Abstract Background Obefazimod (Obe) is an investigational, oral, once-daily (QD), small molecule which enhances expression of microRNA-124 for the treatment of moderately to severely active ulcerative colitis (UC). Here we report efficacy data from two Phase 3, 8-week, induction trials on patient-reported, disease-specific and overall quality-of-life (QoL). Methods In the phase 3 ABTECT-1 NCT05507203 and ABTECT-2 NCT05507216 trials, patients (pts) with UC were randomized 2:1:1 to receive Obe 50 mg QD (Obe-50), Obe 25 mg QD (Obe-25) or placebo (PBO) QD for 8 weeks. Pts reported disease-specific QoL with the Inflammatory Bowel Disease Questionnaire (IBDQ) and overall QoL with the EuroQol-5 Dimension-5 Level (EQ-5D-5L) questionnaire. The IBDQ has four domains, scores range 32-224; higher scores=better QoL. Meaningful within patient change (MWPC) for IBDQ total score was defined as ≥ 16 point change and remission as ≥ 170 points. The EQ-5D-5L scores range 0-1; higher scores=better QoL. The EQ-5D-5L also has a visual analogue scale (VAS) with range 0-100; higher scores=better QoL. MWPC was defined as ≥ 0.076 points on the EQ-5D-5L Index and ≥10.9 on the VAS. All p-values are nominal. Results 1272 pts were randomized and treated in ABTECT-1 (n = 636) and ABTECT-2 (n = 636); 1207 had IBDQ, 1137 had EQ-5D-5L Index and 1,180 had EQ-5D-5L VAS data at baseline. At baseline, pts had mean IBDQ total scores of 110.8, 110.8, and 109.7 for Obe-50, Obe-25, and PBO, respectively. At Week 8, Obe-treated pts reported higher mean IBDQ scores vs PBO: 161.9, 159.2, and 135.7 in the Obe-50, Obe-25 and PBO groups respectively (Obe-50:Δ25.97 and Obe-25:Δ22.33, p 0.0001). At Week 8, a greater proportion of Obe-treated pts had a MWPC: 60.9% for Obe-50 and 56.9% for Obe-25 vs 39.8% for PBO (Obe-50:Δ21.20 and Obe-25:Δ17.07, p 0.0001). More Obe-treated pts without IBDQ remission at baseline achieved IBDQ remission: 36.7% for Obe-50 and 33.2% for Obe-25 vs 19.6% for PBO (Obe-50:Δ17.13 and Obe-25:Δ13.56, p 0.001). At baseline, mean EQ-5D-5L Index scores were 0.66, 0.64, and 0.63 for Obe-50, Obe-25, and PBO, respectively. At Week 8, Obe-treated pts reported higher EQ-5D-5L Index scores vs PBO: mean 0.82, 0.81, and 0.71 in the Obe-50, Obe-25 and PBO groups, respectively (Obe-50:Δ0.10 and Obe-25:Δ0.09, p 0.0001). At Week 8, a greater proportion of Obe-treated pts had a MWPC on the EQ-5D-5L Index: 41.0% for Obe-50 and 38.9% for Obe-25 vs 28.5% for PBO (Obe-50:Δ12.59 and Obe-25:Δ10.36, p 0.01). Similar results were observed for the EQ-5D-5L VAS. See Table. Conclusion Treatment with Obe in the ABTECT induction trials produced marked improvement in disease-specific and overall QoL in adults with moderately to severely active UC compared to PBO. Conflict of interest: Baert, Filip J.: Grant: AbbVie, Amgen, EG, J & J, Takeda. Personal Fees: AbbVie, Abivax, Alpha Sigma, Arena, BMS,Celltrion, Eli Lilly, Falk, Ferring, Fresenius, Galapagos, J & J, Pfizer, Sandoz, Takeda, Vifor. Atreya, Raja: RA has served as a speaker, or consultant, or received research grants from AbbVie, Abivax, AlfaSigma, Arena Pharmaceuticals, Astra-Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Galapagos, Gilead, GlaxoSmithKline, InDex Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Merck Sharpe & Dohme, Pfizer, Roche Pharma, Takeda Pharma, Viatris. Mihalkanin, Lubomir: none. no conflicts of interest Korga, Patryk: Principle investigator for clinical trials and research funding paid to my institution from Abivax, Eli Lilly, Roche, AbbVie, Morphic Therapeutic, Janssen, Microbiotica, Optimapharm, Genentech, Bristol Myers Squibb, Cinclus Pharma, Boehringer Ingelheim, Pfizer Fedurco, Miroslav: TO ADD Seidler, Ursula: Consultant for AbbVie, Abivax, Amgen, Galapagos, Janssen, Eli Lilly speaker for Abivax, Amgen, Galapagos, Eli Lilly, Janssen and research grants from Abbvie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead Sciences, Galapagos, Janssen, Pfizer, Roche, and Takeda Pharmaceuticals Tretón, Xavier: Personal Fees: Lectures and advisory board : Abbvie, Calltrion, MSD, johnson&Johnson, Takeda, Amgen, Alphasigma, Lilly Other: participations: Thabor Therapeutics Rabbat, Chris: Employee of Abivax Fine, Jennifer T: Employee of Abivax Shan, Kejia: Employee of Abivax Dolan, Chantal M.: Paid Consultant for Genentech, Roche, Abivax, Regenxbio, Boerhinger Ingelhiem, Pharmacoevidence, Mcure Bio Jacobstein, Doug: Employee of Abivax Cataldi, Fabio: Employee of Abivax Sands, Bruce E: Grant: Janssen, Bristol Myers Squibb, Pfizer Personal Fees: Abivax SA Abbvie Adiso Therapeutics Agomab Therapeutics Alimentiv Amgen AnaptysBio AstraZeneca Biora Therapeutics Boehringer-Ingeleim Bristol Myers Squibb Celltrion, Inc. 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Baert et al. (Thu,) studied this question.