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Clinical Trial
. 2023 Oct 27;7(11):e0276.
doi: 10.1097/HC9.0000000000000276. eCollection 2023 Nov 1.

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

Eric J Lawitz  1 , Thomas Reiberger  2   3 , Jörn M Schattenberg  4 , Corinna Schoelch  5 , Harvey O Coxson  5 , Diane Wong  6 , Judith Ertle  7
Affiliations
Clinical Trial

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

Eric J Lawitz et al. Hepatol Commun. .

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.

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Conflict of interest statement

Eric J. Lawitz received grants from 89bio, Allergan, Akero Therapeutics, AstraZeneca, Axcella Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DURECT, Eli Lilly, Elobix, Enanta, ENYO, Galmed, GENFIT, Gilead, Hanmi, Intercept, Laboratory for Advanced Medicine, Madrigal, Merck, Metacrine, Novartis, Novo Nordisk, Octeta, Poxel, Roche, Viking, and Zydus. Thomas Reiberger consults, advises, is on the speakers' bureau, received grants, and received compensation from AbbVie and Gilead. He consults, advises, received grants, and received compensation from Boehringer Ingelheim. He consults, advises, is on the speakers' bureau, and received grants from Intercept and MSD. He consults, advises, and received grants from Siemens. He consults and advises Bayer. He is on the speakers' bureau and received grants from Gore. He is on the speakers' bureau and received compensation from Roche. He received grants from MYR, Philips Healthcare, and Pliant. Jörn M. Schattenberg consults and received grants from Boehringer Ingelheim, Gilead, and Siemens Healthcare. He consults for Bayer, Bristol Myers Squibb, GENFIT, Intercept, Madrigal, Merck, Nordic Bioscience, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi. He is on the speakers' bureau for Falk Foundation. Corinna Schoelch is employed by Boehringer Ingelheim. Harvey O. Coxson is employed by Boehringer Ingelheim. Diane Wong is employed by Boehringer Ingelheim. Judith Ertle is employed by Boehringer Ingelheim.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Participant disposition. (A) Child–Pugh class A and B patients; (B) healthy volunteers. *One CP-B patient in the 2 mg BID group was removed from the trial due to a serious AE of delirium. Abbreviations: AE, adverse event; BID, twice daily; CP, Child–Pugh.
FIGURE 2
FIGURE 2
Pharmacokinetic outcomes of BI 685509 in plasma. (A) Plasma concentration–time profiles of BI 685509 in Child–Pugh class A and B patients and matched healthy volunteers after single-dose administration. Plasma Cmax,ss (B) and AUC0–τ,ss (C) of BI 685509 across dose groups and Child–Pugh classifications. Dose-normalized Cmax,ss (D) and AUC0–τ,ss (E) across cirrhosis etiologies. Abbreviations: BID, twice daily; CP, Child -Pugh; gMean, geometric mean; HV, healthy volunteer.
FIGURE 3
FIGURE 3
Spleen stiffness in patients with Child -Pugh class A cirrhosis. Data are presented as mean±SD, with individual values represented. Abbreviations: BID, twice daily; EoT, end of treatment.
FIGURE 4
FIGURE 4
Change in portal–systemic shunt fraction in patients with Child–Pugh class A cirrhosis as measured by the HepQuant SHUNT test. Data are presented as mean±SD. Abbreviations: BID, twice daily.
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References

    1. GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5:245–266. - PMC - PubMed
    1. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2017;65:310–335. - PubMed
    1. Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. . Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353:2254–2261. - PubMed
    1. Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, et al. . Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133:481–488. - PubMed
    1. Zipprich A, Garcia-Tsao G, Rogowski S, Fleig WE, Seufferlein T, Dollinger MM. Prognostic indicators of survival in patients with compensated and decompensated cirrhosis. Liver Int. 2012;32:1407–1414. - PMC - PubMed

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