Introduction

Obefazimod is an investigational, oral, once-daily (od), small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC at week-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. Here we present results for effects of obefazimod induction on histologic and combined histologic and endoscopic outcomes at week 8.

Aims & Methods

Patients with a modified Mayo score of 5-9 and a centrally read Mayo endoscopy subscore ≥2 at induction baseline were randomized 1:1:1:1 to receive either obefazimod 25mg, 50mg or 100mg od or placebo. Rectal or sigmoidal biopsies were collected during endoscopy at baseline and week 8 to evaluate treatment effect on histopathology scores utilizing the Geboes Index. Histologic improvement (Geboes histologic score ≤3.1), and histo-endoscopic mucosal improvement (Geboes histologic score ≤3.1 + Mayo endoscopy subscore of 0 or 1 with no friability; HEMI) were evaluated at week 8.

Results

Of the 252 patients randomized (with a mean age of 41.2 years; 41.3% female; mean UC disease duration of 8.05 years), 188 received obefazimod treatment, and 64 were administered a placebo. Baseline demographics, disease characteristics and histologic activity were consistent across treatment groups. The proportion of patients with histologic improvement at week 8 was 43% among obefazimod-treated patients (all doses) and 31% among those receiving placebo (Table 1). The proportion of patients with endoscopic improvement at week 8 was 35% among obefazimod-treated patients (all doses) and 13% among those receiving placebo. The proportion of obefazimod-treated patients who achieved HEMI at week 8 was greater than placebo-treated patients (27% vs 13%, respectively). Consistently positive histological outcomes were observed when evaluating all three obefazimod induction doses individually compared to placebo (Table 1).

Table 1: Histologic and combined histologic and endoscopic outcomes at week 8

1: Histological improvement: Neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system (ie, Geboes histologic score ≤3.1); 2: Endoscopic improvement: endoscopic sub-score ≤1; 3: Histo-endoscopic mucosal improvement: A combination of histologic improvement (ie, Geboes histologic score ≤ 3.1) and endoscopic improvement (Mayo endoscopy subscore of 0 or 1 with no friability).

Conclusion

In this Phase 2b induction trial, patients with moderately to severely active UC treated with obefazimod experienced clinically meaningful improvements in histologic and combined histologic and endoscopic outcomes at week 8.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.

Disclosure

Bruce E Sands has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio, and stock options from Ventyx Biosciences.
Séverine Vermeire has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; SV has received consulting and/or speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.
Laurent Peyrin-Biroulet has received grants from Celltrion, Fresenius Kabi, Takeda; LPB has served as a consultant or received speaker’s fees from Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, Connect Biopharm , Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilea, Gossamer Bio, GSK, Hac Pharm, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopa, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio, Ventyx, Ysopia.
Silvio Danese has served as consultant or received speaker’s fees from AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
Parambir Dulai received speaker’s fees from Abbvie, Abivax, Adiso, Bristol Meyer Squibb, Geneoscopy, GSK, Janssen, Lilly, Pfizer, Takeda.
Herbert Tilg has served as a consultant or received speaker’s fees from Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).