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Safety, pharmacokinetic, and pharmacodynamic study of sibofimloc, a novel FimH blocker in patients with active Crohn's disease

Authors :
Walter Reinisch
Xavier Hébuterne
Anthony Buisson
Stefan Schreiber
Pierre Desreumaux
Christian Primas
Jean‐Michel Paillarse
Grégoire Chevalier
Christophe Bonny
Medizinische Universität Wien = Medical University of Vienna
Centre Hospitalier Universitaire de Nice (CHU Nice)
Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand]
CHU Estaing [Clermont-Ferrand]
CHU Clermont-Ferrand-CHU Clermont-Ferrand
Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP )
Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI)
Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA)
University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH)
Kiel University
CHU Lille
Enterome
Source :
Journal of Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, 2022, 37 (5), pp.832-840. ⟨10.1111/jgh.15828⟩
Publication Year :
2022
Publisher :
Wiley, 2022.

Abstract

Essai clinique - Phase I; International audience; Background and aim: Expression of FimH adhesin by invasive Escherichia coli in the gastrointestinal tract of patients with Crohn's disease (CD) facilitates binding to epithelial glycoproteins and release of pro-inflammatory cytokines. Sibofimloc is a first-in-class FimH blocker that showed little systemic absorption in healthy volunteers. The current study evaluated systemic absorption, safety, and effect on inflammatory biomarkers of sibofimloc in patients with CD.Methods: This was an open-label, multicenter phase 1b study in adults with active CD. In part 1, two patients received a single oral dose of 3000-mg sibofimloc followed by 1500 mg b.i.d. for 13 days. In part 2, six patients received 1500-mg sibofimloc b.i.d. for 13 days. Blood was drawn for pharmacokinetic and biomarker analysis, and stool was collected for biomarker and microbiome analysis.Results: Eight patients with active ileal or ileocolonic CD were enrolled into the study. Systemic sibofimloc exposure was low. Sibofimloc was well tolerated with only grade 1-2 events observed. Several pro-inflammatory biomarkers, including IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and calprotectin, were decreased in stool by end of study.Conclusions: This first study of the novel FimH blocker, sibofimloc, in patients with active CD demonstrated minimal systemic exposure with good tolerance, while decreasing several inflammatory biomarkers. EudraCT number: 2017-003279-70.

Details

ISSN :
14401746 and 08159319
Volume :
37
Database :
OpenAIRE
Journal :
Journal of Gastroenterology and Hepatology
Accession number :
edsair.doi.dedup.....5532cb9801c671ed3dab0cf7db3b0c0f
Full Text :
https://doi.org/10.1111/jgh.15828