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/m 2 , 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 m 2 . 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 m 2 with lorundrostat and from 42.9±15.1 to 42.1±15.8 mL/min per 1.73 m 2 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.