Add-on zilebesiran helps lower BP in uncontrolled hypertension

The addition of a single subcutaneous dose of zilebesiran to background therapies appears to provide blood pressure (BP)-lowering benefit in patients with uncontrolled hypertension, according to the phase II KARDIA-2 study.

From baseline to 3 months, add-on zilebesiran yielded significantly greater reductions in 24-hour mean ambulatory systolic BP (SBP) levels, the primary endpoint, compared with placebo. The corresponding between-treatment difference was –12.1 mm Hg (95 percent confidence interval [CI], −16.5 to −7.6; p<0.001) among patients on indapamide, −9.7 mm Hg (95 percent CI, −12.9 to −6.6; p<0.001) among those on amlodipine, and −4.5 mm Hg (95 percent CI, −8.2 to −0.8; p=0.02) among those on olmesartan. [JAMA 2025;doi:10.1001/jama.2025.6681]

“Significant BP reductions from baseline with zilebesiran persisted through 6 months in the indapamide and amlodipine cohorts, but were attenuated in the olmesartan cohort,” the investigators noted.

Consistently fewer patients in the zilebesiran group than in the placebo group required rescue antihypertensive therapy at 6 months across the indapamide (15.5 percent vs 41.7 percent), amlodipine 25.2 percent vs 64.2 percent), and olmesartan (42.5 percent vs 54.0 percent) cohorts.

Zilebesiran was also associated with greater reductions in both ambulatory and office SBP levels at 6 months compared with placebo. However, this benefit was only observed in the indapamide (ambulatory: difference, −11.0 mm Hg; office: difference, −13.6 mm Hg) and amlodipine cohorts (ambulatory: difference, −7.9 mm Hg; office: difference, −8.6 mm Hg).

Accordingly, the likelihood of meeting the prespecified BP response criterion (ie, 24-h mean ambulatory SBP <130 mm Hg and/or reduction from baseline of ≤20 mm Hg without rescue antihypertensive medication) at 6 months was significantly greater with zilebesiran vs placebo in the indapamide (64.2 percent vs 14.0 percent; odds ratio [OR], 12.4, 95 percent CI, 4.6–33.3; p<0.001) and amlodipine (39.8 percent 13.7 percent; OR, 5.1, 95 percent CI, 2.4–10.6; p<0.001) cohorts.

In terms of safety in the overall population, zilebesiran was associated with a greater frequency of adverse events (AEs), specifically hyperkalemia (5.5 percent vs 1.8 percent), hypotension (4.3 percent vs 2.1 percent), and acute kidney failure (4.9 percent vs 1.5 percent) compared with placebo. The investigators noted that most episodes were mild and resolved without medical intervention.

The incidence of serious AEs was similar in the zilebesiran and placebo groups, with no reports of death during the 6-month double-blind period.

“These data from KARDIA-2 amplify and extend the results from the dose-ranging KARDIA-1 study by confirming sustained reductions in circulating angiotensinogen levels for 6 months, as well as clinically meaningful reductions in ambulatory and office SBP after a single dose of zilebesiran 600 mg across a range of background antihypertensive treatments,” the investigators said. [JAMA 2024;331:740-749]

“The enduring antihypertensive effect of zilebesiran offers the potential for a biannual subcutaneous dosing approach that might help to overcome challenges with therapeutic inertia and poor patient adherence to daily antihypertensive treatments, which are key drivers of inadequate BP control,” they added.

Zilebesiran is an investigational RNA interference therapeutic agent that targets the hepatic synthesis of angiotensinogen. Using this drug in addition to olmesartan, a potent RAS inhibitor, presented an uncertainty regarding the extent of further BP reduction and its potential impact on the safety profile, according to the investigators.

While the rates of hyperkalemia and worsening kidney function were low overall, the less-incremental BP-lowering efficacy of zilebesiran on top of olmesartan warrants additional studies of longer duration and involving patients with higher risk of adverse effects, they said. These studies should provide further insight into the balance of safety and efficacy of zilebesiran use in combination with oral RAS inhibitors, they added.

KARDIA-2 included 663 adult patients with uncontrolled hypertension despite receiving treatment with indapamide 2.5 mg (n=130), amlodipine 5 mg (n=240), or olmesartan 40 mg (n=293) once daily for at least 4 weeks. These patients were randomly assigned to treatment with a single subcutaneous dose of zilebesiran at 600 mg (n=332) or matching placebo (n=331).