Over the years, the neurotherapeutic landscape in multiple sclerosis (MS) has evolved rapidly. New disease-modifying treatments have been developed with various novel mechanisms that demonstrate improved efficacy and safety. It is believed that a more tailored treatment approach would 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 to other therapies.
To date, 4 S1P receptor modulators have been approved by the FDA and the European Medicines Agency for the treatment of MS: fingolimod (Gilenya; Novartis), ozanimod (Zeposia; BMS), ponesimod (Ponvory; Janssen), and siponimod (Mayzent; Novartis). Fingolimod, a non-selective S1P receptor modulator that targets S1P1, S1P3, S1P4, and S1P5, was the first approved therapy in this class and dates back to 2010. This class of drugs blocks the exit of lymphocytes from the lymph nodes, resulting in 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, discuss the pros and cons of S1P-modulating treatments and their role in the clinical management of MS. The duo provide background on the differences between each treatment and their respective benefits, as well as how clinicians have optimized these treatments as they have gained experience.
In this section, Subei, medical director of the multiple sclerosis program at Neurology Consultants of Dallas, highlighted ponesimod, the most recently approved S1P receptor modulator. He explained its unique study design, which compared it to teriflunomide (Aubagio; Sanofi) and showed a significant reduction in relapse rates. He also noted that while ponesimod is effective, it came to market later than other similar drugs, which has affected its notoriety.
Transcript edited for clarity.
Adnan Subei, DO: Ponesimod is a little different because it focuses exclusively on the S1P1 receptor. The study design for ponesimod was also unique. In the Optimum study, ponesimod was compared to teriflunomide as an active comparator and met the primary endpoint, which showed a 30 percent reduction in annual relapse rate compared to teriflunomide. The study also had endpoints related to combined unique active lesions on MRI. They also included a unique outcome, the Fatigue Symptom Impact Questionnaire, and we were able to see efficacy there in terms of a reduction in fatigue in patients on ponesimod.
Now, I will say that we have excellent data on these selective S1P receptor modulators, and we now have three of them in addition to the originator drug, fingolimod. So at some point the question becomes how do these compare? How are they different? We don’t have any clinical trials comparing these directly, so we really can’t judge whether one is superior to the other. Other than that, it’s a matter of who got there first and who got there last. One of the unfortunate situations with ponesimod, in my opinion, is that it just came to market too late. Because of that, it’s not marketed as heavily these days because the focus has shifted from that perspective.
