Alnylam Advances Zilebesiran to Phase 3 Cardiovascular Outcomes Trial Following Positive KARDIA-3 Results
核心洞察
Zilebesiran demonstrated clinically meaningful reductions in office systolic blood pressure (-5.0 mmHg) at the Month 3 primary endpoint in patients with uncontrolled hypertension (搜索) and high cardiovascular risk.
The investigational RNAi therapeutic showed sustained blood pressure benefits through Month 6 with encouraging safety when combined with two or more antihypertensives.
Alnylam plans to initiate the global Phase 3 cardiovascular outcomes trial ZENITH by year-end 2025, supported by a biannual dosing regimen.
Alnylam Pharmaceuticals (搜索) announced plans to advance zilebesiran into a Phase 3 cardiovascular outcomes trial following positive results from the KARDIA-3 Phase 2 study presented at the European Society of Cardiology Congress 2025. The investigational RNAi therapeutic demonstrated clinically meaningful blood pressure reductions in patients with uncontrolled hypertension (搜索) and high cardiovascular risk.
KARDIA-3 Study Results
The KARDIA-3 study evaluated zilebesiran in patients with uncontrolled hypertension (搜索) and high cardiovascular risk who were receiving two or more background antihypertensive medications. Results showed that a single 300 mg dose of zilebesiran achieved a statistically significant, placebo-adjusted reduction in office systolic blood pressure of -5.0 mmHg at the Month 3 primary endpoint (p=0.0431).
The blood pressure benefits were sustained through Month 6, with a placebo-adjusted reduction of -3.9 mmHg (95% CI: -8.5, 0.7). The higher 600 mg dose did not demonstrate additional benefits, showing reductions of -3.3 mmHg at Month 3 (p=0.1830) and -3.6 mmHg at Month 6 (95% CI: -8.2, 1.0).
Safety Profile and Dosing Strategy
Zilebesiran displayed encouraging safety when combined with two or more antihypertensive medications. The results support a biannual dosing regimen, which could offer significant advantages for patient compliance and continuous blood pressure control.
Phase 3 Trial Design
The comprehensive KARDIA Phase 2 program, including KARDIA-3, has informed the design of the global Phase 3 cardiovascular outcomes trial called ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension (搜索)). The Phase 3 trial is expected to initiate by year-end 2025 and will evaluate zilebesiran's potential to reduce the risk of major adverse cardiovascular events.
Mechanism of Action
Zilebesiran targets angiotensinogen (搜索) (AGT), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS (搜索)), which plays a key role in blood pressure regulation and impacts cardiovascular and renal health. By inhibiting AGT synthesis in the liver, zilebesiran potentially leads to durable reductions in AGT protein and ultimately in the vasoconstrictor angiotensin II.
The therapeutic utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, enabling infrequent biannual subcutaneous dosing with increased selectivity and the potential to achieve continuous blood pressure control.
Clinical Context
Cardiovascular disease (搜索) represents a global health crisis, responsible for approximately 20 million deaths annually. Hypertension (搜索) is the primary cause and number one modifiable risk factor for cardiovascular disease. An estimated one in three adults worldwide have hypertension, and despite wide availability of antihypertensives, up to 80% of all patients and up to a third of treated patients do not reach and maintain blood pressure targets.
Even when blood pressure appears well managed, continuous control may remain suboptimal, leading to variability during the 24-hour period and long-term, putting patients at greater risk of cardiovascular events and end organ damage. These patients require novel approaches that not only reduce blood pressure but also lower overall cardiovascular risk.
Development Partnership
Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA, or any other health authority.