CAMBRIDGE, Mass.– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) announced plans to begin a global Phase 3 cardiovascular outcomes trial (CVOT) of zilebesiran, based on results from its KARDIA Phase 2 program. Findings from the KARDIA-3 study were presented today as a late-breaking abstract at the European Society of Cardiology (ESC) Congress in Madrid, Spain.
Zilebesiran, an investigational subcutaneous RNAi therapeutic, lowers blood pressure by targeting liver-expressed angiotensinogen (AGT), the upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS).
In KARDIA-3, patients with uncontrolled hypertension and high cardiovascular risk on two or more background therapies received a single 300 mg dose of zilebesiran, which produced clinically meaningful, placebo-adjusted reductions in office systolic blood pressure at three months (-5.0 mmHg; p=0.0431) with sustained benefits through six months (-3.9 mmHg; 95% CI: -8.5, 0.7). Patients with baseline systolic blood pressure of 140 mmHg or higher on a diuretic plus at least one additional antihypertensive achieved reductions of eight mmHg or more, sustained for six months.
The trial did not meet its pre-specified statistical significance threshold due to multiplicity requirements, but zilebesiran was generally well tolerated. Over 90 percent of participants were already taking an ACE inhibitor or angiotensin receptor blocker, supporting the drug’s use alongside standard therapies.
Alnylam and partner Roche have submitted applications to regulators for the Phase 3 ZENITH trial, expected to begin by the end of 2025. The study will enroll about 11,000 patients with uncontrolled hypertension and established or high cardiovascular risk, all on at least two antihypertensives including a diuretic. ZENITH will evaluate 300 mg of zilebesiran given every six months compared to placebo.
“Cardiovascular disease, largely driven by uncontrolled hypertension, is a global health crisis and remains the leading addressable cause of cardiovascular morbidity and mortality,” said Pushkal Garg, M.D., Chief Research and Development Officer of Alnylam. “The KARDIA-3 results demonstrate that a single dose of zilebesiran provided continuous control of blood pressure over the 24-hour period, day and night, for up to six months, while also showing the potential to improve cardiac and renal biomarkers independent of blood pressure reduction. Taken together with the full KARDIA Phase 2 program data, these findings reinforce that targeting angiotensinogen – the most upstream precursor of the RAAS – with zilebesiran offers a differentiated approach that has the potential to improve blood pressure control and cardiovascular outcomes.”
“Patients with uncontrolled hypertension despite the use of multiple background therapies are at the highest risk of major adverse cardiovascular events. It is well known that reductions in systolic blood pressure of five mmHg or more can result in a reduction in cardiovascular risk,” said Neha Pagidipati, M.D., MPH, FACC, Associate Professor of Medicine, Cardiology, Duke Clinical Research Institute, and KARDIA-3 Lead Investigator. “Therefore, I’m excited by the KARDIA-3 results, which together with the additional Phase 2 data from the KARDIA program, support zilebesiran’s potential to achieve clinically meaningful, sustained blood pressure reductions in high-risk patients. This, in turn, may lead to more consistent long-term blood pressure control and improve cardiovascular outcomes. Zilebesiran’s emerging profile, now including the KARDIA-3 findings, underscores its ability to address the well-known challenges of managing patients with hypertension, and warrants further exploration in a multi-year Phase 3 cardiovascular outcomes trial.”
