Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective Mode of Action

Newshan Behrangi,Felix Fischbach,Markus Kipp

doi:10.3390/cells8010024

Abstract

Multiple sclerosis (MS) is a neuroinflammatory disorder of the central nervous system (CNS), and represents one of the main causes of disability in young adults. On the histopathological level, the disease is characterized by inflammatory demyelination and diffuse neurodegeneration. Although on the surface the development of new inflammatory CNS lesions in MS may appear consistent with a primary recruitment of peripheral immune cells, questions have been raised as to whether lymphocyte and/or monocyte invasion into the brain are really at the root of inflammatory lesion development. In this review article, we discuss a less appreciated inflammation-neurodegeneration interplay, that is: Neurodegeneration can trigger the formation of new, focal inflammatory lesions. We summarize old and recent findings suggesting that new inflammatory lesions develop at sites of focal or diffuse degenerative processes within the CNS. Such a concept is discussed in the context of the EXPAND trial, showing that siponimod exerts anti-inflammatory and neuroprotective activities in secondary progressive MS patients. The verification or rejection of such a concept is vital for the development of new therapeutic strategies for progressive MS.

Highlights

Multiple sclerosis (MS) can be clinically categorized into three groups: Relapsing-remitting, secondary progressive, and primary progressive
Due to the eminent medical need for study in patients with relapsingMS (SPMS), having a moderate-to-advanced disability indicated by an Expanded Disability Status Scale having treatment options during progressive MS, a phase 3, randomized, parallel-group, double(EDSS) score of 3–6 at screening, having documented EDSS progression in the 2 years before the study, blind, placebo-controlled, event-driven, and exposure-driven trial
The primary of siponimod in PAtients with secoNDary progressive multiple sclerosis [EXPAND]) was conducted endpoint of the EXPAND study was the time to 3-month confirmed disability progression, which was to investigate the efficacy and safety of siponimod in patients with secondary progressive MS (SPMS)

Summary

Introduction

Multiple sclerosis (MS) can be clinically categorized into three groups: Relapsing-remitting, secondary progressive, and primary progressive. Many patients with an initial relapsing-remitting disease course after several years develop secondary progressive MS which is characterized by a more or less continuous decline of neurological functioning, with or without occasional attacks. Perivascular inflammatory infiltrates, oligoclonal immunoglobulin G in the cerebrospinal fluid, gadolinium-enhancing lesions on magnetic resonance scans, or the acute appearance of clinical symptoms are believed to be the direct consequence of focal inflammatory CNS lesions. Such inflammatory lesions can be found widespread within the white matter, several studies have clearly shown that diverse brain grey matter structures are affected [1,2].

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