E0345 - Efficacy of Deucravacitinib, an Oral, Selective, TYK2 Inhibitor, in Patients With Moderately to Severely Active Ulcerative Colitis and Prior Exposure to Biologic Therapy: Subanalysis From the Phase 2 LATTICE-UC Study

Introduction: Deucravacitinib (DEUC) is an oral, selective, allosteric inhibitor of tyrosine kinase 2 (TYK2), which mediates signaling of key cytokines in UC pathogenesis. In a phase 2 trial of DEUC in moderate to severe active UC, the primary endpoint was not met; however, a treatment effect was observed in patients with prior exposure to ≥1 biologic agent.

Methods: LATTICE-UC (NCT03934216), a double-blind phase 2 trial, randomized patients with moderate to severe active UC (modified Mayo score [MMS] 5-9 with endoscopic score [MES] ≥2, rectal bleeding score [RBS] ≥1, stool frequency score [SFS] ≥2) 2:1 to DEUC 6 mg or placebo (PBO) twice daily (BID). This post-hoc analysis in biologic-exposed patients assessed clinical remission (MMS ≤2, with SFS ≤1, RBS=0, MES ≤1); clinical response (decrease from baseline [BL] in MMS ≥2 points and ≥30% with decrease in RBS ≥1 point or absolute RBS ≤1); endoscopic improvement (MES ≤1); and change from BL (CFB) in symptomatic Mayo score (RBS + SFS). Colonic tissue transcriptomes were assessed via bulk RNA sequencing in a subset of biologic-exposed patients (DEUC n=17; PBO n=9). Differential expression with limma-voom and pathway enrichment analysis via Gene Set Enrichment Analysis were performed.

Results: Of 131 patients randomized, 48 (36.6%) were biologic-exposed (DEUC, 32/88 [36.4%]; PBO, 16/43 [37.2%]). At week 12, higher response rates were seen in patients receiving DEUC vs PBO in clinical remission (16.1% vs 0.0%), clinical response (29.0% vs 12.5%), and endoscopic improvement (25.8% vs 12.5%). Greater mean CFB in symptomatic Mayo score was observed at week 12 with DEUC (-2.1) vs PBO (-0.1) (Table). Type I interferon (IFN)‒regulated genes (IRG) were significantly reduced in colonic tissues at week 12 compared to BL in DEUC (FDR < 0.1) but not in PBO. Pathway enrichment analysis confirmed that the IFN pathway was down-regulated with DEUC treatment. In patients receiving DEUC who achieved clinical response at week 12, IRG expression was reduced compared with nonresponders; similar trends were seen in clinical remitters and in endoscopic improvers.

Discussion: Biologic-exposed patients treated with DEUC had greater improvements in clinical outcomes compared to PBO and had greater decreases in colonic IRG. The biomarker decreases were associated with clinical response or remission, suggesting inhibition of TYK2 pathways may be beneficial for UC. These results provide evidence the target was engaged and suggest a higher dose may have greater efficacy.