Clinically Meaningful and Well Tolerated Blood Pressure Reduction in Chronic Kidney Disease Participants in the Launch-HTN Trial of the Aldosterone Synthase Inhibitor Lorundrostat

Objective: In chronic kidney disease (CKD), hypertension (HTN) is the leading modifiable risk factor for cardiovascular morbidity and mortality. Up to 50% of CKD patients have uncontrolled blood pressure (BP) despite using multiple BP medications. Aldosterone synthase inhibitors (ASIs) target aldosterone synthesis and offer a novel, mechanism-based approach to improve BP control and cardiorenal outcomes. Lorundrostat, a highly selective ASI, demonstrated significant antihypertensive efficacy in the global Launch-HTN trial, one of the largest phase 3 trials of an ASI in difficult-to-treat HTN. This Launch-HTN analysis examines BP improvement and safety of lorundrostat by CKD status. Design and method: This analysis included 1067 participants with uncontrolled HTN while receiving 2 or >=3 BP medications who received once-daily 50 mg lorundrostat or placebo in the randomized, double-blind, placebo-controlled phase 3 Launch-HTN pivotal trial and had baseline renal data. CKD was defined as eGFR =30 mg/g. Systolic BP (SBP) changes from baseline to 2/6/12 weeks were compared in CKD-vs-non-CKD participants using mixed-model repeated measures. Serum potassium and sodium were examined. Results: Among 1067 analyzed participants, 23.5%(n=251) had CKD. Baseline mean(SD) SBP was 150.9 (13.0)mmHg for CKD and 147.5 (11.4)mmHg for non-CKD participants. A higher proportion of CKD-vs-non-CKD participants had SBP >=160mmHg (27%/n=69-vs-16%/n=127) and were prescribed =>3 BP medications (70%/n=176-vs-57%/n=461). Baseline mean(SD) eGFR was 82.3(21.9) for CKD vs 94.4(14.5) for non-CKD participants; geometric mean UACR was 56.5 mg/g for CKD vs 9.8 mg/g for non-CKD participants. Placebo-adjusted SBP change at 2/6/12 weeks was significant and similar in CKD-vs-non-CKD participants receiving lorundrostat 50 mg (Table); UACR placebo-adjusted percent change was -42.2% in CKD participants (Table). At week 12, a higher proportion of lorundrostat participants achieved target SBP <130mmHg (44.2% CKD; 48.3% non-CKD participants) vs placebo (17.7% CKD; 22.3% non-CKD participants). Serum potassium and sodium 12-week mean changes were comparable.Conclusions: In Launch-HTN, lorundrostat achieved comparable and clinically meaningful SBP reduction and a favorable safety profile in CKD and non-CKD participants. Lorundrostat significantly reduced UACR in CKD participants. The findings support lorundrostat as a potential therapeutic strategy for uncontrolled HTN and cardiorenal risk reduction in CKD patients who have difficult-to-treat HTN.