‘It is very clear’: Blocking TL1A an important factor in treatment of ulcerative colitis
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Key takeaways:
- A greater proportion of patients in the PRA023 group achieved clinical remission at 12 weeks vs. placebo (26.5% vs. 1.5%).
- PRA023 also outperformed placebo in symptomatic remission and mucosal healing.
PRA023, an investigational antibody directed against tumor necrosis factor-like cytokine 1A, induced clinical remission at 12 weeks in significantly more patients with ulcerative colitis vs. placebo, according to data presented at UEG Week.
“There was a strong rationale for implicating its TL1A involvement in both Crohn’s disease and ulcerative colitis,” Bruce E. Sands, MD, MS, chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai, told Healio. “It is involved in inflammatory responses for a number of different key cell types and, interestingly, is also associated with generation of fibrosis by stimulation of fibroblasts.”
Sands continued: “Blocking TL1A could have anti-inflammatory and anti-fibrotic properties, so there was a very strong rationale for investigating the efficacy of this agent and this approach in patients with moderate to severe ulcerative colitis.”
In a placebo-controlled, double-blind, phase 2 study, Sands and colleagues assessed the safety and efficacy of PRA023 induction treatment among 135 adults with moderate to severe UC. Eligible participants had a modified Mayo score of 4 to 9, an endoscopy subscore of at least 2 and a rectal bleeding subscore of at least 1, as well as history of insufficient or loss of response and/or intolerance to conventional or advanced therapies.
Patients were assigned placebo (n = 67) or IV PRA023 1,000 mg on day 1 and 500 mg at weeks 2, 6 and 10 (n = 68). The primary outcome of interest was clinical remission, defined by modified Mayo score at week 12.
Results showed all patients in the treatment group and 89.6% in the placebo group completed the 12-week induction period, with a significantly greater proportion of participants in the treatment group achieving clinical remission at week 12 (26.5% vs. 1.5%).
“The difference between the two is 25%, which was highly statistically significant and among the largest effect sizes that we have seen for almost any agent currently used to treat ulcerative colitis,” Sands said.
PRA023 also outperformed the placebo in secondary endpoints of symptomatic remission (19.1% vs. 6%), mucosal healing (30.8% vs. 3.5%) and IBD questionnaire response (82.4% vs. 49.3%), as well as endoscopic improvement (36.8% vs. 6%), clinical response (66.2% vs. 22.4%), histologic improvement (46.2% vs. 17.5%) and histologic-endoscopic mucosal improvement (30.8% vs. 3.5%).
Further, researchers reported statistically significant reductions in symptom scores (partial Mayo score) as early as week 2 among patients who received PRA023. Compared with placebo, C-reactive protein and fecal calprotectin levels also were significantly reduced throughout the treatment period.
Researchers observed no serious adverse events, and treatment-emergent adverse events were comparable between groups.
“It is very clear that TL1A blockade is an important way of treating ulcerative colitis,” Sands told Healio. “I would add that Pfizer did a phase 1B study with a different TL1A blocker in a similar population and also found evidence of activity, further substantiating the importance of this new therapeutic target.”
*Editor’s note: At the time of our interview, Sands noted Prometheus Biosciences, the owner of PRA023, recently was acquired by Merck. PRA023 has since been renamed MK7240.
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Sands BE, et al. A phase 2, randomized, double-blind, placebo-controlled trial of PRA023 as induction therapy in patients with moderately to severely active ulcerative colitis. Presented at: UEG Week; Oct. 14-17, 2023; Copenhagen, Denmark (hybrid meeting).
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