Lorundrostat Efficacy and Safety in Patients with Uncontrolled Hypertension

Abstract

Background: Aldosterone dysregulation contributes to hypertension. Lorundrostat is an aldosterone synthase inhibitor, but data on its efficacy and safety in patients with hypertension are limited.

Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, we assigned participants who were receiving two to five antihypertensive medications and had a blood-pressure measurement of 140/90 mm Hg or higher obtained during an office visit to undergo a standardized antihypertensive regimen for 3 weeks. Subsequently, participants with an average 24-hour ambulatory blood pressure of 130/80 mm Hg or higher were assigned to receive placebo, lorundrostat at a stable dose of 50 mg daily (the stable-dose group), or lorundrostat at a starting dose of 50 mg daily, with an increase to 100 mg daily if systolic blood pressure was 130 mm Hg or higher after 4 weeks (the dose-adjustment group). The primary end point was the change in 24-hour average systolic blood pressure from baseline to week 12, assessed as the least-squares mean difference from placebo (the placebo-adjusted change) in each lorundrostat group. A key secondary end point was the change in 24-hour average systolic blood pressure from baseline to week 4, assessed as the placebo-adjusted change in the combined lorundrostat groups.

Results: A total of 285 participants underwent randomization; 94 were assigned to the stable-dose group, 96 to the dose-adjustment group, and 95 to the placebo group. The mean age was 60 years, and 150 participants (53%) were Black. After 12 weeks, the least-squares mean change in 24-hour average systolic blood pressure was -15.4 mm Hg in the stable-dose group, -13.9 mm Hg in the dose-adjustment group, and -7.4 mm Hg in the placebo group. The placebo-adjusted change in blood pressure was -7.9 mm Hg (97.5% confidence interval [CI], -13.3 to -2.6) in the stable-dose group and -6.5 mm Hg (97.5% CI, -11.8 to -1.2) in the dose-adjustment group. The placebo-adjusted change in 24-hour average systolic blood pressure from baseline to week 4 in the combined lorundrostat groups was -5.3 mm Hg (95% CI, -8.4 to -2.3). A potassium level above 6.0 mmol per liter occurred in 5 participants (5%) in the stable-dose group, 7 participants (7%) in the dose-adjustment group, and no participants in the placebo group.

Conclusions: Lorundrostat was associated with greater reductions in 24-hour average blood pressure than placebo in participants with uncontrolled and treatment-resistant hypertension. (Funded by Mineralys Therapeutics; Advance-HTN ClinicalTrials.gov number, NCT05769608.).