Future Directions and Unanswered Questions Regarding S1P Modulator Receptors

EP: 1.Overviewing Mechanism of Action of S1P-Modulating Treatments

EP: 2.Setting the Stage of S1Ps With Fingolimod

EP: 3.Clinical Pearls on Siponimod

EP: 4.Effectiveness and Advantages of Ozanimod

EP: 5.Ponesimod and the Future Questions About S1P Modulator Use

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EP: 6.Future Directions and Unanswered Questions Regarding S1P Modulator Receptors

Over the years, the multiple sclerosis (MS) neurotherapeutic landscape has rapidly evolved, with new disease-modifying treatments of various novel mechanisms that have improved efficacy and safety. It has been thought that a more tailored approach to treatment will allow for better personalization of drug selection for patients. Sphingosine 1-phosphate (S1P) receptor modulators, one of the newer drug classes, have emerged as a disease-modifying option for MS that has a unique mechanism of action compared with other therapies.

To date, 4 S1P receptor modulators: fingolimod (Gilenya; Novartis), ozanimod (Zeposia; BMS), ponesimod (Ponvory; Janssen), and siponimod (Mayzent; Novartis), are approved by the FDA and the European Medicines Agency for the treatment of MS. Fingolimod, a nonselective S1P receptor modulator targeting S1P1, S1P3, S1P4, and S1P5, was the first approved therapy in this class, dating back to 2010. This class of medications function by blocking the lymphocytes to egress from lymph notes, leading to a reduction in the number of lymphocytes in the peripheral blood.

As part of a new series, neurologists Patricia Coyle, MD, FAAN, and Adnan Subei, DO, cover the ins and outs of S1P-modulating treatments and their role in the clinical management of MS. The duo give background on how each treatment differs and the advantages each possess, as well as how clinicians have optimized these treatments as experience with them grows.

In this segment, Coyle, a professor of neurology at Stony Brook Medicine, discussed the differences and potential benefits of second-generation S1P receptor modulators compared with the first-generation therapy, fingolimod, for MS. She provided context on the advantages of the newer agents, such as reduced risk of rebound and fewer adverse events like macular edema and high blood pressure. Furthermore, she also mentioned the possibility of using these therapies in other diseases and the need for further studies to fully understand their benefits and limitations.

Transcript edited for clarity.

Patricia Coyle, MD, FAAN: Fingolimod now has generics available. I don't think we'll see another S1P receptor modulator developed for relapsing MS—not without some new data to really support it. But keep in mind that these therapies could be applicable to other diseases, like ozanimod with ulcerative colitis, and there are ongoing studies in stroke and cancer where they might be beneficial. It would be very interesting to determine if there are differences between the second-generation S1P receptor modulators and the first generation, where you could say, "This is an absolute benefit." Rebound is a big one. If some second-generation S1P receptors don't have rebound, that makes them preferable to the parent compound right there.

In theory, the second generation should be preferred to the parent compound because they were developed to have benefits over and above it. You can see the practicality of being able to dose escalate and avoid keeping the patient under observation for six hours. That is a benefit. A rapid washout may also be a benefit. There's interest now in looking at step-down therapy. For example, as we increasingly use high-efficacy, but potentially risky, high-efficacy monoclonals, could you use them for a finite period and then switch to an agent that maybe doesn't have such high efficacy, but maybe that person has had their immune abnormalities reset and no longer requires a high-efficacy agent? People are starting to think about using the S1P receptor modulators for that.

For some of the side effects that have been given a class assignment, it may be that they actually are less likely to occur with some of the second-generation S1P receptor modulators. So if you have good documentation that an agent doesn't cause macular edema, that might be a reason to choose it. Or if this one doesn't cause skin cancer problems, that might be a reason to choose it. Or if it doesn't cause a high blood pressure issue. But I think we need further studies to define all the ins and outs of these second-generation disease-modifying therapies.