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

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.

Figure 1.. Flow of Participants in the KARDIA-1 Trial of Subcutaneous Zilebesiran for Hypertension

^aA patient could have multiple reasons for screen failure and was counted for each reason separately. ^bRandomization was stratified by race (Black or other) and baseline mean 24-hour systolic blood pressure (<145 or ≥145 mm Hg). ^cPatients withdrew consent because of work-related reasons (n = 4), distance to the site (n = 3), no disclosed reason (n = 2), principal care clinician’s advice (n = 2), time constraints (n = 1), the study not being worth their time (n = 1), personal reasons (n = 1), unwillingness to adhere to ambulatory blood pressure monitoring requirements (n = 1), and adverse events (n = 1). ^dPatient was incarcerated during study. ^ePatients enrolled at sites in Ukraine (n = 16) were excluded after randomization because war prevented continued data collection. ^fPrimary analysis was carried out in the full analysis set, which included all randomized patients who received any amount of study drug.

Figure 2.. Ambulatory Systolic Blood Pressure (SBP) Among the Full Analysis Set^a

^aAll randomized patients who received any amount of study drug, analyzed according to randomized treatment. Box plots demonstrate median (thick horizontal line), mean (circle), IQR (box top and bottom), highest and lowest values within 1.5 × the IQR (whiskers), and more extreme values (diamonds). For the efficacy analyses of end points assessed at month 3, the zilebesiran 300 mg and 600 mg groups were combined because both had received the same zilebesiran dose.