*4.5. Ponesimod*

The proportion of patients experiencing at least one treatment emergen<sup>t</sup> AE (TEAE) in OPTIMUM was similar for both PNM and TFM, although discontinuation due to TEAE was higher in the PMN than the TFM group, 8.7% vs. 6.0% respectively. Premature discontinuations due to elevated liver enzymes and respiratory events were relatively higher in the PNM than TFM groups. The most common AEs of special interest were elevated liver function tests in the PNM group, (22.7% vs. 12.2%), hypertension (10.1% vs. 9.0%), and pulmonary events (8.0% vs. 2.7%). Most ALT increases ≥3X ULN were single transient asymptomatic events that spontaneously resolved on treatment or resulted

in protocol mandated discontinuation. Eight seizures were reported in patients treated with PMN compared to one patient on TFM.

Skin malignancies occurred in five patients treated with PMN and in one patient in the TFM group. Four cases of bradycardia (0.7%) occurred in the PMN 20 mg group and an additional three patients experienced first degree atrioventricular block. None of the events were serious or led to treatment discontinuation.

### **5. Potential Therapeutic Opportunities**

As is evident from the data presented, the S1PR modulators are an important addition to the list of DMTs for the treatment of MS. In addition to their oral route of administration, an important addition to patient quality of life, with a higher likelihood of compliance and persistence, they offer significant improvement in clinical efficacy at acceptable levels of risk in studies in which they have been compared to "platform" injectable or oral therapies. Important questions and research opportunities remain. Will agents with more potent S1PR-5 modulation improve remyelination, as a result of improved maturation of OPCs and enhanced myelin formation by OLGs? Will their use reduce inflammatory impact of MS by the enhancement of BBB integrity? Will selective S1PR-2 inhibition stimulate remyelination by blocking the NOGO/LOGO membrane complex, and will simultaneous S1PR-1 and S1PR-2 provide greater synergistic regulation of astrocytes than either agen<sup>t</sup> alone? Since S1PR-3 is up-regulated on astrocytes during CNS inflammation [112] can CNS selective S1PR-3 modulators be developed which do not also increase cardiovascular side effects? Lastly, as more is learned about the intracellular pathways activated or inhibited by S1P and its receptors, the development of pharmacological agents which can manipulate these pathways, and the development of agents that can interact with intracellular S1PRs, offer highly specific, potentially fruitful therapeutic opportunities for MS and numerous other diseases, including rheumatoid arthritis [113–115], systemic lupus [116,117], polymyotisis [118], ulcerative colitis [119], psoriasis [120], colon cancer [121–123], breast cancer [124–126], lung cancer [127,128] and atherosclerosis [129,130].

**Author Contributions:** Conceptualization, S.C., E.L., K.S., and J.B.; writing—original draft preparation, S.C., E.L., K.S., J.B., and C.C.; writing—review and editing, S.C. and C.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** The authors received no funding for writing this review article.

**Acknowledgments:** The authors acknowledge and thank Jessica Garten for producing Figures 1–4.

**Conflicts of Interest:** S.C. has served on advisory boards or steering committees for AbbVie, Biogen, Novartis, Sanofi Genzyme, and Pear Therapeutics; has received research support from AbbVie, Adamas, Biogen, Novartis, Sanofi Genzyme, MedDay, and Roche Genentech; has received speaker honoraria from Biogen, Novartis, Sanofi Genzyme, and Roche Genentech. EL has served on the advisory board for Genentech and Celgene/Bristol Myers Squibb, and received speaking honoraria from Biogen, Genentech, EMD Serono, Genzyme, and Novartis, and research support from Biogen, Novartis, and Celgene/Bristol Myers Squibb. K.S. has received research support from AbbVie, Biogen, Genentech, EMD Serono, MedDay, and IMS Health and consulting fees from Acorda, Biogen, EMD Serono, Genzyme, Genentech, Novartis, and Teva. J.B. has received speaker honoraria from Teva and served on an advisory board for Biogen. C.C. declares no conflict of interest.
