Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis

Abstract

Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.

Induction or escalation therapy for patients with multiple sclerosis?

“…Because the target of all approved DMDs is the focal inflammation, which predominates at the beginning of the disease course, it is logical to concentrate all the therapeutic efforts in the early (first) phase of the disease. Indeed, if some positive effect was recently described in progressive forms of MS with ocrelizumab and siponimod [9,10], results should be interpreted cautiously because when considering patients without any clinical or radiological sign of inflammation, current DMDs might not be expected to be as effective while the focal inflammatory process is less relevant and their action on the neurodegenerative process uncertain. This is probably because the immune derangement characterising MS increases over time and probably also shift from a peripheral immune-pathological profile to a central nervous system compartmentalised profile in late MS [11].…”

Anti-inflammatory treatment with FTY720 starting after onset of symptoms reverses synaptic and memory deficits in an AD mouse model

“…Fingolimod (FTY720) is an FDA approved drug for the treatment of multiple sclerosis (MS) in humans since 2011 and has evolved in recent years as the first line oral medication for relapsing MS in clinical practice (Druart et al, 2018). In target tissue, it can be converted to fingolimod phosphate, which is a potent modulator of sphingosine-1-phosphate receptors (S1PR 1-5 ; (Angelopoulou and Piperi, 2019;Chaudhry et al, 2017). In the immune system, fingolimod induced S1PR receptor modulation promotes the retention of T-lymphocytes within lymph nodes, thereby reducing the invasion of the CNS by lymphocytes where they promote inflammatory processes leading to demyelination (Chaudhry et al, 2017).…”

“…In target tissue, it can be converted to fingolimod phosphate, which is a potent modulator of sphingosine-1-phosphate receptors (S1PR 1-5 ; (Angelopoulou and Piperi, 2019;Chaudhry et al, 2017). In the immune system, fingolimod induced S1PR receptor modulation promotes the retention of T-lymphocytes within lymph nodes, thereby reducing the invasion of the CNS by lymphocytes where they promote inflammatory processes leading to demyelination (Chaudhry et al, 2017). More recently, fingolimod was shown to increase BDNF mRNA and protein levels in mouse models of different neurodegenerative diseases (Deogracias et al, 2012;Di Pardo et al, 2014;Fukumoto et al, 2014;Miguez et al, 2015).…”

Multiple Sclerosis: Unprecedented Progress But Significant Challenges Ahead

“…Baldassari and Rose [2] provide a thoughtful analysis of its place in the DMT landscape. Finally, Chaudhry et al [3] review fingolimod and present a bridge into the pipeline section with a discussion of second-generation sphingosine-1-phosphate receptor modulators with greater receptor subtype specificity.Pipeline treatments include cladribine, which was rejected by the Food and Drug Administration and the European Medicines Agency several years ago but recently received approval from the European Medicines Agency. Gavin Giovannoni [4] contributes a review of this medication, which will soon be joining the MS therapeutic landscape in Europe.…”

“…Baldassari and Rose [2] provide a thoughtful analysis of its place in the DMT landscape. Finally, Chaudhry et al [3] review fingolimod and present a bridge into the pipeline section with a discussion of second-generation sphingosine-1-phosphate receptor modulators with greater receptor subtype specificity.…”