By Liz Switzer
Despite the availability of effective, low-cost medications, about 80% of people with hypertension do not have their blood pressure under control. One reason is deceptively simple: Taking medication every day can be difficult, especially for patients who already take multiple drugs.
Duke cardiologists are studying whether a novel treatment given just twice a year could help close that gap by reducing the burden of daily medication.
Zilebesiran, an investigational RNA interference (RNAi) therapy, is designed to provide sustained blood pressure reduction with a single injection that lasts about six months.
In the Phase 2 KARDIA-3 trial, the drug was studied in high-risk patients whose blood pressure remained uncontrolled despite taking other blood pressure medications.
“Every additional pill that somebody takes means that they are less likely to take that pill,” said Neha Pagidipati, MD, KARDIA-3 co-investigator and a cardiologist at Duke University School of Medicine, who recently presented study findings at the European Society of Cardiology Congress in Munich. “If you can even reduce that by one, it may make it easier for patients to take their remaining medications as well.”
A new approach to an old problem
Zilebesiran takes aim at the renin-angiotensin system, a biological pathway that plays a central role in regulating blood pressure, said Pagidipati.
Unlike commonly used ACE inhibitors and angiotensin receptor blockers, which act farther downstream in the pathway, zilebesiran targets angiotensinogen, a protein produced in the liver at an early point in the pathway.
By reducing the liver production of angiotensinogen, zilebesiran may provide longer-lasting suppression of the pathway. Because the drug remains active for months, it could also offer a way to maintain blood pressure control without requiring patients to remember another pill every day.
The drug is being co-developed by Alnylam Pharmaceuticals with Roche, which funded the study.
Other therapies targeting this pathway are also in development, Pagidipati said. Zilebesiran, however, is among the most advanced investigational approaches being studied as a longer-acting treatment for hypertension.
KARDIA-3
KARDIA-3, led by principal investigator and Duke cardiologist Christopher Granger, MD, was the third study in a Phase 2 program that tested zilebesiran in progressively more complex patients.
Earlier KARDIA studies examined the drug as a stand-alone treatment and in combination with a single other blood pressure medication. KARDIA-3 studied patients already taking multiple medications and at high cardiovascular risk.
An exploratory, post-hoc analysis of KARDIA-3 data presented by Pagidipati in Munich found that patients who were taking a diuretic and had truly uncontrolled blood pressure at the start of the study had numerically greater reductions in blood pressure.
Pagidipati emphasized that the subgroup analysis was not planned and cannot establish that these patients respond better to the drug. The finding did, however, help inform the design of the next stage of research, the Phase 3 ZENITH Cardiovascular Outcomes Trial, also led by Granger.
Beyond lowering blood pressure
ZENITH's primary goal is not simply to lower blood pressure but to determine whether that reduction translates into better long-term health.
The trial is enrolling about 11,000 patients worldwide to determine whether the treatment can reduce major cardiovascular events, including cardiovascular death, heart attack, stroke and heart failure.
That question is important because lowering blood pressure is a means to an end: preventing heart attacks, strokes, heart failure, and other complications that make hypertension one of the world's most consequential chronic diseases.
“If this therapy is effective and safe in the long term for patients, and it does improve cardiovascular outcomes, it can potentially change the way we manage one of the most common chronic diseases in the world,” Pagidipati said.