Introduction

Obefazimod (Obe) is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and has been studied in two Phase 2 induction trials and subsequent open-label maintenance studies [1-3] in patients (pts) with moderately to severely active ulcerative colitis (UC). Here we report efficacy and safety of two Phase 3, 8-week, induction trials in adult pts with UC from ABTECT-1 [NCT05507203] and ABTECT-2 [NCT05507216].

Aims & Methods

The multicenter, randomized, double-blind, placebo-controlled ABTECT trials enrolled pts with moderate-to-severe UC (defined as modified Mayo score (MMS)≥ 5, with rectal bleeding sub-score (RBS) ≥ 1 and centrally read endoscopic score >2) who had inadequate response, loss of response, or intolerance to at least one prior therapy (with no upper limit), including corticosteroids, immunosuppressants, biologics, S1P receptor modulators and/or JAK inhibitors. Pts were randomized 2:1:1 to Obe 50 mg QD (Obe-50), Obe 25 mg QD (Obe-25) or placebo (PBO) for 8 weeks. The primary endpoint was clinical remission (per MMS) and secondary endpoints included clinical response, endoscopic improvement, symptomatic remission, and histo-endoscopic mucosal improvement (HEMI).

Results

1272 pts were randomized and treated in ABTECT-1 (636) and ABTECT-2 (636). In both trials, baseline demographics and disease characteristics were similar between groups; 45.3% and 49.3% of pts had inadequate response to 1 or more advanced therapies. A significantly higher proportion of pts receiving Obe-50 (ABTECT-1:21.7%, ABTECT-2: 19.8%) versus PBO (2.5% and 6.3%) achieved clinical remission (Obe-50-PBO difference: ABTECT-1: 19.3%, p<0.0001; ABTECT-2: 13.4%, p=0.0001) and met all key secondary endpoints in both trials. A significantly higher proportion of pts receiving Obe-25 versus PBO achieved clinical remission (Obe-25-PBO difference: 21.4%, p<0.0001) and met all key secondary endpoints in ABTECT-1. In a pooled analysis, both Obe-50 and Obe-25 met all primary and secondary endpoints with nominal significance (p<0.0001) (Table). The overall rate of serious adverse events and treatment emergent adverse events (TEAEs) leading to study drug discontinuation for pts treated with Obe were similar to PBO. Proportions of pts who reported at least one TEAE in ABTECT-1 were 59.4%, 46.9%, and 53.2% for Obe-50, Obe-25, and PBO, respectively. For ABTECT2, TEAEs occurred in 61.0%, 50.9%, and 48.4% for Obe-50, Obe-25, and PBO, respectively. The most frequent TEAE was headache (Obe-50: 20.8-25.8%; Obe-25: 14.5-15.6%; PBO: 5.7). The headaches were mild, transient, short in duration and not a barrier to treat as evidenced by a low discontinuation rate of 0-1.6%. No signal was observed for serious, severe, or opportunistic infections or malignancies.

Table: 8-week induction efficacy of obefazimod in ABTECT-1 and ABTECT-2 Phase 3 studies, and pooled ABTECT-1 and ABTECT-2^‡

	ABTECT-1					ABTECT-2					Pooled ABTECT-1 and ABTECT-2
Efficacy Endpoints at week 8, % (n)	PBO N= 158	Obe-25 N= 160	Obe-50 N= 318	Between group diff. Obe-25 vs PBO	Between group diff. Obe-50 vs PBO	PBO N= 159	Obe-25 N= 159	Obe-50 N= 318	Between group diff. Obe-25 vs PBO	Between group diff. Obe-50 vs PBO	PBO N= 317	Obe-25 N= 319	Obe-50 N= 636	Between group diff. Obe-25 vs PBO	Between group diff. Obe-50 vs PBO
Clinical remission	2.5 (4)	23.8 (38)	21.7 (69)	21.4 p<0.0001	19.3 p<0.0001	6.3 (10)	11.3 (18)	19.8 (63)	5.1 p=0.1034¥	13.4 p=0.0001	4.4 (14)	17.6 (56)	20.8 (132)	13.2a p<0.0001	16.4a p<0.0001
Clinical response	28.5 (45)	65.6 (105)	61.0 (194)	37.2 p<0.0001	32.6 p<0.0001	33.3 (53)	53.5 (85)	63.2 (201)	20.1 p=0.0002¥	29.6 p<0.0001	30.9 (98)	59.6 (190)	62.1 (395)	28.6a p<0.0001	31.2a p<0.0001
Endoscopic improvement†	5.7 (9)	37.5 (60)	33.3 (106)	32.0 p<0.0001	27.8 p<0.0001	10.1 (16)	22.0 (35)	35.5 (113)	12.0 p=0.0029¥	25.4 p<0.0001	7.9 (25)	29.8 (95)	34.4 (219)	21.9a p<0.0001	26.6a p<0.0001
HEMI	3.2 (5)	23.8 (38)	23.0 (73)	20.7 p<0.0001	20.0 p<0.0001	7.5 (12)	13.2 (21)	23.9 (76)	5.7 p=0.0932¥	16.4 p<0.0001	5.4 (17)	18.5 (59)	23.4 (149)	13.2a p<0.0001	18.2a p<0.0001
Symptomatic remission*†	17.7 (28)	42.5 (68)	41.2 (131)	24.9 p<0.0001	23.7 p<0.0001	22.0 (35)	33.3 (53)	40.3 (128)	11.4 p=0.0227	18.0 p<0.0001	19.9 (63)	37.9 (121)	40.7 (259)	18.1a p<0.0001	21.0a p<0.0001
NRI is used for subjects with missing outcome at Week 8 and subjects reporting any IE prior to Week 8 % Difference is for Obe minus placebo and is based on estimated common risk difference using the Mantel-Haenszel weights adjusting for the randomization stratification factors: inadequate response to advanced therapies (yes/no), baseline oral corticosteroids usage (yes/no), and region (Japan/rest of world) [ABTECT-2 only]. p-values are two sided. a: for pooled analysis, all p-values are nominal Clinical remission: stool frequency sub-score (SFS) ≤1, rectal bleeding sub-score (RBS) = 0 and endoscopic sub-score ≤1 Clinical response: decrease from baseline in the MMS ≥ 2 points and ≥30% from baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1 Endoscopic improvement: endoscopic sub-score ≤1 Symptomatic remission: RBS=0, SFS <1 HEMI: combination of histologic improvement (Geboes histologic score ≤3.1) and endoscopic improvement (endoscopy sub-score ≤1) * Symptomatic remission was an “other secondary” endpoint, not multiplicity controlled, for the FDA protocol † Endoscopic improvement/symptomatic remission were co-primary endpoints for the EMA protocol and were met by both doses in both trials ‡ Hierarchical testing strategy was used starting with 50mg for the primary endpoint followed by the key secondary endpoints; the 25mg was subsequently tested for the primary endpoint followed by the key secondary endpoints. ¥ 25mg did not meet the primary endpoint at week 8 in ABTECT-2 in the FDA testing protocol, therefore p-values for key secondary endpoints for the 25mg arm in ABTECT-2 are nominal

Conclusion

In both ABTECT induction trials, primary and secondary endpoints were met; obe treatment led to statistically significant improvements in clinical, endoscopic, symptomatic and combined endoscopic-histologic endpoints at week 8. Obe was well tolerated with no new safety signals identified.

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.
3. Vermeire S, et al. J Crohns Colitis. 2025 ; 19 : jjaf074

Disclosure

Authors reports following potential conflicts of interest:
BES: Abbvie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Kaleido, Kallyope, Lilly, Merck & Co., Microba, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Janssen, Palisade Bio, Pfizer, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Takeda, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Trex Bio, Union Therapeutics, Ventyx Biosciences.
SV: 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.
LPB: Abbvie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia.
SD: AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
PSD: Abbvie, Abivax, Adiso, Alimentiv, Bristol Meyer Squibb, Celltrion, Genentech, Geneoscopy, Janssen, Pfizer, Takeda.
MD: Abbvie, Abivax, Arena Pharmaceuticals, Astra Zeneca, Boehringer Ingelheim International GmbH, Bristol-Meyer Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, Genentech Inc, Gilead, Janssen Pharmaceuticals, Merck, Pfizer Inc, Prometheus Biosciences, Takeda Pharmaceuticals.
HT: Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
BS: AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Janssen, Landos, Materia Prima, PredictImmune, Pfizer, and Takeda; AlfaSigma, CED Service GmbH, MSD, Ferring, Galapagos, Tr1x bio
TH: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax.
XT: Celltrion, AbbVie, Johnson & Johnson, Lilly, Takeda, Alpha Sigma, Dr. Falk, Abivax, Biogen, Fresenius Kabi, MSD, Pfizer, Tillotts, and Thabor Therapeutics.
RA: AbbVie, Abivax, AstraZeneca, Bristol-Myers Squibb, Celltrion Healthcare, Galapagos, Johnson&Johnson, Lilly, MSD, Pfizer, and Takeda Pharma
US: AbbVie, Abivax, Amgen, Galapagos, Janssen, Eli Lilly, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Gilead Sciences, Pfizer, Roche,Takeda Pharmaceuticals
AA: AbbVie, Abivax, AG Pharma, Alfa Sigma, Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Enthera, Ferring, Galapagos, Gilead, Giuliani, Janssen, Lionhealth, MSD, Nestlé, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sanofi, Sandoz, Takeda, Teva Pharmaceuticals, Tillots Pharma
FB: AbbVie, Amgen, Eurogenerics, J&J, Arena Pharmaceuticals, Celltrion, Ferring, Galapagos, Janssen, Merck Sharp & Dohme, Pfizer Inc, Takeda, Celgene, Fresenius Kabi, Sandoz
DTR: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx.

Introduction

Histological assessment in Inflammatory Bowel Disease (IBD) is often required with endoscopic diagnoses to establish disease activity. This is evident in patients where histological healing is a major therapeutic goal and when endoscopic healing can also exhibit microscopic disease. IBD can manifest in numerous landmark features which are structural and inflammatory related. Histological activity is determined through erosion/ulceration, architectural changes in tissue morphology, mucin depletion and presence of varied inflammatory cells the colonic crypts, Muscularis Mucosae (MM) and Lamina Propria (LP). Histological scoring systems vary in complexity and methodology and subject to discrepancies in inter-rater consensus. Our model aims to provide accurate measurements of key histological features in Ulcerative Colitis (UC) used in scoring systems as both a decision support tool for improving pathologist scoring alignment and sensitive quantitative metrics of inflammatory cells to evaluate disease activity.

Aims & Methods

We developed an ensemble of convolutional neural networks to identify cell types, tissue foreground, crypts, MM, and haemorrhage in H&E images of IBD biopsy data. Models were trained with expert-labelled annotations comprising 34,289 image-annotation pairs (80% training, 20% validation) from in-house and publicly available data. Model accuracy was assessed with 6,464 held-out image-annotation pairs from 26 Whole Slide Images (WSIs) from all sites of the large intestine commonly sampled during endoscopic investigation, while ground truth annotations were reviewed by GI-trained pathologists to certify accuracy. We used geospatial methods to derive boundaries of the LP from other predicted domains, associate cells to delineated regions, measure architectural changes and derive spatially differentiated metrics of inflammatory burden in 66 patients with confirmed UC.

Results

The AI model spatially differentiates and segments cell types and tissue compartments. This produces metrics for inflammatory cell counts in regions of interest such as crypts, LP, and MM. Goblet cell segmentation within crypts allows for measurement of mucin depletion. This can be visualized for pathologists where each inflammatory cell type across the WSI is represented as density metrics. Automated quantification of inflammatory cells across AI-identified tissue domains throughout the bowels of UC patients revealed large intra- and inter-patient variability.

Conclusion

Our AI model can measure histological healing by detecting architectural change, inflammatory cell number, goblet cell reduction and erosions and ulceration. This allows for metrics and visual overlays to assist with pathologist reading and quantifying changes in mucosal biopsies in a clinical trial setting which requires extremely sensitive tools only AI can provide.

Disclosure

DW/AM/RL/PA/PW and CL are employees at Perspectum Ltd. EF and RG are consultants for Perspectum Ltd. All other co-authors have no conflicts of interest to declare relevant to this work.

Introduction

Up to 40% of patients with acute severe ulcerative colitis (ASUC) do not respond to infliximab (IFX)(1) presumably due to insufficient drug exposure (1, 2). We investigated whether personalised IFX induction using predefined serum concentrations was superior to standard dosing.

Aims & Methods

In this prospective, multi-centre trial, adult IFX-naive steroid-refractory ASUC patients were randomised 1:1 to standard (SD) or personalised IFX dosing (PD). After an initial 5 mg/kg IFX infusion, SD was 5 mg/kg IFX at week 2 and 6. In PD, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose™) aiming at IFX serum concentrations >28 ug/mL day 0-28 and >15 ug/mL day 29-42 (3). The primary composite endpoint was clinical and endoscopic response at day 42 (Lichtiger score <10 and ≥3 points drop and UCEIS ≥2 points drop from baseline). Video-endoscopies were performed at baseline, day 42 and 182 and scored by 2 expert readers (XR) with adjudication by a third XR and post hoc also by the DovaVision UC AI tool (AI-R)(4). Key secondary endpoints were day 42 clinical response, day 42 endoscopic response, day 182 clinical remission (Lichtiger ≤3), day 182 endoscopic remission (UCEIS ≤1 on all components), and safety.

Results

48 patients were randomised (23 PD/25 SD) and 31 completed the 26-week study (19 PD/12 SD). Patient characteristics were comparable. Median cumulative IFX dose until day 42 was 18.41 mg/kg [1.77, 20.27] for PD vs 13.79 mg/kg [10.38, 14.82] for SD. The primary composite endpoint at day 42 was not met with XR (57% in PD vs 44% in SD; p=0.564). However, AI-R showed a significantly higher composite response rate in PD (74% in PD vs 32% in SD; p=0.0047). PD showed higher day 42 clinical response vs SD (91% vs 64%; p=0.039). Day 42 endoscopic response was observed in 57% in PD vs 44% in SD (p=0.564) with XR and 74% in PD vs 32% in SD with AI-R (p=0.0047). The proportion of patients in clinical and endoscopic remission at day 182 was higher in PD than in SD (65% vs 36%; p=0.082). Day 182 endoscopic remission with AI-R was higher in PD (52% in PD and 20% in SD; p=0.0337). SAEs occurred in 9% of patients on PD vs 20% of patients on SD. Following an interim analysis, the trial was discontinued based on futility.

Table 1. Baseline characteristics

	Personalised treatment (n=23)	Standard treatment (n=25)
Gender = Male (%)	11 (47.8)	15 (60.0)
Age (year) (median [IQR])	37.00 [24.50, 57.50]	42.00 [30.00, 56.00]
Disease duration (years) (median [IQR])	1.75 [0.62, 5.30]	6.16 [2.61, 17.21]
Naive to advanced therapy (%)	18 (78.3)	21 (84.0)
Lichtiger score (median [IQR])	14 [13, 16]	14 [12, 15]
Total Mayo score (median [IQR])	11 [11, 11]	11 [10, 11]
UCEIS (median [IQR])	6 [5, 7]	6 [5, 7]
CRP (mg/L) (median [IQR])	49.00 [35.70, 70.30]	51.00 [17.00, 105.00]
Albumin (g/L) (median [IQR])	26.00 [23.00, 30.50]	31.00 [23.00, 34.00]

Advanced therapy was defined as treatment with any biologics, JAK inhibitor or S1P modulator. IQR = interquartile range; UCEIS = Ulcerative Colitis Endoscopic Index of Severity, CRP = C-reactive protein.

Conclusion

Personalised IFX dosing was superior to standard dosing in ASUC when endoscopies were read by AI. This is the first IBD study where the primary endpoint, missed by expert assessment, was overturned and met by AI assessment instead. This demonstrates the potential of AI to fundamentally improve clinical trial methodology.

References

1. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49-54.
2. Papamichael K, Van Stappen T, Vande Casteele N, Gils A, Billiet T, Tops S, et al. Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(4):543-9.
3. Ungar B, Mazor Y, Weisshof R, Yanai H, Ron Y, Goren I, et al. Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment Pharmacol Ther. 2016;43(12):1293-9.
4. Byrne M, Requa J, Panaccione R, Panes J, Bressler B, East JE, et al. Development and Validation of a novel AI-based computer vision solution for Ulcerative Colitis severity scoring on video for real world using high-volume expert-annotated video frames. United European Gastroenterol J. 2025 Oct.

Disclosure

This project received grant support from Pfizer Inc. and research support from Baysient LLC, Buhlmann Laboratories and Dova Health Intelligence.

Introduction

The first and further decompensation mark the natural history and the risk of mortality in patients with cirrhosis. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD).

Aims & Methods

International multicenter retrospective study (17 centers) on 6,061 consecutive patients with clinical (LSM>10 kPa) or biopsy-proven (F3-F4 fibrosis) diagnosis of cACLD due to MASLD. First and further decompensation were defined according to Baveno VII criteria. Competing risk analysis by cumulative incidence functions and Cause-specific Cox models with baseline and time-dependent variables were performed. A multistate model was built to better assess the clinical course of cACLD due to MASLD.

Results

The cumulative incidence of the first decompensation was 3.5% (95% C.I 3.0-4.1) at 5 years, increasing 19-fold the risk of LR-D using Cox analysis; the cumulative incidence of further decompensation was 43.9% (95% C.I 37.2-50.2) at 5 years among patients with first decompensation, additionally increasing 1.5-times the risk of LR-D. Ascites, followed by variceal bleeding, were the most common events in both first and further decompensation. Hepatocellular carcinoma (HCC) further independently increased the risk of LR-D by 3- and 1.4-fold in the whole cohort of cACLD due to MASLD and in those who experienced first decompensation, respectively.

Conclusion

The first and further decompensations represent tipping points in the clinical course of patients with cACLD due to MASLD, increasing 19-times and additionally 1.5-times the risk of LR-D. HCC is an independent predictor of LR-D in patients with cACLD due to MASLD, resulting in an additional risk of LR-D when associated with both first and further decompensation.