Results from the Phase 2 Explore-CKD Trial of lorundrostat, a novel aldosterone synthase inhibitor, in participants with uncontrolled hypertension, chronic kidney disease, and albuminuria.

INTRODUCTION: Dysregulated aldosterone plays an important role in the pathogenesis of hypertension (HTN) and chronic kidney disease (CKD). Lorundrostat, a highly selective aldosterone synthase inhibitor, has demonstrated efficacy and safety for uncontrolled HTN (uHTN) and treatment-resistant HTN in multiple well-controlled clinical trials, although its efficacy in patients with uHTN and CKD is not fully established. METHODS: This was a randomized, double-blind, placebo-controlled, crossover trial of lorundrostat (25 mg/day) added to a sodium-glucose cotransporter-2 inhibitor (SGLT2i) in adults with uHTN, CKD, and albuminuria on stable treatment with a renin-angiotensin-aldosterone system blocker. Participants were randomized to lorundrostat-placebo or placebo-lorundrostat in four-week treatment sequences with a four-week washout period. The primary endpoint was change in automated office systolic blood pressure (AOSBP). Other endpoints included change in urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). RESULTS: The 59 participants had a mean age of 64.6 years, mean body mass index of 33 kg/m2, and 76% had type 2 diabetes. At baseline, mean AOSBP was 149±10.4 mm Hg, geometric mean UACR (spot) was 516.8±2.51 mg/g, and cystatin C-eGFR was 43±15.0 mL/min per 1.73 m2. Least squares mean change in AOSBP was -1.8 mm Hg (95% Confidence Interval, -5.6, 2.1) with placebo and -9.3 mm Hg (-13.1, -5.4) with lorundrostat (placebo-adjusted, - 7.5 mm Hg (-12.3, -2.7). Reduction in geometric mean of UACR was 30.5% (-41.0, -18.2) placebo-adjusted, 25.6% ( -37.7, -11.2). eGFR decreased from 42.9±15.2 to 40.1±16.0 mL/min per 1.73 m2 with lorundrostat and from 42.9±15.1 to 42.1±15.8 mL/min per 1.73 m2 with placebo. Three participants discontinued treatment due to adverse events (hyperkalemia/CKD worsening, acute kidney injury, and retinal detachment). CONCLUSIONS: Lorundrostat added to SGLT2i reduced AOSBP and albuminuria in patients with uHTN and CKD, and was associated with an acceptable safety profile. The observed reduction in albuminuria may suggest a potential cardiorenal benefit. However, longer-term studies are needed to determine whether these findings translate into durable kidney or cardiovascular outcomes.