Are more sphingosine 1-phosphate receptor agonists a better therapeutic option against multiple sclerosis? Masahiro Mori, Satoshi Kuwabara Fingolimod is a sphingosine 1-phosphate (S1P) receptor agonist; it was the first oral disease-modifying agent approved for the treatment of multiple sclerosis (MS). Two double-blind randomised clinical trials (TRANSFORMS and FREEDOMS studies) have shown that in comparison with inter- feron β-1a or placebo, fingolimod is superior in improving clinical and MRI outcomes in relapsing-remitting MS (RRMS) patients. 12 The FREEDOMS study demonstrated that 0.5-mg fingolimod reduced the annualised relapse rate of RRMS by 55% relative to placebo. On this basis, fingolimod was approved for RRMS treatment in the USA, EU and other countries. To date, more than 77 000 patients have been treated with fingolimod. In spite of its effectiveness and oral- availability, fingolimod is usually considered as second-line treatment, because it may cause some serious adverse events, particu- larly cardiovascular related. The European Medicines Agency reported an MS patient who died within 24 h of administration of the first dose of fingolimod. Furthermore, the agency reported 13 fatal cases compli- cated with suspected cardiovascular disor- ders, although a causal relationship of fingolimod administration was not proven. Fingolimod is rapidly metabolised by sphingosine kinase into a biologically active form, fingolimod-phosphate, which is a potent modulator of the following four of the five known S1P receptors: S1P1, S1P3, S1P4 and S1P5. S1P1 is reportedly required for lymphocyte recirculation into the blood stream, and some studies have shown that S1P3 is associated with cardiovascular side effects. Therefore, a pharmacological strategy has been sought to find S1P receptor agonists for S1P1, with little or no influence on S1P3, to reduce cardiovascular side effects. As such, it is timely that in this month’s issue of the journal, the study by Olsson et al 3 describes the results of a randomised phase II trial of ponesimod, a selective S1P1 modulator for RRMS. Differences in the efficacy and safety profile between fin- golimod and ponesimod are not directly comparable because of the different study designs. In spite of these differences, the study by Olsson and et al demonstrated that the reduction rate of annualised relapse in the 40-mg ponesimod-treated group compared with the placebo group was 52% at 24 weeks, which was similar to that in the 0.5-mg fingolimod-treated group in the FREEDOMS study. However, in that study, first-degree atrioventricular blocks, second- degree atrioventricular blocks and bradycar- dia were found in 1.9%, 0.9% and 2% of ponesimod-treated groups, respectively, whereas first-degree atrioventricular blocks, second-degree atrioventricular blocks and bradycardia were found in 0.5%, 0% and 2.1% of the 0.5-mg fingolimod-treated group in the FREEDOMS study. Siponimod and ONO-4641 are also next-generation S1P receptor agonists selective for S1P1 and S1P5. In the phase II trials of siponimod for RRMS, 4 first-degree and second-degree atrioventricular blocks were found in 2% and 6% patients treated with 0.5-mg and 2-mg siponimod, respect- ively. Bradycardia was also found in 5% and 6% patients treated with 0.5-mg and 2-mg siponimod, respectively. In the phase II study of ONO-4641 for RRMS, 5 first- degree and second-degree atrioventricular blocks were found in 1.0% and 4.9% patients treated with 0.10 mg ONO-4641. These results, perhaps against our initial expectations, may suggest that very weak effects on S1P3 or the effect just on S1P1 may cause disturbances of heart rate regula- tion. If the former is the predominant role, combined use of S1P receptor agonists and S1P3 blockers 6 could provide safer MS treatment strategies. However, recent studies suggest that the effect of S1P1 play a more dominant role. Some S1P1-selective agonists could activate G-protein-gated inwardly rectifying K + channels, their acti- vation by S1P receptor agonists being thought to cause bradycardia in guinea pigs, and some S1P1-selective agonists seem capable of reducing the heart rate in rats. Moreover, in situ hybridisation and immu- nohistochemistry showed that S1P1 mRNA and proteins, not S1P3, are highly expressed in human cardiovascular tissues including atrial cardiomyocytes. 7 At present, S1P receptor agonists are required to show the safety profile compar- ing other S1P receptor agonists by means of head-to-head, large-scale controlled rando- mised studies or propensity score analyses. In the future, the development of the newer S1P receptor modulators with similar or more efficacy than fingolimod and fewer or no cardiovascular adverse effects will be expected. S1P1 antagonists or S1P lyase inhibitors may meet that expectation. 7 Moreover, an entirely new strategy such as the development of S1P receptor agonists with high selectivity for lymphocytes may be required for safer MS treatment. Contributors MM: conception and drafting manuscript. SK: revising it critically. Competing interests None. Patient consent Obtained. Provenance and peer review Commissioned; internally peer reviewed. To cite Mori M, Kuwabara S. J Neurol Neurosurg Psychiatry Published Online First: [ please include Day Month Year] doi:10.1136/jnnp-2013-307538 Received 3 February 2014 Revised 20 February 2014 Accepted 25 February 2014 ▸ http://dx.doi.org/10.1136/jnnp-2013-307282 J Neurol Neurosurg Psychiatry 2014;0:1. doi:10.1136/jnnp-2013-307538 REFERENCES 1 Kappos L, Radue EW, O’Connor P, et al.A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387–401. 2 Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402–15. 3 Olsson T, Boster A, Fernández Ó, et al. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry 2014. In press. 4 Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 2013;12:756–67. 5 Zipp F, Vollmer TL, Selmaj KW, et al. Efficacy and safety of the S1P receptor agonist ONO-4641 in patients with relapsing-remitting multiple sclerosis: results of a 26-week, double-blind, placebo-controlled, phase II trial (DreaMS), Lyon, France. http:// registration.akm.ch/einsicht.php?XNABSTRACT_ ID=156130&XNSPRACHE_ID=2&XNKONGRESS_ ID=171&XNMASKEN_ID=900 6 Murakami A, Takasugi H, Ohnuma S, et al. Sphingosine 1-phosphate (S1P) regulates vascular contraction via S1P3 receptor: investigation based on a new S1P3 receptor antagonist. Mol Pharmacol 2010;77:704–13. 7 Bigaud M, Guerini D, Billich A, et al. Second generation S1P pathway modulators: research strategies and clinical developments. Biochim Biophys Acta 2013. (in press). Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan Correspondence to Dr Masahiro Mori, Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; morim@faculty.chiba-u.jp Mori M, et al. J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0 1 Editorial commentary JNNP Online First, published on March 21, 2014 as 10.1136/jnnp-2013-307538 Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence. group.bmj.com on March 28, 2014 - Published by jnnp.bmj.com Downloaded from