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Add-on Treatment With Zilebesiran for Inadequately Controlled Hypertension: The KARDIA-2 Randomized Clinical Trial

Publication Details

Journal of the American Medical Association

May 2025

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Author(s)

Akshay S Desai¹, Adam D Karns², Jolita Badariene³, Ahmad Aswad⁴, Joel M Neutel⁵, Farhana Kazi^{6 7}, Wansu Park⁸, Daniel Stiglitz⁸, Nune Makarova⁸, Andrea Havasi⁸, Dion H Zappe⁸, Manish Saxena^{9 10}; KARDIA-2 Study Group

Affiliations

¹Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts; ²Entertainment Medical Group, Beverly Hills, California; ³Medical Faculty, Vilnius University, Vilnius, Lithuania; ⁴Gonzalez MD and Aswad MD Health Care Services, Miami, Florida; ⁵Orange County Research Center, Tustin, California; ⁶Prime Revival Research Institute, Coppell, Texas; ⁷Baylor Scott and White The Heart Hospital - Plano, Coppell, Texas; ⁸Alnylam Pharmaceuticals, Cambridge, Massachusetts; ⁹Barts Health NHS Trust, London, United Kingdom; ¹⁰Queen Mary University of London, London, United Kingdom

Abstract

Importance:

In prior monotherapy studies of patients with hypertension, single subcutaneous doses of zilebesiran, an investigational RNA interference therapeutic, reduced serum angiotensinogen levels and systolic blood pressure (SBP) at 3 and 6 months.

Objective:

To evaluate the efficacy and safety of zilebesiran vs placebo when added to a standard antihypertensive medication.

Design, Setting, and Participants:

This phase 2, randomized, prospective, double-blinded trial enrolled adults with uncontrolled hypertension from 150 sites across 8 countries between January 2022 and June 2023. The final follow-up date was December 11, 2023, and analyses were conducted on March 1, 2024.

Interventions:

Eligible patients were initially randomized in cohorts to receive open-label run-in treatment for at least 4 weeks with indapamide 2.5 mg, amlodipine 5 mg, or olmesartan 40 mg (4:7:10 randomization), each administered once daily. Within cohorts, adherent patients with 24-hour mean ambulatory SBP of 130 mm Hg to 160 mm Hg were subsequently randomized (1:1) to additional blinded treatment to receive single subcutaneous doses of zilebesiran 600 mg or matching placebo.

Main Outcomes and Measures:

The primary end point in each cohort was the difference between zilebesiran and placebo in change from baseline in 24-hour mean ambulatory SBP at 3 months.

Results:

Of 1491 patients entering the run-in phase, 663 (130 receiving indapamide, 240 receiving amlodipine, and 293 receiving olmesartan) were randomized to receive zilebesiran (n = 332) or placebo (n = 331). The least-squares mean difference between zilebesiran and placebo in change from baseline to 3 months in 24-hour mean ambulatory SBP was −12.1 mm Hg (95% CI, −16.5 to −7.6; P < .001) for indapamide, −9.7 mm Hg (95% CI, −12.9 to −6.6; P < .001) for amlodipine, and −4.5 mm Hg (95% CI, −8.2 to −0.8; P = .02) for olmesartan. Across cohorts, more patients who received zilebesiran than placebo experienced hyperkalemia (18 [5.5%] vs 6 [1.8%]), hypotension (14 [4.3%] vs 7 [2.1%]), and acute kidney failure (16 [4.9%] vs 5 [1.5%]) events, but most episodes were mild and resolved without medical intervention.

Conclusions and Relevance:

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.