RNA Interference With Zilebesiran for Mild to Moderate Hypertension
Authors: Bakris George L. , Saxena Manish , Gupta Anil , Chalhoub Fadi , Lee Jongtae , Stiglitz Daniel , Makarova Nune , Goyal Nitender , Guo Weinong , Zappe Dion , Desai Akshay S. ,   KARDIA-1 Study Group, Carr George , Case Christopher , Jaeger Lauren , Bruns Lisa , Stratman Ginger , Kidwell Christy , Cunningham Suzin , Piccone Nicholas , Klein Mordecai , Acuna Maria , Arora Srishti , Clark Amanda , Fink Ezekiel , Garcia Cesia , George Astrid , Gray Elizabeth , Mahaffey Caroline , McElheney Maria , Ortiz Elizabeth , Saumya Sunny , Wallace Adele , Watts Jenelle , Zambrana Daisy , Denham Douglas , Rivera Erica , Avworo Ayoade , Hedges Parke , Fancher Corri , Abadier Rafik , Braud Lisa , Cenatiempo Laura , Elwood Amanda , Gray Linda , Gray Peter , Griffin Kimberly , Khan Hasibul , Kongquee Nadeen , LaTorraca Susan , Liles Tiffany , Livingston Jill , Lozano Marc , Lupton Amy , Lyles Tiffany , Mardini Deana , Moss Susan , Packer Karen , Patel Aakash , Russ Tina , Scinicariello Brianna , 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Hutchison Taylor , Rafuse Autumn , Thorsen Julie , MacDonald Greg , Akhras Ronald , Assef Richard , Irani Elise , Khayat Rania , Guidolin Scott , Gupta Anil , Price David , Gandhi Amisha , Chhabra Ajay , Gandhi Bhavya , Acharya Shrey , Panchal Maheshwari , Kansal Bindu , Bailey Gordon , Harvalik Paula , Demchuk Kerri , Saxena Manish , Collier David , David Colvell , Quiros Benildo Jr , Patel Mital , Balawon Armida , Galera Francis , Michalska Ania , Piniera Brian , Uddin Rahat , Abbott Joanna , Faulkner Karen , Yousef Tamer , Love Kyle , Zagdanski Ariella , Slaney Susan , Anderson Michelle , Leath Aimee , Dunlop Cheryl , Hardy Elizabeth , Wall Shannon , El-Koubani Osman , Kelt Tracy , Connolly Billy-Jean , Marmion Cheryl , Alapati Maheswari , Simmons Louise , Colquhoun Caroline , Clyde Darren , Mooty Adrian , Mullen Nicole , Viljoen Marianne , Trevor Lucy , Pretswell Carol , Austin Catherine , Munthali Chigomezgo , Munsoor Imrozia , Venkate Gowda Madhu , Ozunlu Pembe , Keighley Peter , Jones Alison , James Annette , Pollitt Joanne , Littlewood Wendy , Al-Sheikhly Lena , Lee David , Nistor Denise , Roberts Elaine , Mawdsley Gayle , Sobolewska Kamila , Hannis Katrina , Wojtkiewicz Klaudia , Stopford Lauren , Halliwell Lindsay , Mort Veronica , McGrath Victoria , Osborne Harry , Merrick Alison , Basikolo Cathrine , Ghysels Inge , Fenlon Laura , Beech Lucy , Munoz Olga Lusquinos , Bilton Sarah , Goddard Lyne , Gillon Tracey , Taylor Stacy , Tyson Brianne , Connor Victoria , Felber Hannah , Fallows Angela , Clowes Jacqueline , Cheung Shirley 
Published: February 2024

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 &amp;lt; .001) with zilebesiran, 150 mg, once every 6 months; −16.7 mm Hg (95% CI, −21.2 to −12.3; P &amp;lt; .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 &amp;lt; .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