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

Fistulizing perianal Crohn’s disease (CD) remains a significant therapeutic challenge, with limited randomized controlled trials to date, restricted so far to infliximab and, more recently, filgotinib. The USTAP (NCT04496063) trial aimed to evaluate the efficacy and safety of UST in patients with actively draining perianal fistulas through a multicenter randomized controlled design.

Aims & Methods

This double-blind, placebo-controlled, multicenter trial enrolled adult patients with active draining fistulizing perianal CD. Between April 2020 and June 2024, eligible patients with persistent fistula drainage were randomized 1:1, after seton placement when necessary, to receive either UST (6 mg/kg IV at baseline followed by 90 mg SC at week 8, then every 8 weeks) or placebo. Steroids were allowed at baseline with a standardized steroid taper. Seton removal was planned at week 6. The primary endpoint was combined clinical remission (absence of drainage from all external fistula openings) and radiological remission (defined as the absence of abscesses >2 cm confirmed by blinded central pelvic MRI) at week 12. Secondary endpoints included clinical remission, radiological remission, changes in disease activity (CDAI, PDAI), IBD-DI, and safety. Endpoints were independently reviewed by a blinded adjudication committee. Randomization was stratified by prior anti-TNF exposure and study center. The intended sample size was 73 patients per group to detect a 20% difference in remission rates (power 80%, alpha 5%). Due to slow recruitment, the study was discontinued in June 2024 after randomizing 32 patients, without unblinding the study data. Patients were subsequently followed until week 48.

Results

Thirty-three patients consented to participate with 32 patients (women: 41%; median age: 42) ultimately randomized (UST: 16; placebo: 16) across 10 French centers. Seventy percent had prior anti-TNF exposure (50% in UST arm, 50% in placebo arm), and 23% had previously failed two or more anti-TNF therapies. At baseline, 84% had one draining fistula, 16% had two, and 25% had associated abscesses. At week 12, combined remission was achieved in 62% in the UST group versus 25% in the placebo group (Table). Clinical remission was observed in 69% in the UST group vs. 31% in the placebo group, while radiological remission rates were 87.5% in the UST group and 75% in the placebo group. In the UST arm, mean change in CDAI, PDAI and IBD-DI from baseline to week 12 was -56.3, -2.2 and -4.9, (vs. -9.8, -1.6 and +4.9, in the placebo arm, respectively). Adverse events (AE) and serious adverse events (SAE) were similar in both treatment groups: 23 AE (62%) occurred in the placebo group, and 14 AE (38%) in the UST group. Six SAEs were reported overall, including two gastrointestinal events, one renal disorder, and one anal abscess. Two patients in the placebo group discontinued study by week 6 due to SAEs (an anal abscess and a peri-ileal abscess).

Conclusion

In this trial, where the majority of patients had prior anti-TNF exposure, the observed short-term clinical benefit of UST supports its use in fistulizing perianal CD.

Disclosure

This work was supported by a grant from Johnson & Johnson
Pauline Wils : Johnson & johnson, Takeda, Amgen, Abbvie, Celltrion, Ferring
S Nancey: Abbvie, Johnson and Johnson, Fresenius Kabi, Biogen, Takeda, Medac, Celltrion, MSD, Pfizer, Sandoz, Lilly,Ferring, Amgen
E. Messmer: No conflict of interest for this study
A Bourreille: Johnson and Johnson
A Buisson: Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pileje, Pfizer, Roche, Sandoz, Takeda et Tillotts. Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda
L Caillo: No conflict of interest for this study
L Vuitton: abbvie amgen J&J Pfizer Takeda Lilly MSD Mayoli Ferring Dr Falk Alpha Sigma
R Altwegg: Abbvie, Johnson ans Johnson, Takeda, Pfizer, Lilly, Alphasigma, Celltrion, Amgen, Biogen, Sandoz, Ferring
X Hébuterne reports clinical research funding from Abbvie, Abivax, Amgen, Celltrion, Lilly, Fresenius-Kabi, J&J, InDex Pharmaceuticals, Pfizer, Prometheus, MSD, Roche, Takeda, serving on advisory boards for Abbvie, Biogen, Celltrion, Lilly, J&J, and participating in lectures and educational activities for Abbvie, Amgen, Celltrion, Lilly, Fresenius-Kabi, Galapagos, J&J, MSD, Nestlé Health Sciences, Nutricia, Pfizer, Tillots, Takeda.
O Ernst: No conflict of interest for this study
P Meunier: No conflict of interest for this study
V Laurent: No conflict of interest for this study
D Laharie: received board and lecture fees from: Abbvie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Fresenius-Kabi, Janssen, Lilly, MSD, Pfizer, Roche, Sandoz, Takeda
E Vicaut: No conflict of interest for this study
L Peyrin-Biroulet: Consulting : 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 ; lecture : Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots, Viatris