RNA Interference With Zilebesiran for Mild to Moderate Hypertension
George L. Bakris, Manish Saxena, Anil Gupta, Fadi Chalhoub, Jong-Tae Lee, Daniel Stiglitz, Nune Makarova, Nitender Goyal, Weinong Guo, Dion Zappe, Akshay S. Desai, KARDIA-1 Study Group, George Carr, Christopher Case, Lauren Hubert Jaeger, Lisa Bruns, Ginger Stratman, Christy Kidwell, Suzin Cunningham, Nicholas Piccone, Mordecai Klein, Maria Acuna, Srishti Arora, Amanda Clark, Ezekiel Fink, Cesia Garcia, Astrid George, Elizabeth Gray, Caroline Mahaffey, Maria McElheney, Elizabeth Ortiz, Sunny Saumya, Adele Wallace, Jenelle Watts, Daisy Zambrana, Douglas Denham, Erica Rivera, Ayoade Avworo, Parke Hedges, Corri Fancher, Rafik Abadier, Lisa Braud, Laura Cenatiempo, Amanda Elwood, Linda Gray, Peter Gray, Kimberly Griffin, Hasibul Khan, Nadeen Kongquee, Susan LaTorraca, Tiffany Liles, J. M. Livingston, Marc Lozano, Amy Lupton, Tiffany Lyles, Deana Mardini, Susan Moss, K. Packer, Aakash Patel, Tina Russ, Brianna Scinicariello, Shannon Trull, Blair Warren, Fadi Chalhoub, Susan Angel, Sujeeta Dhakhwa, Ivy Gabon, Leticia Goodwin, Nandita Joshi Jones, Mark Joyce, Niketa Kamble, Brooke McFall, Rose Githiiyu, Leticia Robinson, Lauren A. Tomlinson, Emir Hadziavdic, Stephany Vega, James Greenwald, Jessica Achan, L Poyatos Ruiz, Mehwish Buksh, Omkar Chauhan, Elisee Derisseau, Faith Ferguson, Monika Grabowski, Larisa Gumerova, Miriam Hernandez, Kenna Martin, Krina K. Patel, Dibnain Nanda, José Garcı́a Pérez, Corey Ribeca, Elijah Rueda, Ana Sordi Guth, Nader Zaki, Ebony Green, Nina Mondoc, Robert Buynak, Stephanie Andree, Martha Brazinsky
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: This 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. Trial Registration: ClinicalTrials.gov Identifier: NCT04936035.