TL1A inhibitors in inflammatory bowel disease: A systematic review of phase 2 clinical trials

Abstract

Background: Tumor necrosis factor-like ligand 1A (TL1A) (TNFSF15) signals through DR3 to drive both mucosal inflammation and intestinal fibrosis. Three anti-TL1A antibodies (tulisokibart, afimkibart, and duvakitug) have completed Phase 2 trials in inflammatory bowel disease (IBD). We performed a systematic review (SR) of all Phase 2 data, with the meta-analysis focused on the three randomized controlled trials (RCTs) in ulcerative colitis (UC). Methods: PubMed, Embase, CENTRAL, and ClinicalTrials.gov were searched through January 2026. Risk of bias was assessed using RoB 2.0 and ROBINS-I. Risk ratios (RR), risk differences (RD), and number needed to treat (NNT) were pooled using random-effects models. Results: Six studies from five trials (three RCTs and two single-arm studies; 804 patients) were included. In UC, pooled RR versus placebo was 2.56 (95% CI 1.60–4.09; I² = 0.0%) for clinical remission and 2.13 (1.44–3.16; I² = 0.0%) for endoscopic improvement (both P < 0.001). Corresponding RDs were +22.2% (NNT 4.5) and +22.6% (NNT 4.4). Duvakitug showed a dose-response, with 900 mg approximately doubling the effect of 450 mg. In Crohn’s disease (CD), duvakitug 900 mg achieved endoscopic response RR 3.67 versus placebo (95% CI 1.64–8.20; RD +34.8%, NNT 2.9). Serious adverse event rates were numerically low and comparable to or lower than placebo across trials. GRADE certainty of evidence was moderate for UC efficacy outcomes. Conclusions: Three structurally distinct anti-TL1A antibodies showed consistent Phase 2 efficacy signals in UC with zero between-study heterogeneity (I² = 0.0%), though, given only three UC RCTs and one CD RCT, this apparent class-level signal is underpowered for heterogeneity and remains tentative. Phase 3 trials are needed to confirm these preliminary findings.