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

David Z I Cherney; Dick de Zeeuw; Hiddo J L Heerspink; Jose Cardona; Marc Desch; Arne Wenz; Friedrich Schulze; Masaomi Nangaku

doi:10.1111/dom.15099

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

Diabetes Obes Metab. 2023 Aug;25(8):2218-2226. doi: 10.1111/dom.15099. Epub 2023 May 25.

Authors

David Z I Cherney^{1

2

3}, Dick de Zeeuw⁴, Hiddo J L Heerspink⁴, Jose Cardona⁵, Marc Desch⁶, Arne Wenz⁷, Friedrich Schulze⁶, Masaomi Nangaku⁸

Affiliations

¹ Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada.
² Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
³ Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
⁴ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
⁵ Indago Research and Health Centre, Hialeah, Florida, USA.
⁶ Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
⁷ Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
⁸ Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

PMID: 37232058
DOI: 10.1111/dom.15099

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 m² 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 m² 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.

Keywords: Phase I-II study; clinical trial; diabetic nephropathy; dose-response relationship; pharmacodynamics; pharmacokinetics.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Albuminuria / complications
Albuminuria / drug therapy
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Diabetic Nephropathies*
Double-Blind Method
Glomerular Filtration Rate
Humans
Soluble Guanylyl Cyclase / pharmacology
Soluble Guanylyl Cyclase / therapeutic use

Substances

Soluble Guanylyl Cyclase