Roche and Alnylam will launch a global Phase 3 clinical trial for zilebesiran, an experimental RNA interference therapeutic for hypertension. The trial, called ZENITH, will assess the effectiveness and safety of a twice-yearly 300 mg dose compared to a placebo in patients with uncontrolled hypertension. The decision to advance to Phase 3 was based on promising results from the earlier KARDIA-3 Phase 2 study.
Trial Design and Patient Population
Licencováno společností GoogleThe ZENITH trial will be a large-scale, international study involving approximately 11,000 patients across more than 30 countries. It will specifically target individuals with uncontrolled hypertension who are already taking at least two standard antihypertensive medications, including a diuretic. Additionally, all participants will either have established cardiovascular disease or be at a high risk for it. The primary goal is to evaluate zilebesiran’s ability to reduce the risk of major adverse cardiovascular events (such as cardiovascular death, heart attack, or stroke) compared to a placebo.
Rationale and Mechanism
The decision to proceed with the trial was supported by data from the KARDIA-3 Phase 2 study. This study showed that a single 300 mg dose of zilebesiran led to a clinically meaningful reduction in systolic blood pressure. For the overall study population, a -5.0 mmHg reduction was observed at month 3, which was sustained at -3.9 mmHg at month 6. In a subgroup of patients on a diuretic with a baseline systolic blood pressure above 140 mmHg, the reductions were even more pronounced, at -9.2 mmHg at month 3 and -8.3 mmHg at month 6. The 600 mg dose did not provide additional benefits.
The drug’s mechanism of action is based on RNA interference (RNAi). Zilebesiran is a small interfering RNA (siRNA) designed to target and silence the production of angiotensinogen (AGT), a protein produced primarily in the liver. AGT is the upstream precursor in the renin-angiotensin-aldosterone system (RAAS), a hormonal pathway that plays a critical role in regulating blood pressure. By inhibiting AGT, zilebesiran effectively blocks the entire RAAS cascade, leading to a sustained reduction in blood pressure with a convenient twice-yearly dosing schedule. This frequent dosing could also help improve patient adherence to treatment. The safety profile observed in Phase 2 studies, even when combined with other antihypertensives, also supported the decision to move forward.