Lorundrostat in Participants With Uncontrolled Hypertension and Treatment-Resistant Hypertension

Importance: Uncontrolled hypertension remains a global health concern and dysregulated aldosterone production is a central mechanism. Lorundrostat, a novel aldosterone synthase inhibitor that reduces aldosterone production, demonstrated efficacy in participants with uncontrolled hypertension, including those with treatment-resistant hypertension. Objective: To evaluate the efficacy and safety of lorundrostat for lowering blood pressure (BP) when added to a prescribed regimen of 2 to 5 antihypertensive medications in adults with uncontrolled hypertension and treatment-resistant hypertension. Design, Setting, and Participants: In this phase 3, randomized clinical trial, adults with uncontrolled hypertension, including those with treatment-resistant hypertension, were enrolled between November 2023 and September 2024 at 159 clinic sites across 13 countries. The last date of follow-up was January 24, 2025. Intervention: Randomization ratio of 1:2:1 to 50 mg/d of lorundrostat for 6 weeks followed by 100 mg/d of lorundrostat for 6 weeks (n = 270) if they met prespecified criteria, 50 mg/d of lorundrostat for 12 weeks (n = 541), or daily placebo for 12 weeks (n = 272). The prespecified criteria included systolic BP of 130 mm Hg or greater, potassium level of 4.8 mmol/L or less, sodium level of 135 mmol/L or greater, an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2, and less than a 25% reduction in eGFR. Main Outcome and Measures: The primary outcome was change in automated office systolic BP at week 6 for participants randomized to 50 mg of lorundrostat vs placebo. Adverse events of special interest included dose reduction, interruption, or discontinuation due to events such as hyperkalemia, hyponatremia, and reduction in kidney function. Results: Of the 1083 participants, the mean age was 61.6 years (SD, 10.3 years), 508 (46.9%) were female, 311 (28.7%) were Black or African American, 733 (67.7%) were White, and 685 (63.3%) had a body mass index of 30 or greater (obesity). At randomization, 432 participants (39.9%) were taking 2 prescribed antihypertensive medications and 651 (60.1%) were taking 3 or more. For the pooled 50 mg of lorundrostat group (n = 808), the least-squares mean change in automated office systolic BP at week 6 was -16.9 mm Hg (95% CI, -19.0 to -14.9 mm Hg) vs -7.9 mm Hg (95% CI, -11.5 to -4.2 mm Hg) for the placebo group (least-squares mean difference, -9.1 mm Hg [95% CI, -13.3 to -4.9 mm Hg]; P < .001). Hyponatremia, hyperkalemia, and reduction in kidney function were reported more often with lorundrostat vs placebo. In the 50 mg of lorundrostat group with possible escalation to 100 mg, treatment discontinuation occurred in 1 participant (0.37%) due to hyperkalemia, in 1 (0.37%) due to hyponatremia, and in 0 due to reduction in kidney function. In the 50 mg of lorundrostat group, treatment discontinuation occurred in 2 participants (0.37%) due to hyperkalemia, in 2 (0.37%) due to hyponatremia, and in 3 (0.56%) due to reduction in kidney function. Treatment-emergent adverse events occurred in 49.9% of participants (538/1078) and were mostly mild or moderate in severity. Conclusions and Relevance: The efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, was demonstrated for lowering BP in adults with uncontrolled hypertension, including those with treatment-resistant hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT06153693.