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Review
. 2016 Jan;7(1):18-33.
doi: 10.1177/2040622315617354.

Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

Daniele D'Ambrosio  1 , Mark S Freedman  2 , Joerg Prinz  3
Affiliations
Review

Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

Daniele D'Ambrosio et al. Ther Adv Chronic Dis. 2016 Jan.

Abstract

The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod's side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease.

Keywords: autoimmune disease; lymphocyte migration; multiple sclerosis; psoriasis; transplantation.

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Conflict of interest statement

Declaration of conflicting interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.D’A. is a full-time employee of, and has shares, in Actelion Pharmaceuticals Ltd. M.F. received consultancy fees from Actelion Pharmaceuticals Ltd and is an investigator in an ongoing clinical trial sponsored by Actelion Pharmaceuticals Ltd. J.P. received consultancy fees from Actelion Pharmaceuticals Ltd and has served as member of an independent Data Safety Monitoring Board in a completed clinical trial sponsored by Actelion Pharmaceuticals Ltd.

Figures

Figure 1.
Figure 1.
Chemical structure of ponesimod, C23H25N2O4CIS (molecular weight 460.98).
See this image and copyright information in PMC

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