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Treatment with a single subcutaneous dose of the RNA interference agent zilebesiran was associated with clinically significant reductions in systolic blood pressure compared with placebo at 3 months when added to a standard antihypertensive therapy in the KARDIA-2 study.

These differences were maintained to 6 months in most patients, despite add-on antihypertensive therapy.

In terms of adverse effects, treatment with zilebesiran was associated with increased rates of mild hyperkalemia, hypotension, and a decline in estimated glomerular filtration rate, but most episodes were nonserious, transient, and resolved without intervention.

The full results of the KARDIA-2 study were presented by Akshay Desai, MD, a cardiologist at Brigham and Women's Hospital in Boston, Massachusetts, at the recent American College of Cardiology Annual Scientific Session held in Atlanta, Georgia. 

"Although this phase 2 trial was not adequately powered to ensure long-term safety, these results support the potential for combining biannual dosing of zilebesiran with standard-of care antihypertensives to achieve additive blood pressure reductions," Desai concluded. 

In his presentation, Desai noted that despite the availability of effective therapy, many patients with hypertension do not meet guideline-recommended blood pressure targets, leaving them with unattended risk for cardiovascular events.

"Poor adherence to complex, multidrug oral regimens may contribute to inadequate blood pressure control, and even in those who are treated, residual blood pressure variability and lack of nighttime dipping may further increase cardiovascular risk," he said. 

Zilebesiran, an investigational, subcutaneously administered RNA interference therapeutic targeting hepatic synthesis of angiotensinogen, the most upstream precursor to all angiotensin peptides, may offer an alternative treatment approach for hypertension, Desai explained. 

The KARDIA-2 study enrolled 672 patients (average age, 59 years; 43% women; 28% Black individuals) who had elevated blood pressure despite already taking antihypertensive medication. The average baseline blood pressure was 143 mmHg.

After discontinuing existing antihypertensive medications, patients were randomly assigned to take one of three once-daily medications (indapamide, amlodipine, or olmesartan) that are commonly used in clinical practice, representing different pharmacologic mechanisms for reducing blood pressure. 

After at least 4 weeks, all patients underwent blood pressure monitoring for 24 hours. Those who consistently took their medications and still had average 24-hour systolic blood pressure between 130 mmHg and 160 mmHg were randomly assigned to receive a single injection of either 600 mg zilebesiran or placebo. Patients were then followed for an additional 6 months. 

The addition of other antihypertensive drugs was permitted at 3 months to achieve guideline-recommended blood pressure targets. 

The study's primary endpoint was the change in average 24-hour ambulatory systolic blood pressure at 3 months.

At this timepoint, each group of patients assigned to zilebesiran saw statistically significant additional reductions in their 24-hour ambulatory systolic blood pressure compared with placebo. For those taking indapamide, the average incremental reduction was 12 mmHg; for those on amlodipine, it was 9.7 mmHg; and for those on olmesartan, it was 4 mmHg. 

These differences were sustained out to month 6 in the indapamide and amlodipine cohorts despite add-on antihypertensive therapy.

"The fact that zilebesiran treatment resulted in significant reductions in blood pressure on top of each background treatment at 3 months — which persisted to 6 months in many cases even with treatment with additional medications — suggests that it may be a very potent new strategy for lowering blood pressure while reducing the need for daily pills," Desai commented. 

"Importantly, in the KARDIA-2 study, the addition of zilebesiran to indapamide, amlodipine or olmesartan was associated with no new serious safety concerns with regard to potassium elevations, kidney injury and low blood pressure," Desai said. However, he said that further studies of longer duration in patients at high cardiovascular risk are needed.

A follow-up study, KARDIA-3, is now underway to 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. 

Discussing the study at the American College of Cardiology late breaking clinical trials session, Nanette Wenger, MD, professor of medicine at Emory University School of Medicine, Atlanta, Georgia, said she was "very excited about this new and different approach to therapy."

Wenger noted that only about a quarter of patients in the United States have control of their blood pressure, and this contributes so much to morbidity and mortality.

"While some of this may be a clinical issue of suboptimal titration, I think a great deal of it is because patients get bored with taking medications and don't continue to take them on a regular basis. This new approach where patients could achieve better control with a subcutaneous injection every 6 months could solve this problem," she commented. 

"I'm also pleased that there didn't seem to be any safety signals in this trial," she added. 

Wenger also asked about patient acceptance of an injectable for hypertension. 

Desai replied that the willingness of patients to self-administer a subcutaneous injection has increased in recent years, with several such medications now available. "It is an easy procedure, and I think it is a barrier that can be overcome," he said. 

The study was funded by Alnylam Pharmaceuticals, the manufacturer of zilebesiran.