The Safety, Tolerability, and Pharmacokinetics Profile of BT-11, an Oral, Gut-Restricted Lanthionine Synthetase C-Like 2 Agonist Investigational New Drug for Inflammatory Bowel Disease: A Randomized, Double-Blind, Placebo-Controlled Phase I Clinical Trial.

Abstract

BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts [up to 100 mg/kg daily (QD) for seven days, orally]. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematology, or urinalysis as compared with placebo. Mean fecal concentrations of BT-11 increased linearly with increasing oral doses, with 2.39 mg/g at 7.7 mg/kg on day 7 of the multiple ascending dose (MAD). Analysis of plasma pharmacokinetics indicates that maximum systemic concentrations are approximately 1/6000th of observed concentrations in feces and the distal gastrointestinal tract. Fecal calprotectin levels were lower in BT-11 treated groups as compared to placebo. BT-11 significantly decreases interferon gamma positive (IFNγ+) and tumor necrosis factor alpha positive (TNFα+) cluster of differentiation 4 positive (CD4+) T cells and increases forkhead box P3 positive (FOXP3+) CD4+ T cells in colonic lamina propria mononuclear cells from patients with CD and patients with UC at concentrations of 0.01 µM when treated ex vivo. BT-11 treatment is well-tolerated with no dose-limiting toxicities up to daily oral doses of 100 mg/kg (16 tablets); whereas the efficacious dose is a single tablet (8 mg/kg). Phase II studies in CD and UC patients are ongoing.

• Authors: Andrew Leber, Raquel Hontecillas, Victoria Zoccoli-Rodriguez, Jean-Frederic Colombel, Jyoti Chauhan, Marion Ehrich, Nicholas Farinola, Josep Bassaganya-Riera
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 26 Issue 4 Pg. 643-652 (03 04 2020) ISSN: 1536-4844 [Electronic] England
• PMID: 31077582 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)
• Copyright: © 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Benzimidazoles
• Drugs, Investigational
• LANCL2 protein, human
• Membrane Proteins
• N,N-bis(benzimidazolylpicolinoyl)piperazine
• Phosphate-Binding Proteins
• Piperazines
• Tumor Necrosis Factor-alpha
• Interferon-gamma

Topics

• Administration, Oral
• Adolescent
• Adult
• Benzimidazoles (pharmacokinetics, pharmacology)
• Double-Blind Method
• Drugs, Investigational
• Female
• Healthy Volunteers
• Humans
• Inflammatory Bowel Diseases (pathology)
• Interferon-gamma (blood)
• Intestinal Mucosa (cytology, drug effects)
• Male
• Membrane Proteins (antagonists & inhibitors)
• Middle Aged
• Phosphate-Binding Proteins (antagonists & inhibitors)
• Piperazines (pharmacokinetics, pharmacology)
• Tumor Necrosis Factor-alpha (blood)
• Virginia
• Young Adult