Publications

The material below is provided to support scientific exchange. Any content about investigational therapeutics or investigational uses of locally approved products does not establish the safety or efficacy of these therapeutics or uses, and there is no guarantee of local regulatory approval.

For questions beyond a product’s authorized indications or for information not available here, please contact Alnylam Medical Information.

RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial

Publication Details

The Journal of the American Medical Association

March 2024

Access Here

Author(s)

George L Bakris¹, Manish Saxena^{2 3}, Anil Gupta⁴, Fadi Chalhoub⁵, Jongtae Lee⁶, Daniel Stiglitz⁶, Nune Makarova⁶, Nitender Goyal⁶, Weinong Guo⁶, Dion Zappe⁶, Akshay S Desai⁷; KARDIA-1 Study Group

Affiliations

¹University of Chicago Medicine, Chicago, Illinois; ²Barts Health NHS Trust, London, United Kingdom; ³Queen Mary University of London, London, United Kingdom; ⁴Albion Finch Medical Centre, Toronto, Ontario, Canada; ⁵Clinical Neuroscience Solutions, Jacksonville, Florida; ⁶Alnylam Pharmaceuticals, Cambridge, Massachusetts; ⁷Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts

Abstract

Importance

Angiotensinogen is the most upstream precursor of the renin–angiotensin–aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis.

Objective

To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens.

Design, Setting, and Participants

phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized.

Interventions

Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months.

Main Outcomes and Measures

The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP.

Results:

Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were −7.3 mm Hg (95% CI, −10.3 to −4.4) with zilebesiran, 150 mg, once every 6 months; −10.0 mm Hg (95% CI, −12.0 to −7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; −8.9 mm Hg (95% CI, −11.9 to −6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were −14.1 mm Hg (95% CI, −19.2 to −9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; −16.7 mm Hg (95% CI, −21.2 to −12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and −15.7 mm Hg (95% CI, −20.8 to −10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients.

Conclusions and Relevance

In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3.