Advanced Combination Therapy in Inflammatory Bowel Disease: What Does the Future Hold?

Abstract

In recent years, substantial progress has been achieved in the development of novel therapeutic options for inflammatory bowel disease (IBD). Despite these advances, a significant proportion of patients continue to experience either primary nonresponse or secondary loss of response to biologic agents or small-molecule therapies. In addition, many patients present with heterogeneous and often difficult-to-manage extraintestinal manifestations, highlighting the persistent unmet needs in IBD management. Consequently, multiple therapeutic strategies have been explored to overcome these challenges and to improve long-term disease control. Among emerging approaches, advanced combination therapy (ACT)-defined as the concomitant use of monoclonal antibodies and/or oral small-molecule agents with distinct mechanisms of action-has attracted increasing interest in recent years. ACT aims to enhance therapeutic efficacy, address complex disease phenotypes, and potentially prevent or delay treatment failure. In this review, we summarize the currently available evidence on how to optimally apply combination therapeutic strategies in IBD. Key aspects discussed include the rationale for selecting agents with complementary mechanisms of action, the hypothetical timing and duration of combination treatment, and the clinical criteria that may guide the selection of specific ACT algorithms. Evidence derived from real-world studies and completed randomized clinical trials, including the landmark VEGA trial, is critically reviewed. Furthermore, we present data from ongoing clinical trials-both industry- and investigator-initiated-as well as emerging research on bispecific therapeutic molecules in IBD, which combine two molecular targets within a single compound. Together, these data provide a comprehensive overview of the current and future role of ACT in IBD management.