Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study

Abstract

Background: Portal hypertension is a severe complication of cirrhosis. This Phase Ib study (NCT03842761) assessed the safety, tolerability, and pharmacokinetics of soluble guanylyl cyclase activator BI 685509 in patients with mild or moderate hepatic impairment (Child–Pugh [CP] A or B cirrhosis) and healthy volunteers (HVs). Methods: In this single-center, randomized, placebo-controlled study, patients received BI 685509 (maximum doses: 1, 2, or 3 mg, twice daily [BID]) or placebo for 28 days. HVs received one 0.5 mg dose of BI 685509 or placebo. Results: In total, 64 participants (CP-A, n=24; CP-B, n=25; HVs, n=15) were included; most commonly with NAFLD (36.7%), alcohol-associated (30.6%), or chronic viral hepatitis-related cirrhosis (28.6%). In patients with CP-A cirrhosis, drug-related adverse events (AEs) occurred in 5.6% of BI 685509-treated patients and 16.7% of placebo recipients. In patients with CP-B cirrhosis, drug-related AEs occurred in 26.3% of BI 685509-treated patients only. No serious AEs occurred in patients with CP-A cirrhosis; in patients with CP-B cirrhosis, serious AEs (not drug-related) occurred in 10.5% of BI 685509-treated patients and 16.7% of patients receiving placebo. BI 685509 was rapidly absorbed; exposure increased with dosage and was similar between etiologies and between patients with CP-A cirrhosis and patients with CP-A cirrhosis but lower in HVs. The mean percentage portal–systemic shunt fraction was measured in patients with CP-A cirrhosis and decreased at the end of treatment in the 2 mg BID (–11.2 ± 11.9%) and 3 mg BID (–14.0 ± 8.4%) BI 685509 dose groups, but not in the placebo group (+1.0 ± 27.3%). Conclusion: BI 685509 was generally well tolerated, with 3 serious, not drug-related AEs reported in patients with CP-B cirrhosis. In patients with CP-A cirrhosis, portal–systemic shunt fraction in the exploratory efficacy analysis was reduced by 2 mg BID and 3 mg BID BI 685509.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509, a soluble guanylyl cyclase activator, in healthy volunteers: Results from two randomized controlled trials

“…Nevertheless, transient reductions in BP followed by a compensatory HR increase from baseline confirmed on-target cardiovascular effects for BI 685509. However, the focus of the current study was safety and tolerability, and, based on our findings in this trial, specific PD effects of the following doses of BI 685509 (after uptitration according to individual tolerability) were evaluated in subsequent studies: 1.0 mg to 3.0 mg bid in the 1366.20 Phase Ib trial in people with mild and moderate hepatic impairment (NCT03842761) (Lawitz et al 2023); 3.0 mg qd, or 1.0 mg or 3.0 mg tid, in the 1366.04 Phase Ib trial in people with diabetic kidney disease (NCT03165227) (Cherney et al 2023). Doses of 2.0 mg or 3.0 mg bid (after uptitration according to individual tolerability) will be evaluated in the 1366.21 (NCT05161481) and 1366.29 (NCT05282121) Phase II studies in people with clinically significant portal hypertension.…”