild-to-moderate hypertension. This global, multicenter study enrolled 672 adults with hypertension. Patients who met all inclusion criteria and none of the exclusion criteria during a screening period were first randomized into three different cohorts to receive open-label therapy with olmesartan, amlodipine or indapamide as their protocol-specified background antihypertensive medication during a run-in period of at least four weeks.

Following the run-in period, eligible patients were randomized 1:1 to receive 600 mg zilebesiran or placebo in addition to their protocol-specified background antihypertensive medication for six months. The primary endpoint is the change from baseline in mean SBP at Month 3, assessed by 24-hour ABPM. Additional endpoints include the change in 24-hour mean SBP after six months of treatment assessed by ABPM, change in office SBP at Month 3 and Month 6, and change in diastolic blood pressure (DBP) measured by ABPM and office blood pressure at Month 3 and Month 6. Safety will be assessed throughout the study.

Alnylam and Roche also announced the initiation of the global KARDIA-3 (NCT06272487) Phase 2 study, a randomized, DB, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of zilebesiran used as an add-on therapy in adult patients with high cardiovascular risk and uncontrolled hypertension despite treatment with two to four standard of care antihypertensive medications. Patients with estimated glomerular filtration rate (eGFR) =45 mL/min/1.73m2 will be enrolled to cohort A, and patients with eGFR 30 to <45 mL/min/1.73m2 will be enrolled to cohort B. Patients who meet all of the inclusion and none of the exclusion criteria after the screening period will be randomized to receive 300 or 600 mg zilebesiran or placebo in cohort A on day 1, or 150, 300, or 600 mg zilebesiran or placebo in cohort B on day 1, of a 6-month DB treatment period as add-on therapy to their background antihypertensive medications. After the 6-month DB treatment period, patients will enter the 6-month safety follow-up period.

The primary endpoint is the change from baseline at Month 3 in mean seated office SBP. Additional endpoints include change from baseline at Month 3 in 24-hour mean SBP assessed by ABPM, change from baseline at Month 6 in mean seated office SBP and in 24-hour mean SBP assessed by ABPM. Safety will be assessed throughout the study.