Introduction

Duvakitug, a human IgG1 monoclonal antibody, inhibits TL1A binding to death receptor 3 (DR3), which drives inflammation in Crohn’s disease (CD). The RELIEVE-UCCD trial (NCT05499130), a 14-week induction study, evaluated duvakitug in ulcerative colitis and CD. This was the first placebo-controlled study of an anti-TL1A in moderately to severely active CD. This subgroup analysis was performed to understand the impact of duvakitug in patients with moderate and severe endoscopic inflammation by assessing Week 14 outcomes in subgroups based on endoscopic disease severity at baseline.

Aims & Methods

Patients with CD (N=138) were randomized (1:1:1) to receive a subcutaneous (SC) loading dose (LD) of duvakitug 2250 mg followed by SC duvakitug 900 mg or duvakitug 450 mg every 2 weeks (q2w), or matching placebo LD followed by placebo q2w. Patients were required to have a simple endoscopic score for Crohn’s disease (SES-CD) ≥6 (≥4 for isolated ileal disease) for study eligibility. In this analysis, endoscopic and patient-reported clinical outcomes were assessed by baseline SES-CD scores of ≤15 (moderate) and >15 (severe).¹ Endpoints included response and remission based on endoscopic assessment (SES-CD) and clinical assessment [2-item Patient Reported Outcome assessment tool (PRO2)] at Week 14. Outcomes were analyzed using descriptive summary statistics.

Results

Among patients with severe endoscopic activity (SES-CD >15) at baseline, endoscopic response was achieved by 36% in the duvakitug 900 mg arm, and 18% in the duvakitug 450 mg arm compared to 8% in the placebo arm. In patients with moderate endoscopic activity (SES-CD ≤15) at baseline, endoscopic response was achieved by 51% in the duvakitug 900 mg arm, and 29% in the duvakitug 450 mg arm compared to 15% in the placebo arm (Table). Greater proportion of patients achieved endoscopic remission, clinical response and remission with both doses of duvakitug compared to placebo in the moderate and severe endoscopic subgroups (Table). The overall adverse event profile was similar across treatment arms by disease severity subgroups.

Table: Week 14 endoscopic and clinical response and remission in CD patients with moderate and severe endoscopic activity at baseline

Conclusion

In CD patients, duvakitug demonstrated efficacy in endoscopic and patient-reported clinical outcomes in both moderate and severe endoscopic activity subgroups in this Phase 2b study. Duvakitug was well tolerated across both subgroups. These findings support further development of duvakitug as a potential treatment option for moderately to severely active CD.

References

1. Moskovitz DN, Daperno M, Van Assche G. Defining and validating cut-offs for the Simple Endoscopic Score for Crohn's Disease. Gastroenterology 2007; 132:S1097.

Disclosure

W.R. has served as a speaker for AbbVie, Celltrion, Ferring, Janssen, Galapagos, Merck Sharp & Dohme, Roche, Pfizer, Sobi and Takeda; as a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead,
Index Pharma, Janssen, Medahead, Microbiotica, Pfizer, Teva and Takeda; as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Pfizer and Teva; and have received research funding from AbbVie, Janssen, Sandoz, Sanofi and Takeda.
V.J. has received consulting/advisory board fees from AbbVie, Alimentiv, AnaptyisBio, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ensho, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, MRM Health, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Spyre, Synedgen, Takeda, Teva, Ventyx and Vividion; and speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Eli Lilly, Fresenius Kabi, Janssen, Pfizer, Shire, Takeda and Tillotts.
B.S. has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, 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 has stock options from Ventyx Biosciences.
S.D. reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor; and reports lecture fees from Abbvie, Amgen, Dr Falk Pharma, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda.
K.A., N.G., B.R-D. are employees of Teva Pharmaceutical Industries Ltd.
P.L. is an employee of Sanofi.
Duvakitug is being developed in partnership by Teva and Sanofi.

Introduction

The use of patient-centric monitoring modalities for assessing therapies, such as vedolizumab (VDZ), are of growing interest to optimize disease outcomes in patients with Crohn’s disease (CD). Transmural healing is an emerging outcome assessed by intestinal ultrasonography (IUS), which allows frequent evaluation of CD.^1,2 Real-world evidence on the effectiveness of current treatments for induction and maintenance of a transmural response to inform treatment decisions is limited.

Aims & Methods

The SUNRISE study aims to describe patients with CD treated with VDZ achieving a composite outcome of complete remission, and transmural response, utilizing IUS. SUNRISE is an ongoing observational, prospective study (NCT05192863) being conducted across 10 sites in Canada, Israel and Italy. Adults with moderately to severely active CD, with a bowel wall thickness of > 3 mm based on IUS, and who newly initiated intravenous VDZ are eligible. Complete remission (defined as a composite endpoint of clinically corticosteroid-free [Harvey–Bradshaw Index score of < 5 points and no concomitant corticosteroids], biochemical [C-reactive protein and faecal calprotectin normalization] and transmural remission [assessed by IUS]) and transmural response after VDZ treatment are reported after induction with VDZ (Weeks 10/14) and every 6 months until Month 18 or early discontinuation. In addition, health-related quality of life (as measured by the Short Inflammatory Bowel Disease Questionnaire), healthcare resource utilization and patient satisfaction with IUS are reported.

Results

This interim analysis included 70 patients; median (interquartile range [IQR]) age was 50.0 (39.0–67.0) years, time since CD diagnosis was 4.0 (0.9–17.2) years and treatment duration (n = 69) was 5.0 (3.2–6.1) months. At Month 6 after VDZ initiation, the proportion of patients achieving complete remission, and transmural remission and response were 3/11 (27.3%), 9/28 (32.1%) and 12/28 (42.9%) patients, respectively; data at Weeks 10/14 are shown in the Table. Median (IQR) Short Inflammatory Bowel Disease Questionnaire total score was 4.3 (3.7–5.6) at baseline, 4.5 (3.4–5.3) at Week 10, 4.7 (3.9–5.6) at Week 14 and 5.0 (4.4–6.1) at Month 6. At Month 6, 10/21 patients (47.6%) ranked IUS as their preferred test over colonoscopy, magnetic resonance elastography and computed tomography enterography. Of 40 patients with available data at Month 6, 6 (15.0%) discontinued treatment, 5 (12.5%) switched to subcutaneous VDZ and 1 (2.5%) skipped ≥ 1 dose of VDZ. During the observation period, 2/70 patients (2.9%) had a CD-related hospitalization, and 1/70 patient (1.4%) each had a CD-related emergency room visit or CD-related surgery (fistula removal).

Table​

Conclusion

The SUNRISE study provides real-world evidence for the use of VDZ to achieve transmural healing in patients with CD and supports patient preference for IUS over other monitoring modalities. Additional follow-up data are required to confirm these findings.
This abstract was previously presented at the European Crohn’s and Colitis Organisation (ECCO) 2025 congress. This study and medical writing support was funded by Takeda Pharmaceuticals International AG, Zurich, Switzerland.

References

1. Ilvemark J.F.K.F. et al. J Crohns Colitis 2022;16:554–80.
2. Turner D. et al. Gastroenterol 2021;160:1570–83.

Disclosure

D.C. has received speaker’s fees and/or research support from AbbVie, Janssen, Takeda and Taro, and consultancy fees from AbbVie, Takeda and Taro.
G.F. has received personal fees from AbbVie, Abivax, AlfaSigma, Celltrion, Ferring, Galapagos, Janssen, Lilly, Pfizer, Sandoz, STADA and Takeda.
P.B. is an employee and stockholder of Takeda Pharmaceuticals International AG, Zurich, Switzerland.
F.C. is an employee of the contract research organization IQVIA Solutions Italy s.r.l., hired by Takeda Pharmaceuticals International AG for the following activities: project and site management, data management, quality control and statistical analysis.
M.M. is an employee and stockholder of Takeda Pharma AG, Zurich, Switzerland.
K.L.N. has received advisory board fees from AbbVie, Bristol Myers Squibb, Celltrion, Ferring, Janssen and Pfizer, and speaker’s fees and research support from AbbVie, Janssen and Pfizer.
U.K. has received advisory and speaker’s fees from AbbVie, Bristol Myers Squibb, Celltrion, Janssen, Medtronic, Pfizer and Takeda, and research support from Janssen, Medtronic and Pfizer.

Introduction

The intestinal epithelium as dynamic cellular interface integrates signals from the microbial and metabolic environment to sustain tissue homeostasis. We established a clear mechanistic link between mitochondrial dysfunction of the epithelium and the development and progression of inflammatory bowel diseases (IBD). Several clinical trials targeting disease conditions associated with impaired mitochondrial function use mitochondria-targeted pharmaceutical molecules. Thus, we hypothesize that mitochondria-protective targets can be repurposed for adjuvant IBD therapy. We aim to characterize the effect of 10 metabolic drugs targeting various mitochondrial functions on IBD patient-derived organoids, as well as IBD mouse and pig models.

Aims & Methods

Cellular toxicity of the drugs Acipimox, AICAR, ALCAR, Bezafibrate, Epi-743, Idebenone, Metformin, SS-31 and TUDCA was assessed in the intestinal epithelial cell line Mode-K and murine wild-type (WT) small intestinal (SI) organoids. Furthermore, intestinal organoids from TNF^ΔARE mice, a model for Crohn's Disease (CD) like ileitis, were used to mimic IBD-related inflammatory conditions and treated with a predefined concentration of all drugs. Additionally, the corresponding TNF^ΔARE pig model and organoids generated from resected tissue of CD patients were treated with the compounds. Epithelial stemness and differentiation were analysed via imaging. Drug-related changes on mitochondrial respiration were assessed using respirometry.

Results

Cytotoxicity tests were performed in cell and WT organoid cultures to determine suitable concentration ranges for further treatment studies. Exposure of cells to Metformin inhibited cellular respiration, while Idebenone bypassed complex I inhibition and increased ATP production by 57 %. Furthermore, the 10 tested drugs differentially mediated concentration-dependent effects on seeding efficiency in murine WT organoids. To assess the rescuing capacity of the drugs in an inflammatory context, the predefined concentrations of all 10 compounds were applied to SI organoids generated from the inflamed ileum of TNF^ΔARE mice. Three drugs were excluded from further experiments based on reduced organoid seeding efficiency and de novo crypt formation. In comparison, the remaining seven drugs either did not influence organoid growth and differentiation or were able to increase them. Those seven compounds demonstrated similar results using crypts isolated from acutely inflamed ileal tissue sections of the TNF^ΔARE pig model with Epi-743, Idebenone and SS-31 showing a significant increase in de novo crypt formation. Those three drugs did not affect seeding efficiency and de novo crypt formation of human CD organoids from the resection border, while Acipimox, ALCAR, Bezafibrate and Metformin significantly reduced them. Treatment of strongly inflamed parts of resected CD patient tissue specimens with Epi-743, Idebenone and SS-31 restored growth and differentiation capacity in seeded crypts, indicating an increased stemness upon mitochondrial drug treatment. Those drugs will be tested in vivo in the DSS, TNF^ΔARE and the metabolic injury mouse model Hsp60^Δ/ΔIEC; Il10^-/- as well as the TNF^ΔARE pig model.

Conclusion

Selected drugs targeting mitochondrial functions restored seeding efficiency, differentiation, and stemness of intestinal organoids from inflamed tissue sections of TNF^ΔARE mice, TNF^ΔARE pigs, and CD patients. These findings clearly support the potential of metabolic drug repurposing for adjuvant IBD therapy and indicate putative risks for Metformin.