Phase 2 study of siRNA targeting angiotensinogen in patients with hypertension meets primary endpoint

The KARDIA 1 phase 2 trial showed a reduction in 24-h ambulatory systolic BP of greater than 15 mmHg with the two highest single doses of the siRNA therapeutic zilebesiran, targeting hepatic angiotensinogen synthesis, at month 3 compared with placebo.

It was announced that the KARDIA-1 phase 2 study with the siRNA therapeutic zilebesiran, targeting hepatic angiotensinogen synthesis, met its primary endpoint. Treatment with zilebesiran led to a dose-dependent reduction in systolic blood pressure (SBP) as measured by ambulatory blood pressure monitoring (ABPM), with a greater than 15 mmHg reduction in SBP (P<0.0001) with 300 mg and 600 mg doses of zilebesiran compared with placebo. The study also met key secondary endpoints, including changes in 24-h mean SBP as measured by ABPM at month 6, and significant change in office SBP at month 3 and month 6 for all zilebesiran arms compared with placebo.

The KARDIA-1 is a randomized, double-blind, placebo-controlled, multi-center phase 2 trial that evaluates the efficacy and safety of zilebesiran, with various doses, as monotherapy in adults with mild-to-moderate hypertension. A total of 394 adults were enrolled with untreated hypertension or who were on stable therapy with one or more anti-hypertensive medication. Patients who were on anti-hypertensive medications completed a wash-out period before randomization. Patients were randomized during a 12-month study period and extension period to subcutaneous administration of zilebesiran (150 mg, 300 mg or 600 mg once every six months; 300 mg once every three months) or placebo. Patients in the placebo group were randomized to one of the four initial zilebesiran dose regimens at month 6.

The primary endpoint of KARDIA-1 is the change from baseline in SBP at month 3 as determined by 24-h ABPM. Key secondary and exploratory endpoints were additional measures of BP reduction at month 6, time-adjusted change in BP, and change in daytime average and night-time average BP.

The safety and tolerability profile of zilebesiran was encouraging. Serious adverse events were reported by 3.6% of patients in the zilebesiran arms and by 6.7% in the placebo arm. These events were considered not to be related to study drug. Adverse events occurring in more than 5% of zilebesiran-treated patients were COVID-19, injection site reaction, hyperkalemia, hypertension, upper respiratory tract infection, arthralgia and headache.

Source: Press release Alnylam Pharmaceuticals, September 7, 2023