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New possibilities for the therapy of secondary progressive multiple sclerosis

https://doi.org/10.14412/2074-2711-2019-4-125-129

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Abstract

Patients with multiple sclerosis (MS) are at high risk for transition to secondary progressive MS (SPMS). To date, there has not been a sufficiently effective therapy for SPMS. Siponimod is a selective sphingosine-1-phosphate types 1 and 5 receptor modulator that has been shown to be more effective than placebo in slowing the progression of disability in patients with SPMS in the international phase III (EXPAND) clinical trial. This review analyzes data on the pathophysiology of MS progression, the features of the mechanism of action of siponimod, the efficiency and safety of its use, including those by the results of the EXPAND study. The latter studied the efficacy of siponimod by the time to 3-month confirmed disability progression (3M-CDP) and also assessed other clinical and radiological parameters. The analysis included data on 1,651 patients with SPMS from 31 countries. In the patients who received siponimod, the risk of 3M-CDP decreased by an average of 21% compared with those who took placebo. The administration of siponimod positively affected the speed of cognitive processes. Mild adverse events associated with liver failure, hypertension, and upper respiratory tract infections were more common in the siponimod group. Siponimod did not pose a higher risk for developing malignant neoplasms. The drug reduces the risk of disability progression in patients with SPMS and has a favorable safety profile.

About the Authors

A. M. Petrov
N.P. Bekhtereva Institute of the Human Brain, Russian Academy of Sciences
Russian Federation
9, Acad. Pavlov St., Saint Petersburg 197376


E. V. Ivashkova
N.P. Bekhtereva Institute of the Human Brain, Russian Academy of Sciences
Russian Federation
9, Acad. Pavlov St., Saint Petersburg 197376


I. D. Stolyarov
N.P. Bekhtereva Institute of the Human Brain, Russian Academy of Sciences
Russian Federation
9, Acad. Pavlov St., Saint Petersburg 197376


References

1. Gusev EI, Boiko AN, Stolyarov ID. Rasseyannyi skleroz [Multiple sclerosis]. Moscow: Zdorov'e cheloveka; 2015. 448 p.

2. Lassmann H, van Horssen J, Mahad DH. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012 Nov 5;8(11):647-56. doi: 10.1038/nrneurol.2012.168. Epub 2012 Sep 25.

3. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015 Feb;14(2): 183-93. doi: 10.1016/S1474-4422(14)70256-X.

4. Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 2009 Mar; 8(3):280-91. doi: 10.1016/S1474-4422(09)70043-2.

5. Frischer JM, Weigand SD, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015 Nov;78(5):710-21. doi: 10.1002/ana.24497. Epub 2015 Aug 24.

6. Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007 Apr;130(Pt 4):1089-104.

7. Reynolds R, Roncaroli F, Nicholas R, et al. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 2011 Aug;122(2):155-70. doi: 10.1007/s00401-011-0840-0. Epub 2011 May 28.

8. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006 Oct 5;52(1): 61-76.

9. Kalincik T, Cutter G, Spelman T, et al. Defining reliable disability outcomes in multiple sclerosis. Brain. 2015 Nov;138(Pt 11):3287-98. doi: 10.1093/brain/awv258. Epub 2015 Sep 10.

10. Thompson AJ. Challenge of progressive multiple sclerosis therapy. Curr Opin Neurol. 2017 Jun;30(3):237-240. doi: 10.1097/WCO.0000000000000453.

11. Marrie RA, Montalban X. Disease-modifying therapy in multiple sclerosis: Two guidelines (almost) passing in the night. Mult Scler. 2018 Apr;24(5):558-562. doi: 10.1177/1352458518767323.

12. Boiko AN, Gusev EI. Modern algorithms for diagnosis and treatment of multiple sclerosis based on individual assessment of the patient's condition. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2017;117(2): 92-106. (InRuss.)

13. Kappos L, Weinshenker B, Pozzilli C, et al. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology. 2004 Nov 23;63(10):1779-87.

14. Rio J, Rovira A, Tintore M, et al. Disability progression markers over 6–12 years in interferon-β-treated multiple sclerosis patients. Mult Scler. 2018 Mar;24(3):322-330. doi: 10.1177/1352458517698052. Epub 2017 Mar 13.

15. Zakharova MN, editor. Rasseyannyi skleroz: voprosy diagnostiki i lecheniya: prakticheskoe rukovodstvo dlya vrachei [Multiple sclerosis: diagnosis and treatment: a practical guide for doctors]. Moscow: Media Mente; 2018. 240 p.

16. Il'ves AG, Prakhova LN, Kataeva GV, Petrov AM. Clinical and radiological (PET and MRI) correlations in patients with multiple sclerosis of different severity. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2006;106(3):81-6. (InRuss.)

17. Stolyarov ID, Petrov AM, Ivashkova EV, et al. nnovative mechanism of action of fingolimod in multiple sclerosis. Russkii meditsinskii zhurnal. 2011;(29):1812-5. (InRuss.)

18. Pan S, Gray NS, Gao W, et al. Discovery of BAF312 (Siponimod), a potent and selective S1P receptor modulator. ACS Med Chem Lett. 2013 Mar 14;4(3):333-337.

19. Gergely P, Nuesslein-Hildesheim B, Guerini D, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has speciesspecific effects on heart rate. Br J Pharmacol. 2012 Nov;167(5):1035-1047.

20. Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016 Aug 26;13(1):207. doi: 10.1186/s12974-016-0686-4.

21. Legangneux E, Gardin A, Johns D. Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects. Br J Clin Pharmacol. 2013 Mar;75(3):831-41. doi: 10.1111/j.1365-2125.2012.04400.x

22. Legangneux E, Shakeri-Nejad K, Aslanis V, et al. Cardiac Effects of Siponimod (BAF312) Re-initiation After Variable Periods of Drug Discontinuation in Healthy Subjects. Clin Ther. 2016 Mar;38(3):631-45.e1. doi: 10.1016/j.clinthera.2016.01.021

23. Stolyarov ID, Petrov AM, Votintseva MV, Nikiforova IG. Non-biological complex drugs and their analogues in the pathogenetic therapy of multiple sclerosis: Issues of efficacy and safety in clinical use. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2015;7(1):75-9. (InRuss.) doi: 10.14412/2074-2711-2015-1-75-79

24. Kappos L, Bar-Or A, Bruce A et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a doubleblind, randomised, phase 3 study. Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6.

25. Giovannoni G, Cutter G, Sormani M, et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78. doi: 10.1016/j.msard.2017.01.007.

26. Stolyarov ID, Petrov AM, Votintseva MV, Ivashkova EV. Safety of immunosuppressive drugs that alter the course of multiple sclerosis. Nervnye bolezni. 2018;(3): 16-21. (In Russ.)

27. Behrangi N, Fischbach F, Kipp M. Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective Mode of Action. Cells. 2019 Jan 7;8(1). pii: E24. doi: 10.3390/cells8010024.

28. Planche V, Gibelin M, Cregut D, et al. Cognitive impairment in a population-based study of patients with multiple sclerosis: differences between late relapsing-remitting, secondary progressive and primary progressive multiple sclerosis. Eur J Neurol. 2016 Feb;23(2):282-9. doi: 10.1111/ene.12715

29. Votintseva MV, Mineev KK, Petrov AM, et al. Connection of cognitive disorders with localization of lesions of the white matter of the brain in patients with multiple sclerosis. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2014; 114(2):57-60. (InRuss.)

30. Benedict R, Fox R, Tomic D, et al. Effect of Siponimod on Cognition in Patients with Secondary Progressive Multiple Sclerosis (SPMS): Phase 3 EXPAND Study Subgroup Analysis. Poster presentation. 2019 American Academy of Neurology Annual Meeting.

31. Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. Lancet. 2017 Apr 1; 389(10076):1357-1366. doi: 10.1016/S0140-6736(16)31320-4. Epub 2016 Nov 24.

32. Lassmann H. Targets of therapy in progressive MS. Mult Scler. 2017 Oct;23(12):1593-1599. doi: 10.1177/1352458517729455

33. Dumitrescu L, Constantinescu CS, Tanasescu R. Siponimod for the treatment of secondary progressive multiple sclerosis. Expert Opin Pharmacother. 2019 Feb;20(2):143-150. doi: 10.1080/14656566.2018.1551363


Review

For citations:


Petrov A.M., Ivashkova E.V., Stolyarov I.D. New possibilities for the therapy of secondary progressive multiple sclerosis. Neurology, Neuropsychiatry, Psychosomatics. 2019;11(4):125-129. (In Russ.) https://doi.org/10.14412/2074-2711-2019-4-125-129

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ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)