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Clinical Trial
. 2025 Jul 1;334(1):46-55.
doi: 10.1001/jama.2025.6681.

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

Akshay S Desai  1 , Adam D Karns  2 , Jolita Badariene  3 , Ahmad Aswad  4 , Joel M Neutel  5 , Farhana Kazi  6   7 , Wansu Park  8 , Daniel Stiglitz  8 , Nune Makarova  8 , Andrea Havasi  8 , Dion H Zappe  8 , Manish Saxena  9   10 ; KARDIA-2 Study Group
Collaborators, Affiliations
Clinical Trial

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

Akshay S Desai et al. JAMA. .

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.

Trial registration: ClinicalTrials.gov Identifier: NCT05103332.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Park, Makarova, Havasi, and Zappe and Mr Stiglitz hold stock or stock options in Alnylam Pharmaceuticals as employees. Dr Desai reported receiving research grants to Brigham and Women’s Hospital from Abbott, AstraZeneca, Bayer, Novartis, and Pfizer and personal fees from Abbott, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Endotronix, GlaxoSmithKline, Medpace, Medtronic, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal, Roche, scPharma, Veristat, Verily, and Zydus outside the submitted work. Dr Saxena reported receiving personal fees from Astra Zeneca, Boehringer Ingelheim, C4 Research, Daiichi Sankyo Inc, Mineralys Therapeutics, Novartis, Recor Medical, Vifor Pharma, Arrow Head, Menarini Group, IQVIA, and PPD Pharma and grants from MSD, Recor Medical, Ablative Solutions, and Applied Therapeutics outside the submitted work. No other disclosures were reported.

References

    1. Global Report on Hypertension: the Race Against a Silent Killer. World Health Organization; 2023.
    1. Mehlum MH, Liestøl K, Kjeldsen SE, et al. Blood pressure variability and risk of cardiovascular events and death in patients with hypertension and different baseline risks. Eur Heart J. 2018;39(24):2243-2251. doi: 10.1093/eurheartj/ehx760 - DOI - PubMed
    1. Mezue K, Goyal A, Pressman GS, Matthew R, Horrow JC, Rangaswami J. Blood pressure variability predicts adverse events and cardiovascular outcomes in SPRINT. J Clin Hypertens (Greenwich). 2018;20(9):1247-1252. doi: 10.1111/jch.13346 - DOI - PMC - PubMed
    1. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375(9718):895-905. doi: 10.1016/S0140-6736(10)60308-X - DOI - PubMed
    1. Doumas M, Tsioufis C, Fletcher R, Amdur R, Faselis C, Papademetriou V. Time in therapeutic range, as a determinant of all-cause mortality in patients with hypertension. J Am Heart Assoc. 2017;6(11):e007131. doi: 10.1161/JAHA.117.007131 - DOI - PMC - PubMed

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