How does Siponimod work?

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Recently I have been trying to get my head around the different sphinosine-1-phosphate receptor modulators. This is because it is evident that fingolimod as the first-in-class drug, inhibits the COVID-19 vaccine response. But are the others- (siponimod, ozanimod, ponesimod) going to do the same?

We will find out soon with the release of data at ECTRIMS, but the influence of fingolimod is now pretty robust.

Sormani et al. SSRN SSRN-id3631244.pdf

How does fingolimod and the other sphinogsine-1-phospate modulators work?

They trap cells in the lymph glands is the simple answer. If they can’t get into the blood they can’t get into the brain and contrasts with natalizumab that traps cells in the blood to stop them getting to the brain

However it is too simplistic and it is evident that it depletes cells too but there are other actions that may help it control

Fingolimod or should I say the metabolite (break down product) of fingolimod binds to sphinogosine-1-phosphate one, three, four, and five.  It also has a long half-life meaning it takes a long time to wash out of the body. S1P1 receptor mediates most of the immunological influences of  the S1P modulators. This is because it acts as a receptor for sphingosine which attracts the cells along a gradient to exit the lymph glands. It was suggested that S1P3 may cause some of the adverse effects related to blood pressure and so ponesimod, ozanimod and siponimod  would not do that, but there is still a need for blood pressure monitoring on the first dose with at all S1P drugs suggesting to me that S1P1 is the issue. S1P5 is expressed by oligodedndrocytes and it it hoped that this may influence myelination.

However S1P1 is not only expressed on the lymphocytes to mediate the anti-relapse effect of the S1P modulators to trap them in the lymph gland it seems that S1P1 on astrocytes is important in controling exit of cells from the blood into the brain. The feet of astrocytes help to form the blood brain barrier which limits entry of cells and other things, including drugs into the brain. This is also expressed on the blood vessel cells too

http://www.brainseq.org

This new study suggests that Siponimod influences blood brain barrier activity through an action on astrocytes

Spampinato SF, Merlo S, Costantino G, Sano Y, Kanda T, Sortino MA. Decreased Astrocytic CCL2 Accounts for BAF-312 Effect on PBMCs Transendothelial Migration Through a Blood Brain Barrier in Vitro Model. J Neuroimmune Pharmacol. 2021 Oct 2. doi: 10.1007/s11481-021-10016-5.

Disruption of the blood brain barrier (BBB) is a common event in several neurological diseases and in particular, in multiple sclerosis (MS), it contributes to the infiltration of the central nervous system by peripheral inflammatory cells. Sphingosine-1-phosphate (S1P) is a bioactive molecule with pleiotropic effects. Agonists of S1P receptors such as fingolimod and siponimod (BAF-312) are in clinical practice for MS and have been shown to preserve BBB function in inflammatory conditions. Using an in vitro BBB model of endothelial-astrocytes co-culture exposed to an inflammatory insult (tumor necrosis factor-α and interferon-γ;), we show that BAF-312 reduced the migration of peripheral blood mononuclear cells (PBMCs) through the endothelial layer, only in the presence of astrocytes. This effect was accompanied by decreased expression of the adhesion molecules (intracellular adhesion molecule 1 which is expressed on inflamed blood vessels). BAF-312 also reduced the activation of astrocytes and preventing the increase of proinflammatory cytokine and chemokines. Reduction of CCL2 (chemokine a chemoattractive protein) by BAF-312 may be responsible for the observed effects and, accordingly, addition of exogenous CCL2 was able to counteract BAF-312 effects and rescued responses on PBMC migration, ICAM-1 expression and astrocyte activation. The present results further point out BAF-312 effects on BBB properties, suggesting also the key role of astrocytes in mediating drug effects on endothelial function.

This should come as no surprise as astrocytes are important in the action of fingolimod on blood brain barrier function

van Doorn R, Nijland PG, Dekker N, Witte ME, Lopes-Pinheiro MA, van het Hof B, Kooij G, Reijerkerk A, Dijkstra C, van van der Valk P, van Horssen J, de Vries HE. Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. Acta Neuropathol. 2012 Sep;124(3):397-410.

COI Multiple

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

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