The aldosterone synthase inhibitor BI 690517, combined with renin–angiotensin system inhibition and empagliflozin, may have a beneficial role in the treatment of chronic kidney disease, researchers report. In a phase 2 trial of 586 adults with chronic kidney disease, no unexpected safety signals were identified.
Participants in the multinational trial had estimated glomerular filtration rates (eGFRs) of 30 to less than 90 mL/min/1.73 m2, urine albumin to creatinine ratios (UACRs) of 200 to less than 5000 mg/g, and serum potassium of 4.8 mmol/L or less, and were taking ACE inhibitors or angiotensin receptor blockers. They were randomized to 8 weeks of empagliflozin or placebo run-in, followed by a second randomization to 14 weeks of treatment with once-per-day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo.
Based on a primary endpoint of the change in UACRs measured in the first-morning void urine from baseline (second randomization) to the end of treatment, the investigators found: “At baseline, 33% (n = 196) were women, 67% (n = 390) were men, 42% (n = 244) had a racial identity other than White, and mean participant age was 63.8 years (SD 11.3). Mean baseline eGFR was 51.9 mL/min/1.73 m2 (17.7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was –3% (95% CI –19 to 17) with placebo, –22% (–36 to –7) with BI 690517 3 mg, –39% (–50 to –26) with BI 690517 10 mg, and –37% (–49 to –22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study.”
An accompanying editorial examines the use of clinical development and applications of the aldosterone synthase inhibitors baxdrostat, lorundrostat, and BI 690517.