Introduction
PPARγ full agonists show anti-fibrotic and anti-inflammatory effects; however, their adverse event profile limits long-term use. To maintain efficacy and improve safety, MBF-118 is being developed as an oral PPARγ partial agonist for fibrostenosing Crohn’s disease (CD). In preclinical models and healthy volunteers, MBF-118 showed good safety and tolerability with a differentiated toxicity profile. We report results of a phase 2a study assessing safety, tolerability, pharmacokinetics and preliminary efficacy.
Aims & Methods
In this open-label proof-of-concept trial (EU CT 2022-501464-18-00), adults with fibrostenosing CD received MBF-118 (100 or 200 mg daily) for 28 days. Eligibility required ≥1 imaging-confirmed stenosis and stable CD therapy, including biologics (anti-TNFα, anti-integrin, anti-IL-12/23). Stenosis was assessed by ultrasound and endoscopy at baseline and end of treatment. Patients on low dose entered a 90-day extension. Preliminary efficacy by assessed clinical parameters including Crohn’s disease activity index (CDAI) scores and clinical response through endoscopy and ultrasound imaging. All potential adverse events (AEs) were recorded. Secondary objectives included confirming the compound’s systemic and tissue pharmacokinetic profile, and pharmacodynamic response through changes to systemic adiponectin levels.
Results
Five patients received 100 mg MBF-118 daily and five patients received 200 mg, daily. No placebo was used. Patients’ age ranged from 29-73 years (n = 10, Mean 48.3±14.1), and 60% were diagnosed with CD before the age of 40. Six patients (60%) had undergone at least one surgical resection for CD prior to enrolment. All ten patients (100%) were on stable biological therapy prior to enrolment and presented clinical remission at baseline (CDAI mean score 32±23, range 4-72).
During either the 84-day (28 treatment days, 54 follow-up days) or 132-day (90 treatment days, 42 follow-up days) observation period, no serious AEs nor treatment-related AEs leading to discontinuation were reported. Almost all AEs were tabulated as mild (grade 1). No AEs were deemed related to the use of MBF-118. There were no clinically relevant changes in vital signs, laboratory values or ECG parameters which raise any safety concerns.
Pharmacokinetic analysis indicated steady-state plasma concentrations were reached and therapeutically relevant levels in colonic and ileal biopsy tissue, confirming GI tissue distribution of MBF-118. Increases in plasma adiponectin levels confirmed a pharmacodynamic effect of MBF-118 at both dose levels.
An improvement in the scores of the Abdominal Pain and Stool Frequency Instrument (PRO-2, 50% of patients) and the Numeric Rating Scale for abdominal pain (NRS-11, 40% of patients) was observed. Other clinical readouts remained stable throughout the treatment periods of 1 or 3 months. By imaging, 3 patients showed a reduction in pre-stenotic dilation, 3 patients showed an increase in lumen diameter and 2 patients showed a reduction in stenotic length.
Conclusion
Oral MBF-118 was well tolerated during ether the 4-week or 13-week treatment period. Its excellent safety profile, GI tissue distribution and promising trends of clinical activity may provide a potential therapeutic option for the treatment and/or management of fibrosis in Crohn’s disease patients.
Disclosure
The corresponding author is also a medical consultant for Medibiofarma. The remaining authors have no potential conflicts of interest to disclose
