Zilebesiran Reduces SBP by Up to 14 mm Hg on Background SOC in Uncontrolled Hypertension: KARDIA-2

Zilebesiran, the investigational RNA interference (RNAi) therapeutic for treatment of inadequately controlled hypertension, significantly reduced ambulatory systolic blood pressure (SBP) by an average of 12 to 14 mm Hg at 3 months when added to common standard of care (SOC) treatments for hypertension.¹

Akshay Desai, MD, MPH
(Courtesy ACC)

“In most cases, these differences persisted at six-month follow up despite the addition of other antihypertensive treatments. No new serious safety concerns were observed,” Akshay Desai, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston and a coauthor of the phase 2 KARDIA-2 study, said in a press statement. The findings were presented at the 2024 American College of Cardiology Scientific Sessions, April 6-8, in Atlanta, GA.

KARDIA-2 evaluated the efficacy and safety of zilebesiran added to standard-of-care antihypertensive treatment in 672 adults with mild-to-moderate hypertension that remained uncontrolled despite up to 2 antihypertensive medications. At the start of a 4-week run-in period, all previous hypertension medications were discontinued and study participants were randomly assigned to open label treatment with once-daily oral olmesartan (20 or 40 mg), amlodipine (5 mg) or indapamide (2.5 mg). Those eligible after the run-in period, participants with 24-hour (24h) mean SBP of 130-160 mm Hg, were randomly assigned in a 1:1 ratio to receive a single subcutaneous dose of 600 mg zilebesiran or placebo as add-on therapy to the protocol-specified background antihypertensive medication for 6 months.

The study’s primary endpoint was the change from baseline in mean SBP at month 3, assessed by 24h ABPM (ambulatory blood pressure monitoring). Key secondary endpoints included change from baseline to month 3 in office SBP and time-adjusted change from baseline to month 6 in 24h mean ambulatory and office SBP.

KARDIA-2 study participants had a mean age of 59 years; 43% were women and 28% were Black. Approximately 1 in 4 patients had diabetes other than type 1 in addition to hypertension. Average SBP among participants before receiving zilebesiran or placebo was 143 mmHg.

KARDIA-2 Findings

Desai and colleagues reported that at 3 months, participants receiving zilebesiran in each of the 3 SOC groups experienced significant additional reductions in 24h ambulatory SBP vs placebo. Average incremental reductions for each were:

• indapamide 12 mmHg
• amlodipine 9.7 mmHg
• olmesartan 4 mmHg

While allowance was made during the study for add-on therapy to meet guideline-recommended blood pressure targets after month 3, time-adjusted reductions in office SBP between zilebesiran and placebo remained statistically significant through month 6 for each of the 3 groups.

“The fact that zilebesiran treatment resulted in significant reductions in blood pressure 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 blood pressure while reducing the need for daily pills,” Desai observed in the ACC statement. He acknowledged at the same time that additional longer studies are needed and in individuals at increased cardiovascular risk.

Zilebesiran development partners Alnylam Pharmaceuticals and Roche have initiated the KARDIA-3 study for that purpose. The follow-up study will test the efficacy and safety of zilebesiran in individuals with hypertension uncontrolled despite treatment with 2 to 4 antihypertensive agents who have high CV risk or advanced chronic kidney disease.¹

The novel agent, administered subcutaneously every 3 to 6 months, is an RNAi therapeutic that targets liver-expressed angiotensinogen (AGT), the most upstream precursor in the renin-angiotensin-aldosterone system. Through inhibition of hepatic AGT synthesis, zilebesiran may lead to enduring reductions in AGT protein and ultimately, reductions in the vasoconstrictor angiotensin II, according to the codevelopers.¹

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