Safety, tolerability, pharmacodynamics and pharmacokinetics of the soluble guanylyl cyclase activator BI 685509 in patients with diabetic kidney disease: A randomized trial

Abstract Aims Albuminuria is associated with abnormalities in the nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cyclic guanosine monophosphate pathway. We assessed safety and efficacy of the NO‐independent sGC activator BI 685509 in patients with diabetic kidney disease and albuminuria. Materials and methods In this Phase Ib trial (NCT03165227), we randomized patients with type 1 or 2 diabetes, estimated glomerular filtration rate (eGFR) 20–75 mL/min/1.73 m 2 and urinary albumin:creatinine ratio (UACR) 200–3500 mg/g to oral BI 685509 (1 mg three times daily, n = 20; 3 mg once daily, n = 19; 3 mg three times daily, n = 20, after final titration) or placebo ( n = 15) for 28 days. Changes from baseline in UACR in first morning void (UACR FMV ) and 10‐hour (UACR 10h ) urine (3 mg once daily/three times daily only) were assessed. Results Baseline median eGFR and UACR were 47.0 mL/min/1.73 m 2 and 641.5 mg/g, respectively. Twelve patients had drug‐related adverse events (AEs; 16.2%: BI 685509, n = 9; placebo, n = 3), most frequently hypotension (4.1%: BI 685509, n = 2; placebo, n = 1) and diarrhoea (2.7%: BI 685509, n = 2; placebo, n = 0). Four patients experienced AEs leading to study discontinuation (5.4%: BI 685509, n = 3; placebo, n = 1). Placebo‐corrected mean UACR FMV decreased from baseline in the 3‐mg once‐daily (28.8%, P = 0.23) and three‐times‐daily groups (10.2%, P = 0.71) and increased in the 1‐mg three‐times‐daily group (6.6%, P = 0.82); changes were not significant. UACR 10h decreased by 35.3% (3 mg once daily, P = 0.34) and 56.7% (3 mg three times daily, P = 0.09); ≥50.0% of patients (UACR 10h 3 mg once daily/three times daily) responded (≥20% UACR decrease from baseline). Conclusions BI 685509 was generally well tolerated. Effects on UACR lowering merit further investigation.