Adjunctive zilebesiran shows efficacy in uncontrolled hypertension

Among patients with ongoing, uncontrolled hypertension in spite of treatment with indapamide, amlodipine, or olmesartan, the addition of a single dose of investigative zilebesiran has, at 3 months, resulted in significant systolic blood pressure (SBP) reductions, when compared with patients assigned one of the approved treatments plus placebo.

Researchers reported their findings on May 28, 2025 in JAMA, the Journal of the American Medical Association.

“In this phase 2 trial, a single subcutaneous dose of zilebesiran 600 mg added to indapamide, amlodipine, or olmesartan background therapy showed significant additional reductions in 24-hour mean ambulatory and office systolic blood pressure at 3 months, regardless of background treatment, the investigators said.

“These data support the potential for use of subcutaneously administered zilebesiran as an effective and well-tolerated treatment for continuous control of blood pressure in combination with commonly used first-line oral antihypertensive medications,” they added.

In this phase2, randomized trial enrolled, the investigators enrolled adults with uncontrolled hypertension from 8 countries.

They randomized eligible subjects to receive open-label run-in treatment for at least 4 weeks with indapamide 2.5mg, amlodipine 5mg or olmesartan 40mg (4:7:10 randomization), each given daily.

Subjects achieving a 24-hour mean ambulatory SBP of 130mm Hg to 160mm Hg were then randomized (1:1) to additional blinded treatment and to adjunctive subcutaneous doses of zilebesiran 600mg or matching placebo.

The primary endpoint was the difference between zilebesiran-treated subjects and placebo subjects in change from baseline for 24-hour mean ambulatory SBP at 3months.

Of 1491 subjects entering the run-in phase, 663 (130 receiving indapamide, 240 receiving amlodipine, and 293 receiving olmesartan) were randomized to adjunctive zilebesiran (n =332) or placebo (n=331).

The difference between zilebesiran and placebo in change from baseline to 3 months for 24-hour mean ambulatory SBP was −12.1 mm Hg(P < .001, a significant difference) for indapamide, −9.7mm Hg(P < .001, a significant difference) for amlodipine, and−4.5mm Hg(P =.02, a significant difference) for olmesartan.

Notably, more patients who received zilebesiran than placebo experienced hyperkalemia, hypotension and acute kidney failure. “But most events were resolved without medical intervention, the authors said.

The authors concluded, “In patients with uncontrolled hypertension despite treatment with indapamide, amlodipine, or olmesartan, the addition of single-dose zilebesiran resulted in significant SBP reductions compared with placebo at 3 months, with low rates of serious adverse events.”