Reaching the therapeutic ceiling in IBD: Can Advanced Combination Treatment (ACT) offer a solution?

Abstract

The term Advanced Combination Treatment involves the combination of at least two biologics or the use of a biologic with a small molecule drug, each with different mechanisms of action. This narrative review evaluates the current evidence supporting ACT in inflammatory bowel disease (IBD), focusing on preclinical studies, real-world evidence, and randomised controlled trials. A systematic review of randomized controlled trials has concluded that ACT significantly improves clinical outcomes, without significant safety concerns in patient with IBD. However, variability in trial designs and the lack of standardized outcome measures have led to initiatives aimed at mitigating these issues through a clear expert consensus. While the evidence for ACT in IBD is compelling, substantial challenges remain in standardizing treatment protocols and ensuring long-term safety. In the meantime, the use of ACT in clinical practice remains off-label and requires careful consideration of patient-specific factors. Future clinical trials should consider robust biomarkers for patient selection and leverage mechanistic insights to select combination components. • Combination Approaches: Advanced Combination Treatment (ACT) has emerged as the preferred terminology, emphasizing a strategic focus on leveraging multiple therapeutic mechanisms for more effective disease control. • Viable Treatment Option: Current evidence supports ACT as a promising alternative for IBD patients, offering targeted treatment that contrasts with traditional monotherapy strategies. • Ideal Candidates: ACT should be prioritized for patients with refractory disease, high-risk phenotypes, or concomitant EIMs or IMIDs, where conventional therapies have failed or are unlikely to succeed. • Optimal Timing and Setting: Begin combination therapy when disease risks outweigh treatment risks, and ideally in specialized centres with multidisciplinary teams for comprehensive care and access to clinical trials. • Monitoring and Adjustment: Regularly reassess treatment every six months to ensure efficacy and safety. Adjust or discontinue agents as necessary, and prioritize therapies with well-established safety profiles, such as vedolizumab or ustekinumab, when possible. Research Agenda • Mechanistic Approaches: Further investigation into the biological mechanisms underlying ACT will enhance the precision of therapy selection and optimize treatment outcomes. • Bispecific Antibodies: Explore bispecific antibodies, like SOR102, which can target multiple inflammatory pathways simultaneously, to improve disease control. • Extended half-life mAbs against alpha4beta7 (SPY001), TL1A (SPY002), and IL-23 (SPY003) are under development as combination therapies for IBD. • Consensus Initiatives: Develop standardized definitions, guidelines, and consensus frameworks for ACT to enable broader clinical adoption and improve consistency in treatment approaches. • Cost-effectiveness: As biosimilars become more widely available, the cost-effectiveness of combination therapies is expected to improve, making ACT more accessible and affordable for a wider patient population. • Future Research Needs: Research should focus on determining whether ACT is beneficial not only in refractory cases but also in early-stage disease, with the goal of improving long-term disease outcomes. Key trials such as VICTRIVA, DUET-CD, DUET-UC, and Target CD (NCT06548542) are exploring promising combination regimens to refine treatment strategies.

Topics & Concepts