Identification of Drug Repurposing Opportunities of Immunomodulatory Drugs for Inflammatory Bowel Disease Through Inverse Pharmacovigilance Signal Detection in the FAERS Database

Background/Objectives: Drug repurposing represents a promising strategy to expand therapeutic options for inflammatory bowel disease (IBD), a chronic condition with persistent unmet clinical needs. This study aimed to identify existing drugs with potential relevance for IBD by exploring inverse associations in the FDA Adverse Event Reporting System (FAERS) as a hypothesis-generating, real-world data approach. Methods: In this retrospective observational pharmacovigilance study, drug–IBD associations were extracted from the FAERS database using OpenVigil 2.1. Inverse associations were identified based on reporting odds ratios (ROR) < 1 with adjusted p-values < 0.05. Identified drug–event pairs were further evaluated for pharmacokinetic feasibility, clinical applicability, and biological plausibility in the context of IBD, with the exclusion of drugs with implausible indications, contraindications, or mechanisms inconsistent with IBD pathophysiology. Given the immune-mediated nature of IBD and the breadth of the identified candidates, detailed evaluation focused on immunomodulatory agents. Results: Among the 3585 initial drug–IBD combinations, 73 candidates met the predefined criteria for statistical significance and feasibility. From these, nine drugs were prioritized based on inverse signal strength and mechanistic relevance to immune modulation pathways implicated in IBD. The strongest inverse association with IBD was observed for lenalidomide (ROR 0.056, 95% CI 0.043–0.073), followed by dupilumab (ROR 0.213, 95% CI 0.185–0.245), cyclophosphamide (ROR 0.215, 95% CI 0.175–0.265), fingolimod (ROR 0.216, 95% CI 0.205–0.334), dimethyl fumarate (ROR 0.332, 95% CI 0.275–0.400), apremilast (ROR 0.357, 95% CI 0.296–0.431), imatinib (ROR 0.423, 95% CI 0.339–0.527), glatiramer acetate (ROR 0.446, 95% CI 0.352–0.565), and interferon beta-1a (ROR 0.594, 95% CI 0.533–0.662). These agents possess immunomodulatory properties relevant to inflammatory pathways implicated in IBD; however, clinical evidence supporting the therapeutic efficacy of some candidates remains variable or incomplete. Conclusions: By integrating inverse signal detection with clinical and biological assessment, this study demonstrates how pharmacovigilance data can be extended from traditional safety surveillance toward systematic drug repurposing applications. The findings generate testable hypotheses and highlight candidate therapies that warrant further experimental and clinical investigation in IBD.