Strategies to Overcome the Drug Plateau in IBD

Overcoming the plateau in rates of response and/or remission with current therapies in inflammatory bowel disease (IBD) requires the identification of rational combinations of therapies with complementary mechanisms of action, according to an article published in Gastroenterology.

Current treatments for IBD are suboptimal, with approximately 30% of patients being primary nonresponders to initial treatment and around 50% of patients becoming secondary nonresponders. Although many strategies are attempted in clinical practice to maintain or enhance response or remission, the long-term rates of these remain unsatisfactory. This leads to disease progression and complications, including surgery, in many patients.

Therefore, researchers investigated how to overcome this response plateau and found that the most practical approach is by combining two medications with differing mechanisms of action resulting in additive, supra-additive, or synergistic effects, with infra-additive toxicity. This approach also requires that potential drugs have compatible pharmacokinetic profiles, thus avoiding “irrational” combinations with antagonistic effects that worsen IBD or have supra-additive adverse effects.

This rational combination approach requires underpinnings not only in mucosal immunology and bacteriology, but also in systems biology to achieve a relevant understanding of individual drug mechanisms, as well as their potential impact on intersecting biological pathways and networks across differing compounds. The researchers proposed that the next steps are to develop a mechanistic map of inflammation cascades with relevant crosstalk for these therapeutic alternatives.

The authors concluded, “Current therapeutic approaches in IBD have reached a plateau in the rates of response and/or remission.” They added, “A deeper understanding of the individual drug mechanism(s), as well as the potential impact on intersecting biological pathways and networks across different compounds through mucosal immunology, bacteriology and systems biology, may lead to the realization of potential combinations.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Stalgis C, Deepak P, Mehandru S, Colombel J-F. Rational combination therapy to overcome the plateau of drug efficacy in inflammatory bowel disease. Gastroenterol. Published online April 22, 2021. doi: 10.1053/j.gastro.2021.04.068