A single subcutaneous injection of the investigational drug zilebesiran, when added to existing treatment with a standard antihypertensive medication, reduced systolic blood pressure (SBP) by between 4 to 12 mm Hg on average at three months in patients whose BP had remained uncontrolled despite adherence with their medication regimen, according to results from the KARDIA-2 study presented in a Late-Breaking Clinical Trial session at ACC.24.

The phase 2, double-blind, placebo-controlled study, presented by Akshay S. Desai, MD, FACC, evaluated the efficacy and safety of adding zilebesiran, which blocks production of angiotensinogen, in 672 patients (59 years old, 43% women, 28% Black). At baseline, the average SBP was 143 mm Hg, and most patients were taking one or two antihypertensive medications.

After discontinuing previous antihypertensive medications, patients were randomized to take one of three once-daily medications: indapamide, amlodipine or olmesartan. After at least four weeks, all patients underwent 24-hour BP monitoring. Those who consistently took their medications and still had an average 24-hour SBP between 130 mm Hg and 160 mm Hg were randomized to receive a single injection of either zilebesiran 600 mg or placebo. Patients were then followed for an additional six months. The addition of other antihypertensive drugs was permitted at three months to achieve guideline-recommended BP targets.

The study's primary endpoint was the change in average 24-hour ambulatory SBP at three months. Results showed significant additional reductions in 24-hour ambulatory SBP with zilebesiran compared with placebo. For patients assigned to indapamide, the average incremental reduction was 12 mm Hg, and it was 9.7 mm Hg for amlodipine and 4 mm Hg for olmesartan.

For the secondary endpoint of change in SBP measured in the clinician's office at three months, the reductions in the indapamide, amlodipine and olmesartan groups were 18.5 mm Hg, 10.2 mm Hg and 7.0 mm Hg, respectively. Of note, for the secondary endpoint of time-adjusted reductions in office SBP between zilebesiran and placebo remained statistically significant through month six for each group. No safety concerns were observed for potassium elevations, kidney injury and low BP.

"The fact that zilebesiran treatment resulted in significant reductions in BP on top of each background treatment at three months – which persisted to six months in many cases even with treatment with additional medications – suggests that it may be a very potent new strategy for lowering BP while reducing the need for daily pills," said Desai.

KARDIA-3 will test the efficacy and safety of zilebesiran in patients with hypertension uncontrolled on two to four BP medications who have high cardiovascular risk or advanced chronic kidney disease.