Alnylam Advances Heart Drug Zilebesiran to Phase 3 Trial Despite Mid-Stage Statistical Miss
核心洞察
Alnylam Pharmaceuticals (搜索) and partner Roche will initiate a global Phase 3 cardiovascular outcomes trial for zilebesiran later this year, despite the drug not meeting pre-specified statistical significance in its mid-stage KARDIA-3 study.
The KARDIA-3 Phase 2 study demonstrated clinically meaningful reductions in office systolic blood pressure at Month 3 with sustained benefits through Month 6 using a single 300 mg dose of zilebesiran in patients with uncontrolled hypertension (搜索).
The upcoming ZENITH Phase 3 trial will enroll approximately 11,000 patients across over 30 countries to evaluate zilebesiran's impact on reducing major adverse cardiovascular events in high-risk hypertensive patients.
Alnylam Pharmaceuticals (搜索) and partner Roche are moving forward with a global Phase 3 cardiovascular outcomes trial for zilebesiran, an investigational RNAi therapeutic for heart disease (搜索), despite the drug failing to meet pre-specified statistical significance in its mid-stage trial. The companies plan to initiate the late-stage trial by the end of 2025, demonstrating continued confidence in the therapy's potential despite the setback.
KARDIA-3 Study Results Show Promise Despite Statistical Miss
The decision to advance zilebesiran is based on comprehensive results from the KARDIA Phase 2 program, including the pivotal KARDIA-3 Phase 2 study presented as a late-breaking abstract at the European Society of Cardiology Congress 2025 in Madrid, Spain. The study evaluated zilebesiran's efficacy and safety in patients with uncontrolled hypertension (搜索) and high cardiovascular risk who were already on two or more background antihypertensive medications.
Despite not meeting the pre-specified definition for statistical significance, the KARDIA-3 study met its primary objective by demonstrating clinically meaningful reductions in office systolic blood pressure at Month 3, with sustained benefits extending through Month 6 following a single 300 mg dose of zilebesiran. The results supported a biannual dosing regimen and informed the design of the upcoming Phase 3 trial.
Novel Mechanism Targets Upstream RAAS Pathway
Zilebesiran represents a novel approach to hypertension (搜索) treatment by targeting liver-expressed angiotensinogen (搜索) (AGT (搜索)), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS). This mechanism of action differentiates it from existing therapies by intervening earlier in the blood pressure regulation cascade. The study results showed encouraging safety profiles, with no additional benefits observed at the higher 600 mg dose compared to the 300 mg dose.
Phase 3 ZENITH Trial Design and Scope
Clinical trial applications for the ZENITH Phase 3 trial (ZilebEsiraN CardIovascular OuTcome Study in Hypertension (搜索)) have been submitted to global regulators. The trial will enroll approximately 11,000 patients across more than 30 countries to evaluate zilebesiran 300 mg in patients with uncontrolled hypertension despite using at least two standard of care antihypertensives, with one being a diuretic.
The study population will include patients with either established cardiovascular disease (搜索) or those at high risk for cardiovascular disease. The primary objective of ZENITH will be to assess zilebesiran's impact on reducing the risk of major adverse cardiovascular events, addressing what the companies describe as an area of significant unmet medical need in cardiovascular care.
Commitment Despite Setback
Alnylam remains committed to zilebesiran's development despite the mid-stage trial setback, highlighting the therapy's potential to address uncontrolled hypertension (搜索) in high-risk patients. The company's decision to proceed with the Phase 3 trial reflects confidence in the clinical meaningfulness of the observed blood pressure reductions and the drug's safety profile demonstrated in the KARDIA-3 study.