Modulation of sphingosine-1-phosphate in ulcerative colitis

ABSTRACT

Introduction: Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid signaling molecule implicated in various physiological and pathological processes, such as regulation of the immune, cardiovascular, pulmonary, and nervous systems and theoretical cancer-related risks, through extracellular activation of S1P1-5 receptors.

Areas covered: S1P receptor agonism is a novel strategy for the treatment of UC targeting lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. We conducted an extensive literature review on PUBMED on currently available data on molecular aspects of S1P modulation, the mechanisms of action of S1PR agonists (fingolimod, ozanimod, etrasimod, and KRP-203), and their potential efficacy and safety for the treatment of patients with ulcerative colitis.

Expert opinion: Selective S1P modulators have emerged to enlarge the efficacy and safety profile of this class of agents. Phase 3 programs should add the potential body of evidence to prove their benefit for the management of UC patients.

KEYWORDS:

• Small-molecule drugs
• sphingosine-1-phosphate
• sphingosine-1-phosphate agonists
• treatment
• ulcerative colitis

Article highlights

• A great proportion of patients with ulcerative colitis do not respond or lose response over time to conventional therapy and/or to biological agents.

• Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid signaling molecule implicated in various physiological and pathological processes.

• Sphingosine-1-phosphate receptor (S1PR) agonism is a novel strategy for the treatment of UC targeting lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes.

• Fingolimod, a nonselective S1P modulator, has shown benefit for the treatment of multiple sclerosis, however, accompanied by an increased risk for serious adverse events, thus providing a clear rationale for developing selective S1PR modulators.

• Selective S1PR agonists (ozanimod, etrasimod, and KRP-203), are under investigation and should access their potential efficacy and safety for the treatment of patients with ulcerative colitis.

Declaration of interest

S Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, MSD, UCB Pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Alphawasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor and Johnson & Johnson, Nikkiso Europe GMBH, Theravance. LP Biroulet has served as a speaker, consultant, and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boehringer Ingelheim, Lilly, HAC Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, Theravance. M Argollo has served as a speaker, consultant, and advisory board member for Abbvie, Janssen, Takeda, Pfizer. D Gilardi has served as a speaker, consultant, and advisory board member for Nikkiso GMBH, Sofar Spa, Biofer Spa, J&J, Pfizer, Takeda, Roche. F Furfaro has served as speaker and consultant for Abbvie, Amgen, Pfizer, and Janssen. M Allocca reports personal fees from Nikkiso Europe, Pfizer, Janssen, Abbvie, and Mundipharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has no funding support.