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Sajida Sabsabi,1 Elio Mikhael,2 Georges Jalkh,1 Gabrielle Macaron,1,3 Mary Rensel3 1Department of Neurology, Hotel Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon; 2Department of Internal Medicine, Hotel Dieu de France Hospital, Saint Joseph University, Beirut, Lebanon; 3Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USACorrespondence: Mary Rensel, Email renselm@ccf.orgIntroduction: A number of disease-modifying therapies have been approved for use in relapsing-remitting multiple sclerosis (MS) in the past two decades. However, only few treatment options are available for patients with secondary progressive multiple sclerosis (SPMS). Siponimod has recently been approved for use in patients with active forms of SPMS (who experience clinical relapses or new lesions on MRI superimposed on secondary progression independent of relapse activity).Objective: The aim of this article is to provide a comprehensive review on the mechanism of action, efficacy, safety, cost effectiveness and patient adherence with siponimod.Methods: We performed a PubMed search using the search terms: “siponimod”, “secondary progressive multiple sclerosis”, “sphingosine 1-phosphate modulators”. Titles and abstract were screened and selected for relevance to the key section of this article.Findings: Siponimod is an oral sphingosine-1-phosphate receptor (S1PR) modulator with selectivity to S1PR-1 and 5. Modulation of this receptor on lymphocytes causes its internalization and degradation, preventing their egress from lymphoid tissues to the blood. In the pivotal Phase 3 randomized controlled trial EXPAND, siponimod was superior to placebo in reducing the risk of disability progression confirmed at 3 and 6 months, as well as the development of new MRI lesions and the rate of brain volume loss. Secondary analysis also showed a benefit on measures of cognitive functioning. The risk of lymphopenia and first-dose bradycardia appears to be lower with siponimod compared to non-selective S1P1R modulators. Different CYP2C9 genotypes affect the metabolism of siponimod; hence, genetic testing is required to adapt the titration and final dose accordingly.Conclusion: Long-term extension and real-world studies will allow further evaluation of efficacy and safety in this population. Future research should focus on better defining SPMS, and identifying biomarkers of progression and outcome measures of treatment response in this category of patients.Keywords: secondary progressive multiple sclerosis, siponimod, efficacy, safety