Global phase III trial commences for Zilebesiran, a drug developed by Genentech and Alnylam, in the worldwide population experiencing uncontrolled hypertension to evaluate its impact on cardiovascular outcomes.

In a significant development for the treatment of hypertension, Genentech has announced the initiation of a Phase III cardiovascular outcomes trial (CVOT) for the potential best-in-disease RNAi antihypertensive, zilebesiran. This drug, which requires twice-yearly subcutaneous dosing, is expected to be a game-changer in managing uncontrolled hypertension.

Zilebesiran is set to be evaluated in the global ZENITH Phase III trial, which is expected to enroll approximately 11,000 patients. The trial will assess the ability of zilebesiran to reduce the risk of major adverse cardiovascular events in patients with uncontrolled hypertension. ZENITH will focus on patients with either established cardiovascular disease or those at high risk for CV disease, who are on two or more antihypertensives, one being a diuretic.

Preliminary results from the Phase II KARDIA-3 study have been promising. In the Cohort A study population, zilebesiran 300 mg achieved clinically meaningful reductions in office SBP at month three, with sustained benefits out to month six, compared to placebo. Incremental reductions were also observed at nighttime. An analysis of patients on diuretics and with a baseline BP > 140 mmHg showed placebo-adjusted reductions of -9.2 mmHg at month three and -8.3 mmHg at month six.

Zilebesiran demonstrated an encouraging safety profile when added to two or more background antihypertensives. Most adverse events were mild or moderate, non-serious, and transient, with few requiring intervention. No deaths were reported during the six-month double-blind period, and across study arms, serious adverse events were observed in 3.8% and 4.5% in zilebesiran and placebo-treated patients, respectively.

Results from KARDIA-3 Cohort B are expected to be presented at an upcoming medical meeting. Post-hoc analyses suggest that a greater blood pressure-lowering effect with zilebesiran was observed in patients on diuretic therapy and uncontrolled hypertension at baseline.

In a separate announcement, Genentech has also revealed plans for a Phase III study involving the drug andexanet alfa. This novel antidote is designed to reverse the anticoagulant effects of Factor Xa inhibitors such as apixaban, rivaroxaban, edoxaban, or enoxaparin.

Hypertension, being the primary cause of and number one modifiable risk factor for cardiovascular disease, remains a significant public health concern. Up to 80% of people with hypertension do not achieve adequate blood pressure control, despite the wide availability of antihypertensives. The initiation of these Phase III trials offers hope for improved management and control of hypertension, potentially reducing the incidence of cardiovascular disease.

Global phase III trial commences for Zilebesiran, a drug developed by Genentech and Alnylam, in the worldwide population experiencing uncontrolled hypertension to evaluate its impact on cardiovascular outcomes.