A single subcutaneous injection of the investigational drug zilebesiran demonstrated clinically meaningful blood pressure reductions when added to standard antihypertensive therapy in patients with inadequately controlled hypertension, according to results from the Phase 2 KARDIA-2 study presented at the American College of Cardiology's Annual Scientific Session.
The global study enrolled 672 patients whose blood pressure remained uncontrolled despite compliance with their medication regimen. When added to existing treatment with standard antihypertensive medications, a single injection of zilebesiran reduced systolic blood pressure by between 4 to 12 mmHg on average at three months compared to placebo.
Study Design and Patient Population
The KARDIA-2 study enrolled patients with an average age of 59 years, with 43% women and 28% Black participants. Approximately one in four patients had diabetes in addition to high blood pressure. Patients' average systolic blood pressure before receiving treatment was 143 mmHg.
After discontinuing their existing medications, patients were randomly assigned to take one of three once-daily medications commonly used in clinical practice: indapamide, amlodipine, or olmesartan, representing different pharmacologic mechanisms for reducing blood pressure. After at least four weeks, patients underwent 24-hour blood pressure monitoring. Those who consistently took their medications and still had average 24-hour systolic blood pressure between 130-160 mmHg were randomly assigned to receive either a single injection of zilebesiran 600 mg or placebo.
Primary Results and Efficacy
At three months, each group of patients assigned to zilebesiran demonstrated statistically significant additional reductions in their 24-hour ambulatory systolic blood pressure compared to placebo. For those taking indapamide, the average incremental reduction was 12 mmHg; for amlodipine, 9.7 mmHg; and for olmesartan, 4 mmHg.
"Compared to placebo, a single injection of zilebesiran resulted in clinically meaningful reductions in blood pressure at three months when added to commonly used antihypertensive treatments," said Akshay Desai, MD, MPH, a cardiologist at Brigham and Women's Hospital in Boston and study co-author. "In most cases, these differences persisted at six-month follow up despite the addition of other antihypertensive treatments."
Despite allowance for add-on therapy to meet guideline-recommended blood pressure targets after three months, time-adjusted reductions in office systolic blood pressure between zilebesiran and placebo remained statistically significant through month six for each group.
Mechanism of Action and Clinical Significance
Zilebesiran works by reducing the body's production of angiotensinogen, a hormone primarily made in the liver that helps regulate blood pressure by constricting blood vessels. Reducing blood-vessel constriction allows blood pressure to fall. Unlike blood-pressure medications that need to be taken one or more times daily, zilebesiran is administered by injection once every three or six months.
Previous studies have shown that reducing systolic blood pressure by 10 mmHg results in a 20% reduction in the risk of heart attack or stroke, according to Desai. The CDC estimates that nearly half of U.S. adults—about 120 million people—have high blood pressure, but blood pressure is well-controlled with medication in only about 25% of those with the condition.
"A safe and effective blood pressure treatment that could be dosed as infrequently as twice a year might improve consistency in blood pressure control, reduce the overall burden of pills needed to treat high blood pressure and significantly reduce patients' cardiovascular risk," Desai said.
Safety Profile
"Importantly, in the KARDIA-2 study, the addition of zilebesiran to indapamide, amlodipine and olmesartan was associated with no new serious safety concerns with regard to potassium elevations, kidney injury and low blood pressure," Desai noted.
Future Research Directions
A follow-up study, KARDIA-3, will test the efficacy and safety of zilebesiran in patients with hypertension uncontrolled on two to four blood pressure medications who have high cardiovascular risk or advanced chronic kidney disease.
"More studies are certainly needed, but if we can truly demonstrate safe and consistent reduction in blood pressure with two injections a year, this approach might dramatically alter the approach to managing hypertension in clinical practice," Desai said.
The study was funded by Alnylam Pharmaceuticals, the manufacturer of zilebesiran.
