Roche’s hypertension candidate zilebesiran may have missed the main goal in the last of three midstage trials, yet the pharma giant maintains the results are strong enough to advance the Alnylam-partnered therapy into phase 3.
The KARDIA-3 study featured two groups of patients with uncontrolled hypertension. One group included 270 participants with an approximate glomerular filtration rate (eGFR) of 45 mL/min/1.73m² or above, while the other enrolled patients with lower eGFR values, signaling more advanced kidney impairment.
In the end, the trial failed to show a statistically meaningful reduction in systolic blood pressure (SBP) at the three-month mark, missing its primary endpoint and, in turn, the secondary measures.
Presenting the results Sunday in Spain, Roche explained in its press release that the shortfall was tied to the multiplicity statistical testing method. This required both the 300-mg and 600-mg dose groups to carry p-values below 0.05, or for a single dose group to fall below 0.025.
In data from cohort A, the 300-mg dose appeared to pass the threshold, producing a placebo-adjusted drop in SBP of 5 mmHg with a p-value of 0.0431. By contrast, the 600-mg arm weakened the outcome, showing only a 3.3 mmHg decline.
Even with the overall miss, Roche stressed that the trial achieved its goal of pinpointing patients who may benefit most from zilebesiran, while also delivering favorable safety findings and clinically relevant placebo-adjusted blood pressure decreases.
The Swiss drugmaker examined a section of patients on diuretics who started with systolic blood pressure of 140 mmHg or higher. In this group, SBP fell by 9.2 mmHg at three months, with the effect maintained through six months.
Roche reported that zilebesiran continued to show a favorable safety profile when used alongside two or more background hypertension treatments, typically an ACE inhibitor or angiotensin receptor blocker. Serious adverse events occurred in 3.8% of zilebesiran patients compared to 4.5% on placebo, while rates of hyperkalemia, kidney impairment, and hypotension remained low.
Roche said it will hold back results from the second KARDIA-3 cohort until an upcoming medical meeting but emphasized that it is preparing to initiate a phase 3 trial of zilebesiran by year’s end. The study will enroll 11,000 participants across more than 30 countries. The company credited the move to the overall strength of the KARDIA program, which also includes the well-performing KARDIA-1 and KARDIA-2 trials reported in 2023 and 2024.
Roche’s CMO Levi Garraway noted in the Aug. 30 release that zilebesiran could emerge as a leading therapy for patients struggling to manage hypertension. He emphasized that its ability to lower blood pressure with only twice-yearly administration may help reduce the likelihood of severe complications and mortality. Garraway also highlighted that, even with existing treatments, as many as 80% of individuals with hypertension fail to achieve sufficient BP control, leaving them vulnerable to cardiovascular risks.
