Early clinical data suggest TL1A blockade could reshape treatment options.
A proof-of-concept phase 2 has demonstrated that tulisokibart, a first-in-class anti-TL1A monoclonal antibody, can significantly improve clinical outcomes in patients with moderately to severely active Crohn’s disease who have not responded to conventional or biologic therapies.
The randomised, double-blind, placebo-controlled study enrolled adults with inadequate response or intolerance to standard treatments, including corticosteroids, immunosuppressants, and existing biologics such as anti-TNF agents, anti-IL-12/23 antibodies, and integrin inhibitors.
Participants were assigned to receive tulisokibart or placebo, with efficacy assessed by clinical response and remission rates at prespecified time points.
The trial results have been published in The Lancet Gastroenterology & Hepatology.
“The clinical efficacy and safety findings support further development of tulisokibart in the treatment of patients with moderately to severely active Crohn’s disease,” the authors wrote.
“Translational data further support that targeting TL1A can be a promising therapeutic approach for Crohn’s disease.”
The researchers reported that patients receiving tulisokibart experienced clinically meaningful improvements compared to placebo, with a higher proportion achieving both response and remission.
Benefits emerged early and were sustained through the study duration. Importantly, the therapy was well tolerated, and no unexpected safety signals emerged. Adverse events were generally mild to moderate and comparable between treatment arms.
TL1A (TNFSF15) is a cytokine implicated in gut inflammation and fibrosis, acting through the DR3 receptor to amplify immune activation in the intestinal mucosa. This makes it a compelling target for intervention in inflammatory bowel disease.
Unlike current biologics that block tumour necrosis factor or interleukin pathways, TL1A inhibition offers a novel mechanism with potential utility in patients who have exhausted other options, the researchers said.
“A key strength of this trial was that an objective measure of centrally read endoscopy was used as the primary endpoint,” the authors wrote.
“Limitations of this study include its open-label design, as well as the small sample size and the use of historical placebo controls as the basis for statistical inference.”
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While these results were promising, the researchers cautioned that phase 3 data was needed before tulisokibart could be integrated into treatment algorithms.
Larger trials will be critical to confirm efficacy, durability of response, and safety over longer treatment periods. Investigators are also exploring biomarker strategies to identify patients most likely to respond, which could further personalise therapy in Crohn’s disease.
“Collectively, these observations provide important evidence that blockade of TL1A with tulisokibart is a novel mechanism of action in Crohn’s disease,” the researchers concluded.
“The results of this proof-of-concept study are consistent with the notion that tulisokibart might be an effective therapy and support further investigation for the treatment of patients with Crohn’s disease.
“Randomised controlled trials with longer duration and with contemporaneous controls are needed to confirm these results.”
