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Significantly more patients with moderately to severely active ulcerative colitis achieved clinical remission with the investigational monoclonal antibody tulisokibart compared with placebo, a randomized phase II trial showed.

Among 135 adults, 26% achieved clinical remission at 12 weeks with tulisokibart compared with 1% of those receiving placebo (P<0.001), reported Bruce E. Sands, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues in the .

In a group of patients with a positive genetic-based diagnostic test for likelihood of response to the drug, 32% achieved clinical remission compared with 11% of those who received placebo (P=0.02).

Tulisokibart is a tumor necrosis factor (TNF)-like cytokine 1A (TL1A) monoclonal antibody with a different mechanism of action than any of the currently approved drugs for ulcerative colitis.

"TL1A is interesting because in genome-wide association studies, TL1A comes up as being implicated in the pathogenesis of inflammatory bowel disease [IBD]," Sands told 乌鸦传媒. "What's unique about this is it affects not only the immune response that's particular to IBD and a number of other autoimmune and inflammatory conditions, [but] the mechanism of action, at least in animal models and in preclinical evaluation, seems to affect fibrosis as well, and fibrosis is an important process in both Crohn's disease and ulcerative colitis that complicates the disease."

"This is really the first time a double-blinded, placebo-controlled trial has shown that targeting TL1A, this new cytokine, can work in immune-mediated diseases," he added. "It may work for a number of other immune-mediated diseases potentially."

Abdallah Beano, MD, a gastroenterologist at Northwell Health Lenox Hill Hospital in New York City, said the results of this trial are encouraging.

"This drug targets a new molecule that has not been targeted by prior advanced therapies for ulcerative colitis, and the trial focused on patients who already have a severe disease that failed the established medications that we have, and showed positive results," Beano told 乌鸦传媒, adding that he hopes that additional data reveal similarly high performance that could lead to another option for complex and severe cases of ulcerative colitis.

New therapies in ulcerative colitis are particularly needed because of the number of patients who fail current therapies, Beano noted.

"While there are multiple advanced therapy drugs for ulcerative colitis, some patients never show improvement with these medications, or show initial improvement that eventually wanes, and they experience symptom recurrence," he said. "This, of course, burdens patients with symptoms and affects quality of life, but can also expose them to dangerous complications associated with ulcerative colitis."

"Many of those patients who fail therapy become dependent on taking corticosteroids for the long term, and corticosteroids have many side effects," he pointed out. "Some patients might even require surgical removal of their colon to manage their disease."

A of tulisokibart in moderately to severely active ulcerative colitis is currently recruiting.

The double-blind, placebo-controlled was a phase II study conducted in 14 countries and included patients who had moderately to severely active disease extending at least 15 cm from the anal verge. The participants were predominantly white and non-Hispanic; 35-53% were women, mean age was 37-42, and duration of disease was 6-8 years across treatment groups.

Disease activity was determined by a modified Mayo score of 4 to 9, which included a rectal-bleeding subscore (0-3), a stool-frequency subscore (0-3), and an endoscopic subscore (0-3). The endoscopic subscore had to be at least 2, and the rectal-bleeding subscore had to be at least 1.

Patients could enroll if they had glucocorticoid dependence or had failed treatment with glucocorticoids, immunosuppressants, TNF antagonists, vedolizumab (Entyvio), ustekinumab (Stelara), Janus kinase inhibitors, or ozanimod (Zeposia). Patients were excluded, however, if they had failed more than three drug classes or four advanced therapies approved for ulcerative colitis. Patients could continue to take aminosalicylates, immunosuppressants, or oral glucocorticoids during the trial if they had stable doses for several weeks before randomization and throughout the 12 weeks.

The study included two cohorts, the smaller of which included only patients with a positive test for likelihood of response to tulisokibart. The participants assigned to tulisokibart received an intravenous dose of 1,000 mg on day 1, followed by 500 mg at weeks 2, 6, and 10, with placebo delivered intravenously at the same time points.

Clinical remission at 12 weeks, the primary endpoint, was defined as a modified Mayo endoscopic subscore of 0 or 1, a rectal-bleeding subscore of 0, and a stool-frequency subscore of 0 or 1 that was not higher than the baseline value. Across the first cohort of 135 patients and the second cohort of 43 patients, a total of 75 patients had genetic likelihood for drug response.

"This is maybe one of the first phase II trials to incorporate at least an attempt for a predictive biomarker, a precision medicine approach in an immune condition, but especially in inflammatory bowel disease," Sands said. "What we want to see is some enrichment for the likelihood of response that could steer a certain patient toward using this medication as opposed to a different medication."

In cohort 1, prespecified secondary endpoints were significantly improved with tulisokibart versus placebo, including endoscopic improvement (37% vs 6%, respectively, P<0.001) and clinical response (66% vs 22%, P<0.001). There were also significant improvements in symptomatic remission, histologic improvement, histologic-endoscopic mucosal improvement, mucosal healing, and Inflammatory Bowel Disease Questionnaire response.

Adverse events occurred at similar rates with tulisokibart (46%) and placebo (43%), with no acute infusion reactions, one peri-infusion reaction in the placebo group, and identical rates of infection (18%) in both groups.

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