The rise of anti-TL1A therapies was the talk of ECCO, and it’s a theme that isn’t going away soon. Everyone working in IBD will be competing with these either directly or indirectly in the coming months and years.
This year’s congress included three notable presentations on the impact of TL1A inhibitors from the RELIEVE program for Crohn’s disease (CD)i,ii and ulcerative colitis (UC) and the TUSCANY-2 study in UC.iii These anti-TL1A therapies target the TNF-like cytokine 1A (TL1A), also known as vascular endothelial growth inhibitor (VEGI) and TNF superfamily member 15 (TNFSF15).
With the promising response rate and safety results demonstrated by this drug class, they’re disrupting the IBD landscape. More than 30 trials are now listed in Citeline, and everyone working in IBD will be competing with these either directly or indirectly in the coming months and years.
So, what is an anti-TL1A therapy? Drugs that inhibit TL1A are significant for their dual mechanism of action, dialing down the multiple pathways of inflammation and fibrosis in disease. Here’s a closer look.
Anti-TL1A in Brief
- TL1A, a member of the TNF superfamily, is a cytokine implicated in the risk and pathogenesis of IBDiv,v
- While both TNF and TL1A have similar “jelly roll”-like structures, only TL1A signals via the DR3 receptor,iv,vi
- In the healthy intestine, neither TL1A nor DR3 is constitutively expressed by mucosal lymphoid cells/fibroblastsvii
- TL1A and DR3 are induced upon activation of the major immune and pro-fibrotic cell types featuring in IBD pathobiologyvii
- Upon induction, TL1A dials up activation/dysregulation states across these multiple active pathways to perpetuate disease chronicity in IBDviii
- Anti-TL1A antibodies dial down these active disease pathways in parallel and thereby offer the potential to be best in diseaseix,x
These drugs are poised to transform the already competitive landscape of gastrointestinal (GI) clinical research, alongside other research from the conference in novel areas such as bispecific antibodies and combination therapies.
PSI has already worked on several pivotal trials for TL1A inhibitors, we understand what it takes to get sites excited for these studies – and also how to position other clinical studies around them.
If you’re planning an IBD study and looking to navigate this space, reach out. Let’s find the best way to position your drug in this competitive field so we can deliver enrollment on time.
i Jairath V, Kierkus J, Duvall GA, et al. OP40 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active Crohn’s disease: results from a phase 2b, randomised, double-blind, placebo-controlled dose-ranging, basket trial (RELIEVE UCCD). Journal of Crohn’s and Colitis. 2025;19(Supplement_1):i77-i78. doi:10.1093/ecco-jcc/jjae190.0039a
ii Reinisch W, Stepek D, Kempinski R, et al. OP41 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active ulcerative colitis: Results from a phase 2b, randomised, double-blind, placebo-controlled, dose-ranging, basket trial (RELIEVE UCCD). Journal of Crohn’s and Colitis. 2025;19(Supplement_1):i79-i80. doi:10.1093/ecco-jcc/jjae190.0039b
iii Jairath V, Allegretti JR, Yarur A, et al. OP39 Treatment with RO7790121 induces and maintains histologic and histologic-endoscopic improvement and remission in moderately to severely active ulcerative colitis – Results from TUSCANY-2. Journal of Crohn’s and Colitis. 2025;19(Supplement_1):i75-i76. doi:10.1093/ecco-jcc/jjae190.0039
iv Zhan C, Yan Q, Patskovsky Y, et al. Biochemical and structural characterization of the human TL1A ectodomain,. Biochemistry. 2009;48(32):7636-7645. doi:10.1021/bi900031w
v Xu WD, Li R, Huang AF. Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive review. Frontiers in Immunology. 2022;13. doi:10.3389/fimmu.2022.891328
vi Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DCR3 and functions as a T cell costimulator. Immunity. 2002;16(3):479-492. doi:10.1016/s1074-7613(02)00283-2
vii Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): a co-stimulatory system of cytokines with diverse functions in gut mucosal immunity. Frontiers in Immunology. 2019;10. doi:10.3389/fimmu.2019.00583
viii Bamias G, Menghini P, Pizarro TT, Cominelli F. Targeting TL1A and DR3: the new frontier of anti-cytokine therapy in IBD. Gut. Published online September 11, 2024:gutjnl-332504. doi:10.1136/gutjnl-2024-332504
ix Takedatsu H, Michelsen KS, Wei B, et al. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-Helper 1 and T-Helper 17 activation. Gastroenterology. 2008;135(2):552-567.e2. doi:10.1053/j.gastro.2008.04.037
x Hassan-Zahraee M, Ye Z, Xi L, et al. Antitumor necrosis factor-like Ligand 1A therapy targets tissue inflammation and fibrosis pathways and reduces gut pathobionts in ulcerative colitis. Inflammatory Bowel Diseases. 2021;28(3):434-446. doi:10.1093/ibd/izab193
