#1418 Phase II dose-selection, randomised, controlled trial of ASi BI 690517 with and without EMPA in CKD: subgroup analysis by T2D status

Abstract

Abstract Background and Aims High aldosterone levels accelerate chronic kidney disease (CKD) progression. BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. ASi may reduce deleterious haemodynamic, inflammatory, and fibrotic actions of aldosterone. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may also mitigate the risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given either alone or in combination with empagliflozin (EMPA), in people who had CKD with or without type 2 diabetes (T2D) [1, 2]. Here, we present an analysis by T2D status (pooled for background randomizedon to EMPA or placebo [PBOEMPA]). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomized (R1) 1:1 to an 8-week run-in to receive background EMPA 10 mg or PBOEMPA, then randomized again (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBOASI for 14 weeks. The primary endpoint was the change from R2 baseline in urine albumin:creatinine ratio (UACR) in the first morning void of urine at Week 14. A secondary endpoint was UACR response (≥30% reduction from R2 baseline in UACR at Week 14). Changes in systolic blood pressure (SBP) and estimated glomerular filtration rate (eGFR) from R2 baseline to Week 14 were also assessed, as were safety outcomes. Results Of 586 people randomized at R2, 414 (70.6%) were reported to have T2D and 172 (29.4%) did not have T2D. Baseline demographics and clinical characteristics were mostly similar between these two groups [1]; however, those with T2D had higher mean BMI (30.6 vs 28.3 kg/m2), SBP (135.3 vs 130.2 mmHg) and eGFR (53.0 vs 49.4 mL/min/1.73 m2), and higher median UACR (444.7 vs 409.2 mg/g) than those without T2D. BI 690517 consistently reduced UACR versus PBOASI in people with and without T2D (p = 0.38, indicating no difference in treatment effect between these groups), with the largest reductions observed in the 10 mg and 20 mg dose groups; however, for the 3 mg dose group, UACR reduction was only observed in people with T2D (Figure). UACR response rates (≥30% reduction) were achieved in more than half of people with and without T2D in the BI 690517 10 mg and 20 mg dose groups, with the highest response rates in those also receiving EMPA (10 mg dose group: with T2D, 74.3%; without T2D, 64.0%). Decreases in SBP and small decreases in eGFR were also observed in people with and without T2D in response to BI 690517 10 mg and 20 mg, and were consistent with the observed changes in the overall population; however, for the 3 mg dose group, eGFR reduction was only observed in people with T2D. Adverse events leading to discontinuation in BI 690517 10 mg and 20 mg dose groups were more common among people with T2D than those without T2D who were receiving the same dose of BI 690517. Conclusion In people who had CKD, with or without T2D, BI 690517 dose-dependently reduced UACR, with high rates of UACR response suggestive of additive beneficial effects when given with EMPA.