This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI685509 after oral single rising doses (SRDs) or multiple rising doses (MRDs) in healthy volunteers. In the SRD trial (NCT02694354; February 29, 2016), within each of the three dose groups (DGs), six subjects received BI685509 (1.0, 2.5, or 5.0mg) and two received placebo (N = 24). In the MRD trial (NCT03116906; April17, 2017), within each of the five DGs, nine subjects received BI685509 (uptitrated to 1mg once daily [qd; DG1], 2.5mg twice daily [DG2], 5.0mg qd [DG3]; 3.0mg three times daily [tid; DG4] or 4.0mg tid [DG5]) and three received placebo, for 14-17days (N = 60). In the SRD trial, 7/24 subjects (29.2%) had ≥ 1 adverse event (AE), most frequently orthostatic dysregulation (n = 4). In the MRD trial, 26/45 subjects (57.8%) receiving BI685509 had ≥ 1 AE, most frequently orthostatic dysregulation and fatigue (each n = 12). Tolerance development led to a marked decrease in orthostatic dysregulation events (DG3). BI685509 was rapidly absorbed after oral administration, and exposure increased in a dose-proportional manner after single doses. Multiple dosing resulted in near-dose-proportional increase in exposure and limited accumulation. BI685509 pharmacokinetics appeared linear with time; steady state occurred 3-5days after each multiple-dosing period. Increased plasma cyclic guanosine monophosphate and decreased blood pressure followed by a compensatory increase in heart rate indicated target engagement. BI 685509 was generally well tolerated; orthostatic dysregulation may be appropriately countered by careful uptitration.