New Biologic Tulisokibart Beats Placebo in UC Trial

The experimental monoclonal antibody tulisokibart safely induced clinical remission in a phase 2 randomized trial of moderately to severely active ulcerative colitis (UC).

In one cohort of 135 patients, the primary endpoint of clinical remission occurred in 26% of those given the novel antibody to tumor necrosis factor–like cytokine 1A (TL1A) vs 1% given placebo (95% CI, 14-37, P < .001). In a smaller cohort of 43 patients genetically pretested for likely response to the new biologic, remission after treatment was only slightly higher at 32% vs 11% (95% CI, 2-38, P = .02).

The incidence of adverse events was similar in both arms, and most events were mild.

The 12-week induction trial, conducted in 14 countries by the ARTEMIS-UC Study Group and led by Bruce E. Sands, MD, MS, a professor of medicine at Icahn School of Medicine at Mount Sinai and system chief in the Division of Gastroenterology at Mount Sinai Health System in New York City, was published in The New England Journal of Medicine. 

“Our results suggest that important clinical benefit may be achieved through TL1A blockade in patients with UC,” Sands said in an interview, adding that this is the first rigorous study of a drug class with an entirely new mechanism of action that may be beneficial in other immune-mediated and fibrotic diseases. 

“And it is also the first prospective randomized controlled trial in IBD to incorporate a precision-medicine approach using a predictive biomarker for response in a drug development program,” he added.

Sands stressed the urgent need for new therapies since, despite the approval of multiple new classes of agents, both small molecules and biologics, “there is still a plateau of efficacy in that less than 50% of patients achieve remission at a year.”

He added that UC may progress over time owing to fibrosis of the bowel, a condition not directly or safely addressed by any existing therapies. “Identifying novel targets such as TL1A may allow us to address a different subpopulation of patients who may not respond to the targets addressed by existing therapies,” he said.

In agreement is Jason K. Hou, MD, MS, an associate professor of medicine at Baylor College of Medicine and section chief of gastroenterology at Michael E. DeBakey VA Medical Center in Houston, Texas. “Although it’s a very exciting time with more options in the last few years for treating UC, even inhibitors with new agents such as JAK inhibitors and interleukin 23 antagonists, many patients have no or only a partial response,” he said in an interview. “Targeting molecules, which has been studied for decades, may offer more than a shot in the dark.” 

Why Target TL1A?

Genome-wide studies have shown elevated TL1A, a member of the TNF superfamily, in patients with inflammatory bowel disease (IBD).

“The interaction of TL1A and its ligand, death domain receptor 3, contributes to the immune-mediated inflammation and fibrosis seen in IBD through the downstream production of proinflammatory cytokines by multiple different immune cells, and the elaboration of collagen by fibroblasts,” Sands explained.

With the intention of targeting TL1A, his group randomly assigned patients with moderate to severe active UC who were glucocorticoid-dependent or had not responded to conventional or advanced therapies, with disease extending a minimum of 15 cm from the anal verge. Across arms, the age of the mainly White, non-Hispanic participants ranged from about 37 to about 42, 35%-53% were female, and disease duration was approximately 6-8 years. 

The arms received either placebo or intravenous tulisokibart at 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10. Cohort 1 included patients regardless of biomarker status for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.

Hou was surprised that response to tulisokibart vs placebo was not greater in test-identified probable responders. “The biomarker didn’t make a huge difference, just a numerical one,” he said. “It may be that more genes are involved than the test could identify, and response is more complicated. Or perhaps the placebo response was particularly high in this small group. We need a deeper dive into why.” 

Earlier Application?

“This was a phase 2 study, so it’s too soon to say if tulisokibart could be used as early therapy or in severe disease,” Sands said. “However, the excellent safety profile and efficacy suggest that these populations should be explored in later studies. 

Further work is needed to validate the test to predict higher likelihood of response, he added, and recruiting for a phase 3 study is now underway.

The study was supported by Prometheus Biosciences, a subsidiary of Merck. 

Sands disclosed multiple ties to private companies, including research support, consulting, data safety monitoring, travel, a gift, and a stock option. Several co-authors reported, variously, research support from and/or consulting for multiple private companies. Others reported employment, variously, with Prometheus and/or Merck, Spyre Therapeutics, and Mirador Therapeutics, or patent holding for IBD drugs. Hou had no relevant competing interests to disclose but will participate in the phase 3 trial.