Phase 1 studies of the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 690517 (vicadrostat), a novel aldosterone synthase inhibitor, in healthy male volunteers.

purposeIn chronic kidney disease (CKD), raised plasma aldosterone levels are strongly associated with adverse cardiorenal outcomes. Current standard of care may improve outcomes; however, elevated aldosterone levels often persist. We report safety results for BI 690517 (vicadrostat), a potent, selective aldosterone synthase inhibitor under investigation for CKD.

methodsFour phase 1 studies of BI 690517 conducted in healthy European/Chinese/Japanese men: two single rising dose (SRD) and two multiple rising dose (MRD) studies. PRIMARY ENDPOINT: proportion of participants with investigator-defined drug-related adverse events (AEs).

resultsSingle and multiple doses of BI 690517 ≤ 80 mg (0.7-80 mg [European SRD]; 3-80 mg [Chinese/Japanese SRD and MRD]) were well tolerated. Proportions of participants with drug-related AEs: European SRD, 8.3% (4/48); Chinese/Japanese SRD, 21.4% (12/56); European MRD, 13.9% (10/72); Japanese MRD, 2.8% (1/36). No serious AEs, deaths, or AEs leading to treatment discontinuation were reported; one AE of severe orthostatic hypotension occurred (European SRD). Plasma exposure to BI 690517 increased dose dependently; median time to maximum concentration was 0.50-1.75 h and mean half-life was 4.4-6.3 h. Exposure was slightly higher in Asians versus Europeans and may relate to lower body weight in Asian participants. A standardized high-fat/high-calorie meal reduced the rate, but not extent, of BI 690517 absorption. Plasma aldosterone concentrations decreased markedly 1-2 h after BI 690517 administration; decreases were more pronounced with increasing BI 690517 doses.

conclusionBI 690517 was well tolerated and demonstrated dose-dependent inhibition of aldosterone synthesis. Larger studies are warranted to confirm these findings.