S212 A Phase 2 Study Design to Investigate the Efficacy and Safety of Dupilumab Therapy Compared With Placebo in Adults With Moderately to Severely Active Ulcerative Colitis With an Eosinophilic Phenotype

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease, heterogeneous in nature with many different drivers of pathogenesis, characterized by inflammation of the colon mucosa, relapsing–remitting disease course, and variable response to therapy. Despite the variety of molecular targeted agents available, the proportion of patients with UC refractory to these during the induction phase persists at 30–55%. Recent studies suggest that higher colonic eosinophil levels may be associated with increased disease activity, poorer clinical outcomes, and response to therapy. Dupilumab (DPL), a fully human monoclonal antibody blocks the shared receptor component for interleukin IL-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases, including atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and prurigo nodularis. The Phase 2 LIBERTY-UC SUCCEED (NCT05731128) study is designed to investigate the efficacy and safety of DPL vs placebo (PBO) in adults with moderately to severely active UC with a Type 2 inflammatory phenotype as reflected by eosinophilia. Methods: Patients will be randomized 1:1 to receive DPL or PBO. Key inclusion criteria include age ≥18 years, moderately to severely active UC (modified Mayo score 5–9), biomarker enrichment, and inadequate/non-response, loss of response, or intolerance to standard biologic therapy and/or oral corticosteroids, ASA compounds, immunomodulators, or small molecules. Key exclusion criteria include severe extensive colitis (current hospitalization, likely to require surgery for UC within 12 weeks of screening), prior medical history of eosinophilic colitis, or presence of intestinal failure (Table 1). Results: The primary endpoint is proportion of patients in clinical remission at Week 24, defined as a modified Mayo score of ≤2 with a stool frequency score ≤1, a rectal bleeding score = 0, and a Mayo endoscopic subscore ≤1 with absence of friability. Higher scores indicate greater disease severity. Secondary endpoints include the proportion of patients achieving clinical response by modified Mayo score at Week 8, 24, and 52, and incidence of treatment-emergent or serious adverse events. Conclusion: The Phase 2 LIBERTY-UC SUCCEED study will determine the efficacy and safety of DPL therapy in adults with moderately to severely active UC with a Type 2 phenotype. This will aid in addressing the need for precision medicine-directed approaches to treat UC. Table 1. - Primary and Secondary Endpoints of the Phase 2 LIBERTY-UC SUCCEED Study Primary endpoint Proportion of patients in clinical remission• Clinical remission defined as a modified Mayo score of ≤2 with a stool frequency score ≤1, a rectal bleeding score = 0, and a Mayo endoscope subscore ≤1 with absence of friability Week 24 Secondary efficacy endpoints Proportion of patients achieving clinical response by modified Mayo scoreProportion of patients achieving histologic–endoscopic healingProportion of patients with a Mayo endoscopic subscore of 0 or 1 without friabilityProportion of patients with a Mayo endoscopic subscore of 0Change from baseline in Abdominal Pain NRS score Weeks 8, 24, and 52 Proportion of patients in clinical remission by modified Mayo score Weeks 8 and 52 Proportion of patients in clinical remission who are off concomitant OCS for ≥4 weeks priorProportion of patients in clinical remission who are off concomitant OCS for ≥4 weeks prior who were receiving OCS at baseline Week 52 Normalized Enrichment Scores for the relative change in the EoE diagnostic panel transcriptome signatureNormalized Enrichment Scores for the relative change in the type 2 inflammation transcriptome signature Weeks 16 and 52 Proportion of patients in symptomatic remission over time•Symptomatic remission defined as Mayo stool frequency score = 0, or Mayo stool frequency score = 1 with a ≥1-point decrease from baseline, and Mayo rectal bleeding score = 0 During treatment period Secondary safety endpoints Incidence of treatment-emergent adverse eventsIncidence of treatment-emergent serious adverse eventsConcentration of dupilumab in serum over timeIncidence of treatment-emergent ADAs against dupilumab During treatment period and follow-up period Change from baseline in the NES in type 2 inflammation transcriptome signature Weeks 24 and 52

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