Roche And Alnylam Move Zilebesiran Into Global Phase III Trial To Evaluate Cardiovascular Outcomes In People With Uncontrolled Hypertension

Roche and Alnylam have announced plans to start a Phase III cardiovascular outcomes trial (CVOT) to assess whether zilebesiran, an RNA interference (RNAi) therapeutic, can reduce the risk of major adverse cardiovascular events in people with uncontrolled hypertension. The decision is based on findings from the KARDIA Phase II program, which included the KARDIA-1, KARDIA-2, and KARDIA-3 studies. KARDIA-3 specifically aimed to help identify the patient group most likely to benefit from zilebesiran in the planned outcomes trial.

In KARDIA-3, patients receiving a single 300 mg subcutaneous dose of zilebesiran every six months showed clinically meaningful placebo-adjusted reductions in office systolic blood pressure. At the primary endpoint of month three, the reduction was -5.0 mmHg, and sustained benefits were seen through month six with a reduction of -3.9 mmHg. The higher 600 mg dose did not provide additional benefit at either month three or six. While the trial did not meet the strict statistical threshold for significance due to its testing design, the results highlighted the patient population that could benefit most, while also showing promising safety and reductions in blood pressure.

As seen in KARDIA-2, combining zilebesiran with a diuretic appeared especially effective. In patients with a baseline blood pressure above 140 mmHg who were taking a diuretic, placebo-adjusted reductions of -9.2 mmHg at month three and -8.3 mmHg at month six were reported. These findings align with existing clinical evidence showing the benefits of such combinations in achieving stronger blood pressure control.

Zilebesiran also demonstrated a favorable safety profile, even among patients with multiple conditions who were already being treated with ACE inhibitors or angiotensin receptor blockers. More than 90% of participants were on these therapies, underscoring zilebesiran’s potential to be safely combined with standard antihypertensive treatments.

Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development, said in a statement, “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 zilbesiran into Phase III. Despite current treatment options, up to 80% of people with hypertension do not achieve adequate blood pressure control putting them at higher risk of cardiovascular events. Therefore, additional treatment options are needed.”

Based on these results, Roche and Alnylam have submitted the Phase III ZENITH trial to global regulators, with initiation expected by the end of 2025. ZENITH will enroll about 11,000 patients with uncontrolled hypertension who are already on two or more antihypertensives, including a diuretic, and who either have established cardiovascular disease or are at high risk. The study will evaluate zilebesiran (300 mg every six months) compared with placebo to determine its effect on major cardiovascular outcomes.

Hypertension remains the leading cause and the most significant modifiable risk factor for cardiovascular disease. Globally, more than 1.2 billion people are affected, and despite the availability of multiple antihypertensive options, up to 80% fail to achieve adequate blood pressure control. Poor adherence to daily oral medications plays a major role in this challenge. 

A long-acting therapy like zilebesiran, administered twice a year, may offer a practical solution by providing continuous control and potentially reducing the burden of uncontrolled hypertension. Through its cardiometabolic portfolio and diagnostic expertise, Roche aims to drive new standards of care that can improve outcomes for patients and ease the overall burden on healthcare systems and society.