Genentech, a subsidiary of Roche, and Alnylam have announced plans to initiate a Phase III cardiovascular outcomes trial for zilebesiran, targeting patients with uncontrolled hypertension.
The late-stage trial is dubbed ZENITH, which expands to ZilebEsiraN cardIovascular ouTcome study in Hypertension.
Zilebesiran, an investigational RNAi therapeutic, aims to reduce major adverse cardiovascular events based on findings from the KARDIA Phase II programme, which includes the KARDIA-1, KARDIA-2, and KARDIA-3 studies.
The KARDIA-3 study highlighted zilebesiran’s potential, showing a single 300 mg dose every six months can lead to significant reductions in systolic blood pressure compared to placebo. While the 600 mg dose did not demonstrate additional benefits, the study identified the patient population most likely to benefit from the treatment.
Results from the KARDIA-2 study indicated that combining zilebesiran with a diuretic provides notable benefits in reducing blood pressure. Patients on diuretics with baseline blood pressure over 140 mmHg experienced significant placebo-adjusted reductions at both three and six months.
Genentech chief medical officer and global product development head Levi Garraway said: “Zilebesiran has the potential to become a best-in-disease treatment for many patients with uncontrolled hypertension. Its blood pressure-lowering effects and twice-yearly dosing could reduce the risk of serious health complications and death.
“Detailed analysis of our comprehensive Phase II clinical trials have informed our decision to move zilebesiran into Phase III.”
Zilebesiran also displayed a favourable safety profile in patients taking multiple background therapies, including ACE inhibitors or Angiotensin Receptor Blockers. This outcome supports the potential for its integration with existing antihypertensive treatments.
The global ZENITH Phase III trial has been submitted for regulatory approval and is anticipated to start by the end of this year. It will involve approximately 11,000 patients with uncontrolled hypertension receiving zilebesiran or placebo every six months.
Alnylam chief research and development officer Pushkal Garg said: “Cardiovascular disease, largely driven by uncontrolled hypertension, is a global health crisis and remains the leading addressable cause of cardiovascular morbidity and mortality.
“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 programme 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.”
Zilebesiran targets angiotensinogen to regulate blood pressure. It uses Alnylam’s Enhanced Stabilization Chemistry Plus technology for biannual dosing and heightened selectivity. However, its safety and efficacy have yet to be established by health authorities such as the US Food and Drug Administration (FDA) or the European Medical Agency (EMA).
Under a partnership announced in July 2023, Alnylam and Roche are co-developing zilebesiran. As per the terms, Alnylam received an upfront cash payment of $310m and can attain additional milestones valued at up to $2.8bn.
The companies will co-commercialise zilebesiran in the US, with Roche holding exclusive commercial rights outside the US.
