Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis

Abstract

Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor’s function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the United States in 2010 for relapsing MS after two phase 3 trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience as well as a third phase 3 trial (FREEDOMS II) also showed favorable results. More selective S1P receptor agents: ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303 are still in relatively early stages of development, but phase 1 and 2 trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase 3 clinical trials.

Elevation of serum sphingosine-1-phosphate attenuates impaired cardiac function in experimental sepsis

“…FTY720 is currently being used in the therapy of patients with multiple sclerosis46. Thus, it is, in principle, possible to evaluate the effects of FTY720 in patients with sepsis.…”

Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

“…However, in the case of S1P 1 modulators like fingolimod-phosphate, internalized S1P 1 undergoes proteosomal degradation, resulting in long-time absence of S1P 1 until de novo synthesized (Oo et al ., 2007). This kind of functional antagonism of fingolimod means it has a long action time, which can sometimes be disadvantageous (Subei and Cohen, 2015). The immune modulatory action of fingolimod has also been reported in autoimmune diseases other than multiple sclerosis, such as spontaneous autoimmnune polyneuropathy and experimental autoimmune neuritis (Kim et al ., 2009; Zhang et al ., 2009a).…”

“…The common adverse effects were bradycardia at the first dose or atrioventricular block, macular edema, hypertension, headache, cough, dyspnea, back pain, influenza, and diarrhea (Subei and Cohen, 2015). First dose bradycardia is believed to be mediated via transient S1P 1 activation in atrial myocytes, which would disappear by down-regulation of S1P 1 (Camm et al ., 2014).…”

“…Siponimod is being investigated in the context of multiple sclerosis (Subei and Cohen, 2015). Like fingolimod, siponimod induces lymphopenia by preventing lymphocyte egress from lymph nodes (Fryer et al ., 2012).…”

Nano- and micro-based systems for immunotolerance induction in multiple sclerosis

“…In clinical trials it demonstrated a good efficacy in controlling the disease but concerns regarding its long-term safety, particularly the profound lymphopenia and the risk of a serious opportunistic CNS infection, progressive multifocal leukoencephalopathy (PML), might limit its use. 11 Fingolimod, a functional antagonist of S1P receptors that blocks lymphocyte egress from lymph nodes, 12 has also a good efficacy but similar concerns over lymphopenia and PML. 8 Natalizumab is a highly efficacious monoclonal antibody that blocks lymphocyte entry into the CNS; however, it is associated with a high risk of PML in patients which have antibodies against the causing organism, JC virus, which almost limits its use to seronegative patients representing less than half of MS patients.…”