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Introduction Obefazimod (Obe), an oral, once-daily (OD), small molecule which enhances expression of microRNA-124 was studied in patients (pts) with moderately to severely active ulcerative colitis (UC) in Phase 2 studies. We present efficacy endpoints at week 8 for pts with and without prior inadequate response to advanced therapies (ATIR-Yes, ATIR-No) from the two ABTECT Phase 3 induction trials.Methods The multicentre, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (MMS≥ 5, RBS ≥ 1 and centrally read endoscopic score ≥2) who had inadequate response, loss of response, or intolerance to at least one prior therapy (corticosteroids, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors, JAKi). Pts were randomized 2:1:1 to Obe 50 mg OD (Obe-50), Obe 25 mg OD (Obe-25) or placebo (PBO) for 8 weeks. Clinical remission per MMS, clinical response, endoscopic improvement, symptomatic remission and histo-endoscopic mucosal improvement were analysed among ATIR-Yes and ATIR-No pts; all p-values are nominal.Results Among pts who participated in ABTECT trials, 47.3% (602/1272) were ATIR-Yes. A higher proportion of the ATIR-Yes subgroup receiving Obe-50 achieved clinical remission relative to PBO (Obe-50-PBO Δ: 10.1%, p=0.0009), clinical response (Obe-50-PBO Δ: 34.9%, p<0.0001), endoscopic improvement (Obe-50-PBO Δ: 17.8%, p<0.0001), HEMI (Obe-50-PBO Δ: 11.1%, p=0.0005), and symptomatic remission (Obe-50-PBO Δ: 23.4%, p<0.0001). In the ATIR-Yes subgroup, the difference from PBO across all efficacy measures was larger for pts receiving Obe-50 relative to Obe-25. In the ATIR-No subgroup, larger proportions achieved all efficacy measures relative to PBO including clinical remission (Obe-50-PBO Δ: 22.4%, p<0.0001; Obe-25-PBO Δ: 21.3%, p<0.0001). Obe-50 and Obe-25 performed similarly across efficacy measures. The difference from PBO in clinical response was similar across lines of treatment, from ATIR-No through 4+ ATIRs. In the subset of pts who failed JAKi, higher proportion of pts receiving Obe-50 or Obe-25 achieved clinical response relative to PBO (Obe-50-PBO Δ: 34.4%, p=0.0017; Obe-25-PBO Δ: 27.0%, p=0.0196). Obefazimod was well tolerated with a safety profile similar to previous studies.Conclusion Among ATIR-Yes and ATIR-No subgroups, improvements in clinical, endoscopic, symptomatic and combined endoscopic-histologic measures were observed in pts treated with Obe at week 8 relative to PBO in ABTECT trials. Improvements vs. PBO in clinical response were observed in ATIR-Yes JAKi-IR pts and across lines of therapy up to 4+ ATIR.