The discovery and development of the sphingosine 1-phosphate receptor modulator ozanimod in ulcerative colitis

Sphingosine-1 phosphate (S1P) modulators have received recent FDA-approval for the treatment of moderate-to-severe ulcerative colitis, including agents ozanimod, approved in 2021, and etrasimod, approved in 2023. These oral drugs are uniquely efficacious in UC as they have multimodal mechanisms contributing to their beneficial immunomodulatory effects, while preserving host response to pathogens and attenuating toxicities observed with less specific agents. In this review, the discovery and development of the first approved S1P modulator, ozanimod, is described in detail: from design of initial screens to discover unique binding agents, to extensive chemical modifications to improve pharmacokinetic and safety profiles, and through preclinical and clinical studies validating mechanism and establishing safety and efficacy. Ultimately, this review will not only inform the reader of the unique path to development of a clinical S1P modulator for UC, but will also highlight advances made and gaps remaining to individualize therapeutic approaches for inflammatory bowel disease.