Commentary
Video
Overviewing Mechanism of Action of S1P-Modulating Treatments
Author(s):
In this episode, Patricia Coyle, MD, FAAN, describes the development of S1P modulator receptors, their mechanism of action, potential side effects, and considerations for patient suitability, particularly in comparison to other treatment options like monoclonal antibodies.
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 episode, Coyle, a professor of neurology at Stony Brook Medicine, gave an overview of the S1P modulator class and the history behind this group of treatments. She touched upon the development of second-generation S1Ps that offer greater receptor specificity, fewer adverse events, and fewer washout times than first generation agents. In addition, she talked about some of the contraindications and necessary screenings before prescribing these medications, highlighting their suitability for patients who prefer an oral treatment over injectables.
Transcript edited for clarity.
Patricia Coyle, MD, FAAN: The S1P receptor modulators are an oral MS disease-modifying therapy really aimed at relapsing forms of MS. They form a family, meaning there are four members of these S1P receptor modulators. The first generation was fingolimod. That was actually the first approved oral disease-modifying therapy for relapsing forms of MS. It became available in 2010 in the United States. What it offered was a non-needle, non-injectable way to deliver treatment. So that's how it was very different from the interferon betas and glatiramer acetate that came before it.
In analyzing this oral disease-modifying therapy, it was felt that there were clearly areas for improvement. This led to the development of a total of three second-generation S1P receptor modulators, namely ozanimod, ponesimod, and siponimod. Siponimod is a prodrug—it needs to be phosphorylated to be activated. One of the pushes to develop second-generation fingolimods was that they not be prodrugs, but rather active agents.
In addition, when you look at the S1P receptors, there are five of them—one through five—and they are throughout the body. They're affecting not just the immune system in the brain but also the heart, the lungs, and the vasculature. So, you had some unnecessary or unwanted side effects. The second-generation S1P receptor modulators were really designed to have greater receptor specificity than the parent compound. Finally, there was hope that the second generation would have a shorter half-life and could be washed out faster. There’s a low lymphocyte count in the blood that is produced routinely with the S1P receptor modulators, and people wanted to be able to reverse that more quickly.
Now, the mechanism of action of the S1P receptor modulators, which could be widespread, is really felt to be based on their binding to the S1P receptor 1. S1P receptor 1 is on about 70% of the lymphocytes in the body. This receptor allows lymphocytes to exit the lymphoid tissue, circulate in the blood, and reach different body organs. With the parent compound, fingolimod, once it was activated and phosphorylated, it bound to S1P receptor 1—as well as 3, 4, and 5. But by binding to S1P receptor 1, the receptor was stripped off the surface of the lymphocyte, preventing it from leaving the lymphoid tissue. So, basically, the mechanism of action is that it traps the lymphocyte within the lymphoid tissue. It doesn’t kill the lymphocyte; this is not a lytic agent. It is an immunosuppressive agent, but it keeps those lymphocytes within the lymphoid tissue, which is why you see a lymphopenia in the blood. It’s kind of a false lymphopenia because these lymphocytes are not allowed to circulate in the blood.
Now, there are some uniform contraindications to using any of the S1P receptor modulators. If you’ve had a myocardial infarction or cardiac problems, such as uncontrolled angina, a stroke, or a transient ischemic attack in the last six months, or if you have significant heart disease, particularly with heart block, those are contraindications to using any of the S1P receptor modulators. You would not want to use them if you had signs of vascular disease in the brain or cardiac disease in the last six months.
There are also some routine screening tests you should do before using any of the S1P receptor modulators. You would want to check a CBC with differential to look at the baseline lymphocyte count and make sure it’s not particularly low. You would want to do a hepatic panel and check for IgG to varicella-zoster. The S1P receptor modulators are immunosuppressive agents, so they increase the risk of infections, and reactivation of HSV, for example, is one of the things that can happen. Other things that are routinely done, even if not demanded by the label but as a good practice, include getting an electrocardiogram to make sure there isn’t a significant heart block, and getting optical coherence tomography (OCT) because it’s very easy to screen for macular edema. This is a concern, perhaps not with all S1P receptors, but as a class, it is, particularly if you’re diabetic or have had uveitis or cataract surgery. Another thing that’s probably good practice, even if not all S1P receptor modulators may have a defined problem here, is to check for skin cancers and have an annual skin check to ensure nothing is missed.
As a general rule in this class, you don’t want to be taking it and get pregnant, and you don't want to use this small molecule that probably gets into breast milk if you are breastfeeding. So, in general, with the S1P receptor modulators, you would use a washout period before pregnancy, and you would not use it if someone was planning to breastfeed.
Now, speaking about who the ideal patient is for consideration of an S1P receptor modulator, it’s certainly a non-needle injectable option. So, if someone has needle fatigue or is petrified of needles, this is a very good choice. It’s an easy-to-take, once-a-day oral medication, but you have to consider that it doesn’t match the high efficacy of monoclonal antibodies. So, if someone has extremely active disease or severe MS, highly active MS, then you’re probably going to go with a monoclonal antibody rather than this oral agent. But the S1P receptor class is a nice class. It’s easy to take once a day, provided there are no contraindications. It is typically well tolerated. Generally, the blood pressure may go up a few points, so if someone has hypertension, that’s something to be aware of and to monitor to ensure it doesn’t rise too much. But that’s kind of an introduction to the various members of this four-person family.
