Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a pioneer in RNAi therapeutics, has announced positive results from the KARDIA-2 Phase 2 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) for treating hypertension. The study met its primary endpoint, demonstrating clinically and statistically significant reductions in 24-hour mean systolic blood pressure (SBP) at Month 3, as measured by ambulatory blood pressure monitoring (ABPM), across three independent patient cohorts receiving standard background therapies of either a thiazide-like diuretic (indapamide), calcium channel blocker (amlodipine), or angiotensin receptor blocker (olmesartan). Zilebesiran also exhibited a favorable safety and tolerability profile when added to these standard antihypertensive medications, supporting its further development.
Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam, expressed excitement over the significant reduction in systolic blood pressure achieved with a single dose of zilebesiran in patients who were not adequately controlled with common antihypertensive drugs. These promising results from the KARDIA-2 trial underscore zilebesiran’s potential to provide additional blood pressure reduction alongside standard of care medications, with a reassuring safety profile. Alnylam looks forward to presenting the complete data from the KARDIA-2 trial as a late-breaking clinical trial at the upcoming American College of Cardiology Annual Scientific Session.
The KARDIA-2 Phase 2 study, a randomized, double-blind, placebo-controlled trial, assessed the efficacy and safety of zilebesiran in adults with mild-to-moderate hypertension. The study enrolled 672 participants globally across multiple centers. Patients were initially randomized into three cohorts and received open-label therapy with olmesartan, amlodipine, or indapamide as their background antihypertensive medication during a run-in period. Following this period, eligible patients were randomized to receive either zilebesiran or placebo in addition to their background medication for six months.
Primary endpoint analysis focused on the change in mean SBP at Month 3 measured by 24-hour ABPM. Secondary endpoints included SBP and diastolic blood pressure (DBP) changes at various time points, both by ABPM and office measurements, as well as safety assessments throughout the study duration.
In addition to the KARDIA-2 study, Alnylam and Roche have initiated the global KARDIA-3 Phase 2 trial (NCT06272487). This trial aims to evaluate the efficacy and safety of zilebesiran as an add-on therapy in adult patients with high cardiovascular risk and uncontrolled hypertension despite treatment with two to four standard antihypertensive medications. The study will enroll patients with different levels of estimated glomerular filtration rates (eGFR) and assess zilebesiran’s impact on blood pressure control over a 6-month treatment period, with safety monitoring continuing for an additional 6 months.
Primary endpoints for the KARDIA-3 trial include changes from baseline in mean seated office SBP at Month 3, supplemented by additional assessments of SBP changes by ABPM and office measurements at various time points, alongside safety evaluations throughout the study duration.
