Another chance for TYK2 inhibition in UC

In a post-hoc analysis of the LATTICE-UC trial, deucravacitinib showed to be active in participants with ulcerative colitis (UC) that had prior exposure to at least 1 biologic. Moreover, therapy significantly reduced interferon-responsive gene transcripts; these changes were associated with clinical response, suggesting a role for TYK2 inhibition in the therapeutic armamentarium of UC.

TYK2 mediates signalling of IL-12, IL-23, and type-1 interferon (IFN), which are all key cytokines in the pathogenesis of UC. Deucravacitinib is an oral, selective, allosteric inhibitor of TYK2 that is already approved by the US FDA for the treatment of adults with moderate-to-severe plaque psoriasis.

In the double-blind, placebo-controlled, centrally-read, phase 2 LATTICE-UC trial (NCT03934216), the efficacy and safety of deucravacitinib was assessed in patients with moderately to severely active UC and inadequate response, loss of response, or intolerance to at least 1 conventional or biologic therapy [1]. In this trial, the primary endpoint of clinical remission at week 12 was not met. However, a treatment effect was observed in participants with prior exposure to at least 1 biologic. Now, in a post-hoc analysis, Prof. Stephan Schreiber (University Hospital Schleswig-Holstein, Germany) evaluated the effect of deucravacitinib in biologic-exposed participants with moderately to severely active UC [2].

In the induction phase of LATTICE-UC, from week 0 to week 12, participants were treated with deucravacitinib 6 mg twice daily or placebo. After week 12, a maintenance treatment was performed for up to 52 weeks. Of 131 randomised participants, 48 (36.6%) were biologic-exposed and participants in the deucravacitinib group were heavier and had more often a modified Mayo score >7.

At week 12, clinical remission (primary endpoint) was achieved by 16.1% in the deucravacitinib group compared with 0% in the placebo group. Superior efficacy of the TYK2 inhibitor was also seen in clinical response (29.0% with deucravacitinib vs 12.5% with placebo) and endoscopic improvement rates (25.8% vs 12.5%) in biologic-exposed participants. “Biomarkers also confirmed this clinical observation,” Prof. Schreiber said, since a greater reduction in faecal calprotectin was observed with deucravacitinib versus placebo (P<0.05 at week 12).

“The most interesting part is the transcriptome analysis,” Prof. Schreiber stated. Transcripts of IFN-responsive genes, such as IFI44L and CXCL10, were significantly reduced in colonic tissues at week 12 compared with baseline for deucravacitinib treatment, but not with placebo. The decreases in IFN-responsive genes were associated with clinical response or remission, suggesting that inhibition of TYK2 pathways may be beneficial in UC. “You see very clearly that patients that are successful, also show that imprint in their transcriptome-signatures,” Prof. Schreiber said. He therefore concluded that these results provide evidence of inhibition of the TYK2 pathway and suggests that a higher dose of deucravacitinib needs to be examined for clinical efficacy in UC, a step that is now done in a follow-up trial.

1. Danese S, et al. J Crohn´s Colitis. 2022;16:i091–i092.
2. Schreiber St, et al. Efficacy of deucravacitinib an oral, selective, tyrosine kinase 2 inhibitor, in patients with moderately to severely active Ulcerative Colitis and prior exposure to biologic therapy: subanalysis from the phase 2 LATTICE-UC study. OP198, UEG Week 2022, 8–11 October, Vienna, Austria.

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Posted on 1 December, 2022