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Current Neurology and Neuroscience Reports

Published in:

01-09-2010

Emerging Oral Therapies in Multiple Sclerosis

Authors: Devon Conway, Jeffrey A. Cohen

Published in: Current Neurology and Neuroscience Reports | Issue 5/2010

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The seven therapies currently approved by regulatory agencies are administered by subcutaneous or intramuscular injection or intravenous infusion. Many phase 2 trials involving oral MS therapeutics were recently completed, as were two phase 3 trials of fingolimod and one phase 3 trial of cladribine. Numerous other oral treatments are being investigated in ongoing phase 3 trials. Although an oral route of administration is attractive, these medications also present new challenges in balancing convenience, efficacy, and safety. In this review, we examine the safety and efficacy data from emerging oral therapies in an attempt to clarify their potential future role in the treatment of MS patients.

Klauer T, Zettl UK: Compliance, adherence, and the treatment of multiple sclerosis. J Neurol 2008, 255(Suppl 6):87–92.CrossRefPubMed

Conway D, Cohen JA: Combination therapy in multiple sclerosis. Lancet Neurol 2010, 9:299–308.CrossRefPubMed

Brinkmann V: Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 2007, 115:84–105.CrossRefPubMed

Kappos L, Antel J, Comi G, et al.: Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355:1124–1140.CrossRefPubMed

•• 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. This phase 3 trial of fingolimod demonstrated its superiority to placebo in preventing relapses and disability progression, as well as in various MRI measurements.CrossRefPubMed

•• Cohen JA, Barkhof F, Comi G, et al.: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010, 362:402–415. This phase 3 active-comparator trial showed fingolimod’s superiority to IFN-β-1a (IM) in preventing relapses, GdE lesions, and N/E T2 hyperintensities.CrossRefPubMed

Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS II). Available at http://www.clinicaltrials.gov/ct2/show/NCT00355134 NLM. Accessed February 2010.

Bartosik-Psujek H, Belniak E, Mitosek-Szewczyk K, et al.: Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine. Acta Neurol Scand 2004, 109:390–392.CrossRefPubMed

•• Giovannoni G, Comi G, Cook S, et al.: A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010, 362:416–426. This study, the only published trial of oral cladribine to date, demonstrated cladribine’s superiority to placebo in preventing relapses and decreasing risk of disability progression, and in several MRI measurements.CrossRefPubMed

10.

Phase II Cladribine Add-on to Inteferon-beta (IFN-b) Therapy in MS Subjects With Active Disease (ONWARD). Available at http://www.clinicaltrials.gov/ct2/show/NCT00436826. Accessed December 2009.

11.

Oral Cladribine in Early Multiple Sclerosis (MS) (ORACLE MS). Available at http://www.clinicaltrials.gov/ct2/show/NCT00725985. Accessed February 2010.

12.

Polman CH, Reingold SC, Edan G, et al.: Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria.” Ann Neurol 2005, 58:840–846.CrossRefPubMed

13.

Poser CM, Paty DW, Scheinberg L, et al.: New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983, 13:227–231.CrossRefPubMed

14.

Karussis DM, Lehmann D, Slavin S, et al.: Inhibition of acute, experimental autoimmune encephalomyelitis by the synthetic immunomodulator linomide. Ann Neurol 1993, 34:654–660.CrossRefPubMed

15.

Andersen O, Lycke J, Tollesson PO, et al.: Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology 1996, 47:895–900.PubMed

16.

Noseworthy JH, Wolinsky JS, Lublin FD, et al.: Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology 2000, 54:1726–1733.PubMed

17.

Yang JS, Xu LY, Xiao BG, et al.: Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol 2004, 156:3–9.CrossRefPubMed

18.

Polman C, Barkhof F, Sandberg-Wollheim M, et al.: Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 2005, 64:987–991.PubMed

19.

• Comi G, Pulizzi A, Rovaris M, et al.: Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008, 371:2085–2092. This is the largest clinical trial of laquinimod to date. It found that laquinimod was superior to placebo in reducing GdE lesions, but there was no significant improvement in clinical end points. Based on these results, two phase 3 trials of laquinimod are under way.CrossRefPubMed

20.

Safety and Efficacy of Orally Administered Laquinimod for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS) (ALLEGRO). Available at http://www.clinicaltrials.gov/ct2/show/NCT00509145. Accessed February 2010.

21.

BRAVO Study: Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon β-1a (Avonex). Available at http://www.clinicaltrials.gov/ct2/show/NCT00605215. Accessed February 2010.

22.

Venugopal R, Jaiswal AK: Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 1998, 17:3145–3156.CrossRefPubMed

23.

Wierinckx A, Breve J, Mercier D, et al.: Detoxication enzyme inducers modify cytokine production in rat mixed glial cells. J Neuroimmunol 2005, 166:132–143.CrossRefPubMed

24.

Schilling S, Goelz S, Linker R, et al.: Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 2006, 145:101–107.CrossRefPubMed

25.

• Kappos L, Gold R, Miller DH, 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, 372:1463–1472. In this study, the largest trial of oral fumarate to date, fumarate reduced GdE lesions, N/E T2 lesions, and T1 hypointensities compared with placebo.CrossRefPubMed

26.

Efficacy and Safety of Oral BG00012 in Relapsing-Remitting Multiple Sclerosis (DEFINE). Available at http://www.clinicaltrials.gov/ct2/show/NCT00420212. Accessed February 2010.

27.

Efficacy and Safety Study of Oral BG00012 With Active Reference in Relapsing-Remitting Multiple Sclerosis (CONFIRM). Available at http://www.clinicaltrials.gov/ct2/show/NCT00451451. Accessed February 2010.

28.

Zeyda M, Poglitsch M, Geyeregger R, et al.: Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Arthritis Rheum 2005, 52:2730–2739.CrossRefPubMed

29.

Styren S, Barbier A, Selk D, et al.: Beneficial Effects of Teriflunomide in Experimental Allergic Encephalomyelitis. Program no. 344.5. Washington, DC: Society for Neuroscience; 2004.

30.

• O’Connor PW, Li D, Freedman MS, et al.: A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006, 66:894–900. This phase 2 study enrolling 179 participants demonstrated teriflunomide’s superiority to placebo in reducing active MRI lesions and preventing disability progression. These promising results have prompted four phase 3 trials of teriflunomide.CrossRefPubMed

31.

Freedman MS, Wolinsky J, Byrnes W: Oral teriflunomide or placebo added to interferon beta for 6 months in patients with relapsing multiple sclerosis: safety and efficacy results. Presented at the European Committee for Treatment and Research in Multiple Sclerosis Annual Meeting. Dusseldorf, Germany: September 9–12, 2009.

32.

Chambers CD, Johnson DL, Robinson LK, et al.: Birth outcomes in pregnant women taking leflunomide. Arthritis Rheum 2010, 62(5):1494–1503.PubMed

33.

An Efficacy Study of Teriflunomide in Patients With Relapsing Multiple Sclerosis (TOWER). Available at http://www.clinicaltrials.gov/ct2/show/NCT00751881 NLM. Accessed February 2010.

34.

A Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis (TENERE). Available at http://www.clinicaltrials.gov/ct2/show/NCT00883337 NLM. Accessed December 2009.

35.

Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO). Available at http://www.clinicaltrials.gov/ct2/show/NCT00134563. Accessed February 2010.

36.

Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC). Available at http://www.clinicaltrials.gov/ct2/show/NCT00622700. Accessed February 2010.

37.

Yong VW, Power C, Forsyth P, Edwards DR: Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2001, 2:502–511.CrossRefPubMed

38.

Giuliani F, Metz LM, Wilson T, et al.: Additive effect of the combination of glatiramer acetate and minocycline in a model of MS. J Neuroimmunol 2005, 158:213–221.CrossRefPubMed

39.

Metz LM, Zhang Y, Yeung M, et al.: Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2004, 55:756.CrossRefPubMed

40.

Metz LM, Li D, Traboulsee A, et al.: Glatiramer acetate in combination with minocycline in patients with relapsing-remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler 2009, 15:1183–1194.CrossRefPubMed

41.

Minocycline in Clinically Isolated Syndromes (CIS). Available at http://www.clinicaltrials.gov/ct2/show/NCT00666887. Accessed February 2010.

42.

Minocycline as Add-on to Interferon-Beta-1a (Rebif®) in RRMS (RECYCLINE). Available at http://www.clinicaltrials.gov/ct2/show/NCT00381459. Accessed February 2010.

43.

Neuhaus O, Strasser-Fuchs S, Fazekas F, et al.: Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology 2002, 59:990–997.CrossRefPubMed

44.

Miron VE, Zehntner SP, Kuhlmann T, et al.: Statin therapy inhibits remyelination in the central nervous system. Am J Pathol 2009, 174:1880–1890.CrossRefPubMed

45.

Vollmer T, Key L, Durkalski V, et al.: Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004, 363:1607–1608.CrossRefPubMed

46.

Paul F, Waiczies S, Wuerfel J, et al.: Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis. PLoS One 2008, 3:e1928.CrossRefPubMed

47.

Birnbaum G, Cree B, Altafullah I, et al.: Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 2008, 71:1390–1395.CrossRefPubMed

48.

Waubant E, Pelletier D, Mass M, et al.: Atorvastatin reduces the risk of new brain MRI lesions in patients with clinically isolated syndrome (CIS) compared to placebo. Neurology 2010, 74:A294.

49.

Simvastatin as an Add-on Treatment to Interferon-beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis (SIMCOMBIN). Available at http://www.clinicaltrials.gov/ct2/show/NCT00492765. Accessed December 2009.

50.

Simvastatin as an Add-on Treatment to Copaxone for the Treatment of Relapsing Multiple Sclerosis. Available at http://www.clinicaltrials.gov/ct2/show/NCT00429442. Accessed February 2010.

Title: Emerging Oral Therapies in Multiple Sclerosis
Authors: Devon Conway
Jeffrey A. Cohen
Publication date: 01-09-2010
Publisher: Current Science Inc.
Published in: Current Neurology and Neuroscience Reports / Issue 5/2010
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI: https://doi.org/10.1007/s11910-010-0125-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Emerging Oral Therapies in Multiple Sclerosis

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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