Colon to Rectum
N Engl J Med. 2024;391(12):1119–29
Phase 2 trial of anti-TL1A monoclonal antibody tulisokibart for ulcerative colitis
Background: Tulisokibart is a tumor necrosis factor-like cytokine 1A (TL1A) monoclonal antibody in development for the treatment of moderately to severely active ulcerative colitis. A genetic-based diagnostic test was designed to identify patients with an increased likelihood of response.
Methods: The authors randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response. The primary analysis was performed in cohort 1; the primary end point was clinical remission at week 12. Patients with a positive test for likelihood of response from cohorts 1 and 2 were combined in prespecified analyses.
Results: In cohort 1, a total of 135 patients underwent randomization. A significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%; difference, 25 percentage points; 95% confidence interval [CI]: 14–37; p < 0.001). In cohort 2, a total of 43 patients underwent randomization. A total of 75 patients with a positive test for likelihood of response underwent randomization across both cohorts. Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%; difference, 21 percentage points; 95% CI: 2–38; p = 0.02). Among all the enrolled patients, the incidence of adverse events was similar in the tulisokibart and placebo groups; most adverse events were mild to moderate in severity.
Conclusions: In this short-term trial, tulisokibart was more effective than placebo in inducing clinical remission in patients with moderately to severely active ulcerative colitis.
Prof. Dr. Peter Hasselblatt
Deputy Director Department of Internal Medicine II, University Medical Center Freiburg (Germany)
TL1A – A Novel Therapeutic Target for IBD
Innovative therapies for the treatment of inflammatory bowel disease (IBD) primarily focus on the inhibition of pro-inflammatory cytokines, lymphocyte trafficking, or lymphocyte activation. Inhibiting the pro-inflammatory cytokine tumor necrosis factor (TNF)-like ligand 1a (TL1A) represents a novel and particularly promising approach. The cytokine TL1A belongs to the TNF superfamily and exerts its effect by binding to death receptor 3 (DR3). TL1A is expressed in the inflamed intestine, where it activates the innate immune system in synergy with IL-23 and stimulates the adaptive immune system. This activation leads to the release of TNF and IFN-γ by T lymphocytes. Additionally, TL1A has pro-fibrogenic functions. Several monoclonal antibodies against TL1A are currently being investigated in clinical trials for IBD therapy. Two phase 2 trials with the TL1A antibody RVT-3101 have demonstrated good efficacy and tolerability during induction therapy for ulcerative colitis (UC, TUSCANY studies). The efficacy of RVT-3101 is currently under investigation in phase 3 trials for the treatment of UC and Crohn’s disease. In contrast, the ARTEMIS-UC study presented here investigated the efficacy of the monoclonal TL1A antibody tulisokibart (PRA23) to treat UC in a phase 2 trial. The current publication reports results of the induction therapy after 12 weeks. Of the patients treated with tulisokibart, 26% achieved clinical remission with very good tolerability compared to (a notable) 1% with placebo during this period. Unfortunately, this report does not include data on maintenance therapy, leaving the long-term efficacy uncertain. It also raises the question of whether TL1A inhibition is useful and effective even after failure of TNF antibody treatment. In the ARTEMIS-UC trial, only approximately half of the patients had been pre-treated with biologics, making it difficult to draw conclusions on this issue due to the small number of cases. Interestingly, however, an exploratory biomarker was incorporated into the study program to identify patients with a higher probability of responding to TL1A inhibition. In this subgroup, too, the remission rates were higher with tulisokibart than with placebo. However, it remains unclear whether this biomarker is suitable for identifying patients with an increased probability of a clinical response. Despite these uncertainties, integrating personalized medicine approaches into early clinical trials is highly commendable and could influence future therapeutic algorithms. With ongoing trials, we can look forward to additional results on the potential of TL1A inhibition for treating IBD in the future.