Fingolimod is a sphingosine-1-phosphate modulator and binds to S1P1, S1P3, S1P4, S1P5.
S1P1 is expressed on lymphocytes and astrocytes…..S1P3 may be involved in some of the heart isssues, S1P4 people don’t talk about much and S1P5 is on oligodendrocytes and so is sold as a target for repair.
So out come the new eyemods…..ozanimoid, siponimod and ponesimod to name three….These bind S1P1 and S1P5.
They also do not hang around as long as fingolimod does and so may be easier to transition to something else if the treatement fails to control your MS.
So the question arises do the new imods block vaccine responses like fingolimod if they do not it is is S1P3 and 4. Now admittedly I did some prodding to see what is happening and I have heard from 2 of 3 companies. One said that an answer is coming….just have to wait to ECTRIMS virtual 2021.
However, a big question I have is what does S1P5 really do? Is it really involved in repair.
A bit of biology may allow to get an answer and this what is the difference between ozanimod and siponimod/ponesimod, because a querk of biology means that oxanimod does not work well on S1P5 in mice rats and dogs. So it inhibits mouse EAE but mouse demyelination it wasnt so great but what would fingolimod do…we dont know.
soem extentSelkirk JV, Dines KC, Yan YG, Ching N, Dalvie D, Biswas S, Bortolato A, Schkeryantz JM, Lopez C, Ruiz I, Hargreaves R. Deconstructing the Pharmacological Contribution of Sphingosine-1 Phosphate Receptors to Mouse Models of Multiple Sclerosis Using the Species Selectivity of Ozanimod, a Dual Modulator of Human Sphingosine-1 Phosphate Receptor Subtypes 1 and 5. J Pharmacol Exp Ther. 2021 Sep 17:JPET-AR-2021-000741
Ozanimod, a sphingosine-1 phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P1) and 5 (S1P5), is approved for the treatment of relapsing multiple sclerosis (MS) in multiple countries. Ozanimod profiling revealed a species difference in its potency for S1P5 in mouse, rat, and canine compared with that for human and monkey. Site-directed mutagenesis identified amino acid alanine at position 120 to be responsible for loss of activity for mouse, rat, and canine S1P5 and mutation back to threonine as in human/monkey S1P5 restored activity. Radioligand binding analysis performed with mouse S1P5 confirmed the potency loss is a consequence of a loss of affinity of ozanimod for mouse S1P5 and was restored with mutation of alanine 120 to threonine. Study of ozanimod in preclinical mouse models of MS can now determine the S1P receptor(s) responsible for observed efficacies with receptor engagement as measured using pharmacokinetic exposures of free drug. Hence, in the experimental autoimmune encephalomyelitis model, ozanimod exposures sufficient to engage S1P1, but not S1P5, resulted in reduced circulating lymphocytes, disease scores, and body weight loss; reduced inflammation, demyelination, and apoptotic cell counts in the spinal cord; and reduced circulating levels of the neuronal degeneration marker, neurofilament light. In the demyelinating cuprizone model, ozanimod prevented axonal degradation and myelin loss during toxin challenge but did not facilitate enhanced remyelination post-intoxication. Since free drug levels in this model only engaged S1P1, we concluded that S1P1 activation is neuroprotective but does not appear to affect remyelination. Significance Statement Ozanimod, a selective human S1P1/5 modulator, displays reduced potency for rodent and dog S1P5 compared with human, which results from mutation of threonine to alanine at position 120. Ozanimod can thus be used as a selective S1P1 agonist in mouse models of multiple sclerosis to define efficacies driven by S1P1 but not S1P5 Based on readouts for experimental autoimmune encephalomyelitis and cuprizone intoxication, S1P1 modulation is neuroprotective but S1P5 activity may be required for remyelination.