Bruce Cree, MD, PhD, MAS, discusses the pathophysiology of multiple sclerosis (MS) and how sphinogine-1-phospate (S1P) receptor modulators address the underlying causes. Dr Cree also discusses the differences between the four FDA approved drugs for MS: fingolimod, siponimod, ozanimod, and ponesimod.
Bruce Cree, MD, PhD, MAS: S1P [Multiple sclerosis, sphingosine-1-phosphate] receptor modulators address the fundamental biology of multiple sclerosis because of their critical roles in lymphocyte metabolism and in all of the dendrite, glial, and other central nervous system functions when it sees S1P receptors throughout the body. There are 5 different S1P receptors, and at least 2 or 3 of these have very important implications for multiple sclerosis.
There are 4 S1P receptor modulators that have received US FDA approval, and they are fingolimod, siponimod, ozanimod, and ponesimod. Now, each of these S1P receptor modulators has different specificity for the 5 different S1P receptors. There’s S1P1, S1P2, S1P3, S1P4, and S1P5. Fingolimod is the least selective; it does not have S1P2 activity, but it does have activity against S1P1 as well as S1P3, S1P4, and S1P5. Siponimod was designed to not have activity against S1P3 and S1P4, so it just interacts with the S1P1 and S1P5 receptors, as does ozanimod. That selectivity is important, as I’ll mention in a moment. The fourth S1P receptor modulator, ponesimod, has activity against only the S1P1 receptor. It is the most selective of the 4 approved S1P receptor modulators. Now, the extent of the activity against the different subtypes of these receptors, to some extent, determines some of the adverse events that are of interest. We do want the S1P1 receptors to be engaged because these are the receptors on lymphocytes and we believe that this is an important target for these S1P receptor modulators. We also think that S1P5 receptors within the central nervous system may be an important target as well that may potentially promote myelin repair. That may be a desirable target as well. However, S1P3 mediates a cardiac rhythm. Cardiac arrhythmias and complications associated with combined therapies of other drugs that may prolong the QT interval are potential problems for S1P receptor modulators that engage with S1P3 receptor. We don’t want to have S1P3 receptor activity, but we do want S1P1 and S1P5, and this might account for some of the different adverse events we see across these different S1P receptor modulators.
Transcript edited for clarity.