Skip to main content
SpringerLink
Log in

Efficacy and Safety of Oral Therapies for Relapsing-Remitting Multiple Sclerosis

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Disease-modifying therapies have now become standard treatment for multiple sclerosis. These include five oral therapies for relapsing-remitting multiple sclerosis, namely fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod, although there is some discrepancy on the relative efficacy and safety of these agents. To gain further insight on these oral agents in relapsing-remitting multiple sclerosis, we performed a narrative review of fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod. We limited the analysis to randomized clinical studies in which a comparator was used (i.e., placebo or other disease-modifying therapy). As relapsing-remitting multiple sclerosis is a chronic disease and treatment is lifelong, long-term outcomes were an additional focus. A total of 37 studies met inclusion criteria: 15 for fingolimod, 8 for dimethyl fumarate, 7 for teriflunomide, 4 for cladribine, and 3 for siponimod. All drugs showed some functional and magnetic resonance imaging benefit in nearly all clinical studies. The reduction in annual relapse rate was similar for fingolimod, dimethyl fumarate, and cladribine, and somewhat greater than for teriflunomide; there is limited information on the annual relapse rate for siponimod. For all drugs, the benefits reported at short follow-up times are broadly consistent with those seen at longer follow-up times. For fingolimod and dimethyl fumarate, there was a definite trend towards a progressively lower annual relapse rate with continuing treatment. The safety profile of all five drugs was considered to be acceptable, even after extended treatment. While these results should be treated with caution, they highlight that future head-to-head studies are needed to better understand the long-term benefits of disease-modifying therapies. Such information will be of value when considering the risk-benefit profile of these oral therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: when to start, when to change, when to stop? World J Clin Cases. 2015;3(7):545–55.

    PubMed  PubMed Central  Google Scholar 

  2. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162–73.

    PubMed  Google Scholar 

  3. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–17.

    CAS  PubMed  Google Scholar 

  4. Auricchio F, Scavone C, Cimmaruta D, Di Mauro G, Capuano A, Sportiello L, et al. Drugs approved for the treatment of multiple sclerosis: review of their safety profile. Expert Opin Drug Saf. 2017;16(12):1359–71.

    CAS  PubMed  Google Scholar 

  5. Al-Salama ZT. Siponimod: first global approval. Drugs. 2019;79(9):1009–15.

    CAS  PubMed  Google Scholar 

  6. Hamidi V, Couto E, Ringerike T, Klemp M. A multiple treatment comparison of eleven disease-modifying drugs used for multiple sclerosis. J Clin Med Res. 2018;10(2):88–105.

    PubMed  Google Scholar 

  7. Pike E, Hamidi V, Saeterdal I, Odgaard-Jensen J, Klemp M. Multiple treatment comparison of seven new drugs for patients with advanced malignant melanoma: a systematic review and health economic decision model in a Norwegian setting. BMJ Open. 2017;7(8):e014880.

    PubMed  PubMed Central  Google Scholar 

  8. Ghezzi A. European and American guidelines for multiple sclerosis treatment. Neurol Ther. 2018;7(2):189–94.

    PubMed  PubMed Central  Google Scholar 

  9. Marrie RA, Montalban X. Disease-modifying therapy in multiple sclerosis: two guidelines (almost) passing in the night. Mult Scler. 2018;24(5):558–62.

    PubMed  Google Scholar 

  10. Hadjigeorgiou GM, Doxani C, Miligkos M, Ziakas P, Bakalos G, Papadimitriou D, et al. A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis. J Clin Pharm Ther. 2013;38(6):433–9.

    CAS  PubMed  Google Scholar 

  11. Huisman E, Papadimitropoulou K, Jarrett J, Bending M, Firth Z, Allen F, et al. Systematic literature review and network meta-analysis in highly active relapsing-remitting multiple sclerosis and rapidly evolving severe multiple sclerosis. BMJ Open. 2017;7(3):e013430.

    PubMed  PubMed Central  Google Scholar 

  12. Tramacere I, Del Giovane C, Salanti G, D’Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015;18(9):CD011381.

    Google Scholar 

  13. Tsivgoulis G, Katsanos AH, Grigoriadis N, Hadjigeorgiou GM, Heliopoulos I, Papathanasopoulos P, et al. The effect of disease modifying therapies on disease progression in patients with relapsing-remitting multiple sclerosis: a systematic review and meta-analysis. PLoS One. 2015;10(12):e0144538.

    PubMed  PubMed Central  Google Scholar 

  14. Thomas K, Proschmann U, Ziemssen T. Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis. Expert Opin Pharmacother. 2017;18(15):1649–60.

    CAS  PubMed  Google Scholar 

  15. Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y. Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis. Front Neurol. 2018;9:5.

    PubMed  PubMed Central  Google Scholar 

  16. Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74(6):659–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sorensen P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416–26.

    CAS  PubMed  Google Scholar 

  18. Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflamm. 2016;13(1):207.

    Google Scholar 

  19. Faissner S, Gold R. Oral therapies for multiple sclerosis. Cold Spring Harb Perspect Med. 2019. https://doi.org/10.1101/cshperspect.a032011.

    Article  PubMed  Google Scholar 

  20. Barton S. Which clinical studies provide the best evidence? The best RCT still trumps the best observational study. BMJ. 2000;321(7256):255–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545–56.

    CAS  PubMed  Google Scholar 

  22. Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol. 2011;10(6):520–9.

    CAS  PubMed  Google Scholar 

  23. Montalban X, Comi G, Antel J, O’Connor P, de Vera A, Cremer M, et al. Long-term results from a phase 2 extension study of fingolimod at high and approved dose in relapsing multiple sclerosis. J Neurol. 2015;262(12):2627–34.

    PubMed  Google Scholar 

  24. Cohen JA, Khatri B, Barkhof F, Comi G, Hartung HP, Montalban X, et al. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J Neurol Neurosurg Psychiatry. 2016;87(5):468–75.

    PubMed  Google Scholar 

  25. Kappos L, O’Connor P, Radue EW, Polman C, Hohlfeld R, Selmaj K, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84(15):1582–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Koch-Henriksen N, Magyari M, Sellebjerg F, Soelberg Sorensen P. A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod. Mult Scler. 2017;23(2):234–41.

    CAS  PubMed  Google Scholar 

  27. Radue EW, O’Connor P, Polman CH, Hohlfeld R, Calabresi P, Selmaj K, et al. Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis. Arch Neurol. 2012;69(10):1259–69.

    PubMed  Google Scholar 

  28. Barkhof F, de Jong R, Sfikas N, de Vera A, Francis G, Cohen J, et al. The influence of patient demographics, disease characteristics and treatment on brain volume loss in Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), a phase 3 study of fingolimod in multiple sclerosis. Mult Scler. 2014;20(13):1704–13.

    CAS  PubMed  Google Scholar 

  29. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.

    CAS  PubMed  Google Scholar 

  30. Izquierdo G, O’Connor P, Montalban X, von Rosenstiel P, Cremer M, de Vera A, et al. Five-year results from a phase 2 study of oral fingolimod in relapsing multiple sclerosis. Mult Scler. 2014;20(7):877–81.

    CAS  PubMed  Google Scholar 

  31. Comi G, Patti F, Rocca MA, Mattioli FC, Amato MP, Gallo P, et al. Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study). J Neurol. 2017;264(12):2436–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Gold R, Arnold DL, Bar-Or A, Hutchinson M, Kappos L, Havrdova E, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: interim analysis of ENDORSE, a randomized extension study. Mult Scler. 2017;23(2):253–65.

    CAS  PubMed  Google Scholar 

  33. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–97.

    CAS  PubMed  Google Scholar 

  34. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–107.

    CAS  PubMed  Google Scholar 

  35. O’Connor P, Comi G, Freedman MS, Miller AE, Kappos L, Bouchard JP, et al. Long-term safety and efficacy of teriflunomide: nine-year follow-up of the randomized TEMSO study. Neurology. 2016;86(10):920–30.

    PubMed  PubMed Central  Google Scholar 

  36. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247–56.

    CAS  PubMed  Google Scholar 

  37. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–303.

    PubMed  Google Scholar 

  38. Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, Rieckmann P, Comi G, et al. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. Mult Scler. 2018;24(12):1594–604.

    CAS  PubMed  Google Scholar 

  39. Comi G, Cook S, Rammohan K, Soelberg Sorensen P, Vermersch P, Adeniji AK, et al. Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study. Ther Adv Neurol Disord. 2018;11:1756285617753365.

    PubMed  PubMed Central  Google Scholar 

  40. Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung HP, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014;13(3):257–67.

    CAS  PubMed  Google Scholar 

  41. Freedman MS, Leist TP, Comi G, Cree BA, Coyle PK, Hartung HP, et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017;3(4):2055217317732802.

    PubMed  PubMed Central  Google Scholar 

  42. Kappos L, Li DK, Stuve O, Hartung HP, Freedman MS, Hemmer B, et al. Safety and efficacy of siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis: dose-blinded, randomized extension of the phase 2 BOLD study. JAMA Neurol. 2016;73(9):1089–98.

    PubMed  Google Scholar 

  43. Selmaj K, Li DK, Hartung HP, Hemmer B, Kappos L, Freedman MS, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12(8):756–67.

    CAS  PubMed  Google Scholar 

  44. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263–73.

    CAS  PubMed  Google Scholar 

  45. Confavreux C, Li DK, Freedman MS, Truffinet P, Benzerdjeb H, Wang D, et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult Scler. 2012;18(9):1278–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pakpoor J, Disanto G, Altmann DR, Pavitt S, Turner BP, Marta M, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e158.

    PubMed  PubMed Central  Google Scholar 

  47. Fogarty E, Schmitz S, Tubridy N, Walsh C, Barry M. Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: Systematic review and network meta-analysis. Mult Scler Relat Disord. 2016;9:23–30.

    PubMed  Google Scholar 

  48. He D, Zhang C, Zhao X, Zhang Y, Dai Q, Li Y, et al. Teriflunomide for multiple sclerosis. Cochrane Database Syst Rev. 2016;3:CD009882.

    PubMed  Google Scholar 

  49. Kalincik T, Kubala Havrdova E, Horakova D, Izquierdo G, Prat A, Girard M, et al. Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019;90(4):458–68.

    PubMed  Google Scholar 

  50. Buron MD, Chalmer TA, Sellebjerg F, Frederiksen J, Gora MK, Illes Z, et al. Comparative effectiveness of teriflunomide and dimethyl fumarate: a nationwide cohort study. Neurology. 2019;92(16):e1811–20.

    CAS  PubMed  Google Scholar 

  51. Koudriavtseva T, Thompson AJ, Fiorelli M, Gasperini C, Bastianello S, Bozzao A, et al. Gadolinium enhanced MRI predicts clinical and MRI disease activity in relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 1997;62(3):285–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kappos L, Moeri D, Radue EW, Schoetzau A, Schweikert K, Barkhof F, et al. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group. Lancet. 1999;353(9157):964–9.

    CAS  PubMed  Google Scholar 

  53. Druart C, El Sankari S, van Pesch V. Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis. Patient Relat Outcome Meas. 2018;9:1–10.

    PubMed  Google Scholar 

  54. Kappos L, Cohen J, Collins W, de Vera A, Zhang-Auberson L, Ritter S, et al. Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Relat Disord. 2014;3(4):494–504.

    PubMed  Google Scholar 

  55. EMA. European Medicines Agency. New recommendations to minimise risks of the rare brain infection PML and a type of skin cancer with Gilenya. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/12/news_detail_002447.jsp&mid=WC0b01ac058004d5c1. Accessed 18 Nov 2019.

  56. Gov.UK. Fingolimod (Gilenya): risks of progressive multifocal leukoencephalopathy, basal-cell carcinoma, and opportunistic infections. https://www.gov.uk/drug-safety-update/fingolimod-gilenya-risks-of-progressive-multifocal-leukoencephalopathy-basal-cell-carcinoma-and-opportunistic-infections. Accessed 18 Nov 2019.

  57. Fingolimod, summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/gilenya-epar-product-information_en.pdf. Accessed 18 Nov 2019.

  58. Fragoso YD. Multiple sclerosis treatment with fingolimod: profile of non-cardiologic adverse events. Acta Neurol Belg. 2017;117(4):821–7.

    PubMed  Google Scholar 

  59. Linker RA, Haghikia A. Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Ther Adv Chronic Dis. 2016;7(4):198–207.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K, Cree BA, Zamvil SS. Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e76.

    PubMed  PubMed Central  Google Scholar 

  61. Treumer F, Zhu K, Glaser R, Mrowietz U. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Investig Dermatol. 2003;121(6):1383–8.

    CAS  PubMed  Google Scholar 

  62. Longbrake EE, Naismith RT, Parks BJ, Wu GF, Cross AH. Dimethyl fumarate-associated lymphopenia: risk factors and clinical significance. Mult Scler J Exp Transl Clin. 2015. https://doi.org/10.1177/2055217315596994.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Briner M, Bagnoud M, Miclea A, Friedli C, Diem L, Chan A, et al. Time course of lymphocyte repopulation after dimethyl fumarate-induced grade 3 lymphopenia: contribution of patient age. Ther Adv Neurol Disord. 2019;12:1756286419843450.

    PubMed  PubMed Central  Google Scholar 

  64. Manni A, Iaffaldano A, Lucisani G, D’Onghia M, Mezzapesa DM, Felica V, et al. Lymphocyte count and body mass index as biomarkers of early treatment response in a multiple sclerosis dimethyl fumarate-treated cohort. Front Immunol. 2019;14(10):1343. https://doi.org/10.3389/fimmu.2019.01343.

    Article  CAS  Google Scholar 

  65. Xu M, Lu X, Fang J, Zhu X, Wang J. The efficacy and safety of teriflunomide based therapy in patients with relapsing multiple sclerosis: a meta-analysis of randomized controlled trials. J Clin Neurosci. 2016;33:28–31.

    CAS  PubMed  Google Scholar 

  66. Guarnera C, Bramanti P, Mazzon E. Comparison of efficacy and safety of oral agents for the treatment of relapsing-remitting multiple sclerosis. Drug Des Dev Ther. 2017;11:2193–207.

    CAS  Google Scholar 

  67. Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking C, et al. Cladribine tablets added to IFN-beta in active relapsing MS: the ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018;5(5):e477.

    PubMed  PubMed Central  Google Scholar 

  68. Deeks ED. Cladribine tablets: a review in relapsing MS. CNS Drugs. 2018;32(8):785–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Cook S, Leist T, Comi G, Montalban X, Giovannoni G, Nolting A, et al. Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis. Mult Scler Relat Disord. 2019;29:157–67.

    PubMed  Google Scholar 

  70. Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59–63.

    PubMed  Google Scholar 

  71. Klotz L, Havla J, Schwab N, Hohlfeld R, Barnett M, Reddel S, et al. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Ther Adv Neurol Disord. 2019;12:1756286419836571.

    PubMed  PubMed Central  Google Scholar 

  72. Dimethyl fumarate, summary of product characteristics. https://ec.europa.eu/health/documents/community-register/2018/20180528141209/anx_141209_en.pdf. Accessed 18 Nov 2019.

  73. Teriflunomide, summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/aubagio-epar-product-information_en.pdf. Accessed 18 Nov 2019.

  74. Cladribine, summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/mavenclad-epar-product-information_en.pdf. Accessed 18 Nov 2019.

  75. Alroughani R, Das R, Penner N, Pultz J, Taylor C, Eraly S. Safety and efficacy of delayed-release dimethyl fumarate in pediatric patients with relapsing multiple sclerosis (FOCUS). Pediatr Neurol. 2018;83:19–24.

    PubMed  Google Scholar 

  76. Chitnis T, Arnold DL, Banwell B, Bruck W, Ghezzi A, Giovannoni G, et al. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med. 2018;379(11):1017–27.

    CAS  PubMed  Google Scholar 

  77. Otallah S, Banwell B. Pediatric multiple sclerosis: an update. Curr Neurol Neurosci Rep. 2018;18(11):76.

    PubMed  Google Scholar 

  78. Rostasy K, Bajer-Kornek B. Paediatric multiple sclerosis and other acute demyelinating diseases. Curr Opin Neurol. 2018;31(3):244–8.

    PubMed  Google Scholar 

  79. Comi G, O’Connor P, Montalban X, Antel J, Radue EW, Karlsson G, et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult Scler. 2010;16(2):197–207.

    CAS  PubMed  Google Scholar 

  80. O’Connor P, Comi G, Montalban X, Antel J, Radue EW, de Vera A, et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology. 2009;72(1):73–9.

    PubMed  Google Scholar 

  81. Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355(11):1124–40.

    CAS  PubMed  Google Scholar 

  82. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.

    CAS  PubMed  Google Scholar 

  83. Arnold DL, Gold R, Kappos L, Bar-Or A, Giovannoni G, Selmaj K, et al. Effects of delayed-release dimethyl fumarate on MRI measures in the Phase 3 DEFINE study. J Neurol. 2014;261(9):1794–802.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Arnold DL, Gold R, Kappos L, Bar-Or A, Giovannoni G, Selmaj K, et al. Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study. J Neurol. 2014;261(12):2429–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372(9648):1463–72.

    CAS  PubMed  Google Scholar 

  86. MacManus DG, Miller DH, Kappos L, Gold R, Havrdova E, Limmroth V, et al. BG-12 reduces evolution of new enhancing lesions to T1-hypointense lesions in patients with multiple sclerosis. J Neurol. 2011;258(3):449–56.

    CAS  PubMed  Google Scholar 

  87. Miller DH, Fox RJ, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study. Neurology. 2015;84(11):1145–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Radue EW, Sprenger T, Gaetano L, Mueller-Lenke N, Cavalier S, Thangavelu K, et al. Teriflunomide slows BVL in relapsing MS: a reanalysis of the TEMSO MRI data set using SIENA. Neurol Neuroimmunol Neuroinflamm. 2017;4(5):e390.

    PubMed  PubMed Central  Google Scholar 

  89. Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705–16.

    CAS  PubMed  Google Scholar 

  90. Wolinsky JS, Narayana PA, Nelson F, Datta S, O’Connor P, Confavreux C, et al. Magnetic resonance imaging outcomes from a phase III trial of teriflunomide. Mult Scler. 2013;19(10):1310–9.

    CAS  PubMed  Google Scholar 

  91. Freedman MS, Morawski J, Thangavelu K. Clinical efficacy of teriflunomide over a fixed 2-year duration in the TOWER study. Mult Scler J Exp Transl Clin. 2018;4(2):2055217318775236.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Medical writing and editorial support were provided by Health Publishing & Services srl who, under the input of the authors, prepared, revised, copy edited, and formatted the manuscript according to journal requirements. These services were funded by Biogen.

Author information

Authors and Affiliations

  1. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124, Bari, Italy

    Damiano Paolicelli, Alessia Manni, Antonio Iaffaldano & Maria Trojano

Authors
  1. Damiano Paolicelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessia Manni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonio Iaffaldano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Trojano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Damiano Paolicelli.

Ethics declarations

Funding

Writing and editorial support was provided by Health Publishing & Services srl. These services were funded by Biogen Italia.

Conflict of interest

Damiano Paolicelli has received honoraria for consultancy and/or speaking from Biogen Idec, Merck-Serono, Bayer-Schering, Sanofi-Aventis, TEVA, Novartis, and Genzyme. Alessia Manni and Antonio Iaffaldano have no conflicts of interest that are directly relevant to the content of this article. Maria Trojano has served on scientific advisory boards for Biogen, Novartis, Roche, and Genzyme; has received speaker honoraria from Biogen Idec, Sanofi-Aventis, Merck Serono, Teva, Genzyme, and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono, and Novartis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paolicelli, D., Manni, A., Iaffaldano, A. et al. Efficacy and Safety of Oral Therapies for Relapsing-Remitting Multiple Sclerosis. CNS Drugs 34, 65–92 (2020). https://doi.org/10.1007/s40263-019-00691-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-019-00691-7

Search

Navigation