Current status and new developments in sphingosine-1-phosphate receptor antagonism: fingolimod and more

ABSTRACT

Introduction

Fingolimod was the first oral disease-modifying treatment approved for relapsing-remitting multiple sclerosis (MS) that serves as a sphingosine-1-phosphate receptor (S1PR) agonist. The efficacy is primarily mediated by S1PR subtype 1 activation, leading to agonist-induced down-modulation of receptor expression and further functional antagonism, blocking the egression of auto-aggressive lymphocytes from the lymph nodes in the peripheral compartment. The role of S1P signaling in the regulation of other pathways in human organisms through different S1PR subtypes has received much attention due to its immune-modulatory function and its significance for the regeneration of the central nervous system. The more selective second-generation S1PR modulators have improved safety and tolerability profiles.

Areas covered

This review has been carried out based on current data on S1PR modulators, emphasizing the benefits of recent advances in this emergent class of immunomodulatory treatment for MS.

Expert opinion

Ongoing clinical research suggests that S1PR modulators represent an alternative to first-line therapies in selected cases of MS. A better understanding of the relevance of selective S1PR pathways and the ambition to optimize selective modulation has improved the safety and tolerability of S1PR modulators in MS therapy and opened new perspectives for the treatment of other diseases.

KEYWORDS:

• Sphingosine-1-phosphate receptor modulators
• multiple sclerosis
• fingolimod
• disease-modifying treatments
• cardiac adverse events

Article highlights

• The sphingosine-1-phosphate (S1P) signaling pathways are involved in the control of a wide spectrum of functions via the five subtypes of S1P receptors (S1PR) located at various sites, e.g. in the immune, cardiovascular and nervous systems.

• First targeted as a treatment for multiple sclerosis (MS), S1PR modulators have a complex mechanism of action, exerting their effect mainly through S1PR subtype 1 regulation intervening in the immune cell trafficking and sequestration of autoreactive lymphocytes in the lymph nodes, thereby blocking the subsequent infiltration into the central nervous system.

• Studies supporting the long-term safety and efficacy of S1PR modulators as disease-modifying treatment in MS focused primarily on fingolimod. The second generation of smaller molecules with preserved efficacy and improved pharmacokinetics, which helped to mitigate several cardiovascular adverse effects, further enforced the role of S1PR modulators in a broader spectrum of MS phenotypes including relapsing-remitting and secondary progressive forms, and facilitated the management of pathological and physiological conditions such as opportunistic infections, immunization or pregnancy.

• Moreover, current clinical data might encourage using S1PR modulators as a first-line treatment option in MS patients under certain conditions to prevent the premature accumulation of disability.

• Ongoing studies will provide more information about the S1PR modulators’ mechanism of action based on S1PR selectivity and will potentially allow us to maximize the benefits by applying this knowledge for the activation of other S1PR subtypes than S1PR subtype 1. Targeting the selectivity of receptor subtypes could open new perspectives on treating a broader spectrum of pathologies.

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List of abbreviations

Ach	=	acetylcholine
AKT	=	Akt kinase, protein kinase B or PKB
AV	=	atrioventricular
CCR7	=	C-C chemokine receptor 7
CNS	=	central nervous system
CSF	=	cerebrospinal fluid
DNA	=	deoxyribonucleic acid
EMA	=	European Medicines Agency
eNOS	=	endothelial NO synthase
FDA	=	Food and Drug Administration
FEV1	=	forced expiratory volume in 1 second
GIRK	=	G protein-gated inwardly rectifying potassium channels
IKACh	=	atrial muscarinic-gated potassium channels
M2 receptors	=	muscarinic type-2 receptors
MLC	=	myosin light chain
MLC-K	=	myosin light chain kinase
MLC-P	=	myosin light chain phosphatase
mRNA	=	messenger ribonucleic acid
MRI	=	magnetic resonance imaging
MS	=	multiple sclerosis
NK	=	natural killer
NO	=	nitric oxide
PKC	=	Protein Kinase C
RMS	=	relapsing forms of multiple sclerosis
ROCK	=	Rho-associated protein kinase
RRMS	=	relapsing-remitting multiple sclerosis
S1P	=	sphingosine-1-phosphate
S1PR	=	sphingosine-1-phosphate receptor
S1PR1	=	sphingosine-1-phosphate receptor subtype 1
S1PR2	=	sphingosine-1-phosphate receptor subtype 2
S1PR3	=	sphingosine-1-phosphate receptor subtype 3
S1PR4	=	sphingosine-1-phosphate receptor subtype 4
S1PR5	=	sphingosine-1-phosphate receptor subtype 5
SARS-CoV-2	=	severe acute respiratory syndrome coronavirus type 2
SPMS	=	secondary progressive multiple sclerosis
SPNS 2	=	Spinster homolog 2 sphingolipid transporter
Th1 lymphocyte	=	T helper 1 lymphocyte

Declaration of interest

K Akgün has received personal compensation from Novartis, Biogen Idec, Teva, Sanofi and Roche for consulting services. T Ziemssen has received personal compensation from Alexion, Almirall, Biogen, Bayer, BMS, Hexal, Merck. Novartis, Roche, Sanofi, Teva and Viatris for consulting and speaking services. T Ziemssen has also received additional financial support for research activities from Biogen, Novartis, Roche, Teva, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2022.2138330.

Additional information

Funding

This paper was not funded.