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Neurology and Therapy
Published in: Neurology and Therapy 4/2023

Open Access 17-05-2023 | Multiple Sclerosis | ORIGINAL RESEARCH

Central Versus Peripheral Drug Exposure Ratio, a Key Differentiator for Siponimod Over Fingolimod?

Authors: Marc Bigaud, Pamela Ramseier, Sarah Tisserand, Meike Lang, Beatrice Urban, Christian Beerli, Göril Karlsson

Published in: Neurology and Therapy | Issue 4/2023

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Abstract

Introduction

Siponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy against disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy against disability progression in PPMS. Differentiating siponimod from fingolimod at the level of their central effects is believed to be the key to a better understanding of the underlying characteristics that could make siponimod uniquely efficacious in progressive MS (PMS).

Methods

Here, we compared the central vs. peripheral dose-dependent drug exposures for siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE).

Results

Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady-state drug blood levels, with a central nervous system (CNS)/blood drug-exposure ratio (CNS/bloodDER) of ~ 6 in both healthy and EAE mice. In contrast, fingolimod treatments achieved dose-proportional increases in fingolimod and fingolimod-phosphate blood levels, with respective CNS/bloodDER that were markedly increased (≥ threefold) in EAE vs. healthy mice.

Conclusion

If proven to have translational value, these observations would suggest that CNS/bloodDER may be a key differentiator for siponimod over fingolimod for clinical efficacy in PMS.
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Metadata
Title
Central Versus Peripheral Drug Exposure Ratio, a Key Differentiator for Siponimod Over Fingolimod?
Authors
Marc Bigaud
Pamela Ramseier
Sarah Tisserand
Meike Lang
Beatrice Urban
Christian Beerli
Göril Karlsson
Publication date
17-05-2023
Publisher
Springer Healthcare
Published in
Neurology and Therapy / Issue 4/2023
Print ISSN: 2193-8253
Electronic ISSN: 2193-6536
DOI
https://doi.org/10.1007/s40120-023-00487-4

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