P001 Obefazimod upregulates miR-124 and downregulates the expression of some cytokines in blood and rectal biopsies of patients with moderate-to-severe ulcerative colitis.
Santo, J.(1)*;Gineste, P.(1);Scherrer, D.(2);Nitcheu, J.(1);Ehrlich, H.(3);Sands, B.E.(4);Vermeire, S.(5);
(1)Abivax, Clinical Operations, Paris, France;(2)Abivax, Research and Development, Paris, France;(3)Abivax, Chief Executive Officer, Paris, France;(4)Icahn School of Medicine at Mount Sinai, Division of Gastroenterology, New York, United States;(5)UZ Leuven, Department of Gastroenterology & Hepatology, Leuven, Belgium;
Background
The oral small molecule obefazimod (ABX464) has demonstrated efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC) in a randomized, placebo-controlled, 8-week phase 2b induction study1. We examined the effects of obefazimod on miR-124 and cytokines levels in blood (baseline, weeks 4 and 8) and rectal biopsies (baseline, week 8) of these patients.
Methods
Absolute quantification (QuantaSoft Pro) of the miR-124 copy number was performed by using droplet digital PCR technology on 644 rectal biopsy samples and 1104 whole blood samples from patients receiving obefazimod (25mg, 50mg or 100mg once daily) or placebo. A total of 15 cytokines (IL1b, IL13, IL17, IL6, IL10, IL23, MCP-1, IL34, CXCL-12, IL22, LIF, TGFb, GM-CSF, IFNg and TNFa) were examined by immunohistochemistry (IHC) on 208 rectal biopsies. For each cytokine, antibodies were tested for the chromogenic IHC detection on paraffin tissue sections; repeatability and reproducibility tests were conducted to validate protocols with robust signal. IHC signal was digitized and quantified with Halo® image analysis software. IL17 was also measured in blood samples using an ELLA immunoassay (Bio-Techne).
Results
The three tested doses of obefazimod (25mg, 50mg or 100mg once daily) significantly upregulated miR-124 in blood at week 1 (A) and 8 (B), and in rectal tissue at week 8 (C) (from p<0.001 to p<0.0001 vs. placeb
The three doses of obefazimod significantly reduced IL17 levels in blood of patients at week 1, 4 and 8 (from p<0.01 to p<0.0001 vs. placebo).
IHC protocols in rectal tissue were validated for 4 out of 15 cytokines: IL17, IL23, CXCL-12, INFg. Compared with baseline levels, an 8-week obefazimod treatment significantly down-regulated the expression of IL17 (at all doses, (from p<0.05 to p<0.001), IL23 (p<0.01 at 50mg, p<0.001 at 100 mg), and INFg (p<0.001 at 50 mg). 
Within obefazimod treated subjects, clinical responders showed higher reduction of IL-17A and IL-23 expression in rectal tissue than non-clinical responders at week 8 (reduction in MMS ≥2 points and ≥30% from baseline + decrease in rectal bleeding subscore ≥1 or absolute rectal bleeding subscore ≤1 point). No significant change was observed with CXCL-12.
Conclusion
The 8-week efficacy of obefazimod in patients with moderate-to-severe UC is associated with an increase in miR-124 expression in blood and tissue and with a decrease of IL17, IL23 and INFg in the colorectal tissue.
References
1. Vermeire S, et al. ABX464 (obefazimod) for moderate to severe active ulcerative colitis: a randomised, placebo controlled phase 2b induction trial and 48 week extension. The Lancet Gastroenterology & Hepatology. 2022. https://doi.org/10.1016/S2468-1253(22)00233-3