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CNS Drugs
Erschienen in: CNS Drugs 1/2011

01.01.2011 | Review Article

Oral Therapies for Multiple Sclerosis

A Review of Agents in Phase III Development or Recently Approved

verfasst von: Prof. Ralf Gold

Erschienen in: CNS Drugs | Ausgabe 1/2011

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Abstract

Several disease-modifying therapies are approved for the management of multiple sclerosis (MS). While reasonably effective, these therapies require long-term parenteral self-injection, which is inconvenient for some patients and can be associated with injection-related adverse effects. Consequently, there is a need in MS for an oral therapy option. Currently, five oral therapies are in phase III development or have recently been approved for the treatment of relapsing-remitting MS: cladribine (approved in Russia and Australia), fingolimod (approved in the US and Russia), BG-12 (phase III), laquinimod (phase III) and teriflunomide (phase III). While the availability of oral therapies has been much anticipated by physicians and patients, neurologists will need to be cautious in selecting such therapy, which may appear to have efficacy and convenience advantages versus current therapies, but may also carry novel safety and tolerability concerns. The decision to use these new therapies will most likely be based on an overall assessment of efficacy, safety, tolerability and adherence, the potential need for monitoring and cost effectiveness.
The objective of this article is to review the currently available data for each of these new oral therapies, which addresses the mechanism of action, efficacy and safety, and to provide a perspective on the potential future role of these therapies within clinical practice. Although better patient compliance is expected with the oral agents compared with the injectables, the safety profiles of these new oral drugs will have to be watched carefully.
Literatur
1.
Vosoughi R, Freedman MS. Therapy of MS. Clin Neurol Neurosurg 2010; 112: 365–85PubMed
2.
Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence 2010; 4: 1–9PubMedPubMedCentral
3.
Brandes DW, Callender T, Lathi E, et al. A review of disease-modifying therapies for MS: maximizing adherence and minimizing adverse events. Curr Med Res Opin 2009; 25: 77–92PubMed
4.
Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol 2009; 256: 568–76PubMed
5.
Soos N, Shakery K, Mrowietz U. Localized panniculitis and subsequent lipoatrophy with subcutaneous glatiramer acetate (Copaxone) injection for the treatment of multiple sclerosis. Am J Clin Dermatol 2004; 5: 357–9PubMed
6.
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: 416–26PubMed
7.
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: 387–401PubMed
8.
Cohen J, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–15PubMed
9.
O’Connor P, Wolinsky J, Confavreux C, et al. A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: clinical efficacy and safety outcomes [abstract]. Mult Scler 2010; 16: S23.79
10.
Sipe JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005; 5: 721–7PubMed
11.
Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992; 340: 952–6
12.
Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994; 344: 9–13PubMed
13.
Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996; 93: 1716–20PubMedPubMedCentral
14.
Romine JS, Sipe JC, Koziol JA, et al. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999; 111: 35–44PubMed
15.
Filippi M, Rovaris M, Iannucci G, et al. Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology 2000; 55: 1714–8PubMed
16.
Filippi M, Rovaris M, Rice GP, et al. The effect of cladribine on T(1) ‘black hole’ changes in progressive MS. J Neurol Sci 2000; 176: 42–4PubMed
17.
Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000; 54: 1145–55PubMed
18.
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: 1463–72PubMed
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: 2085–92PubMed
20.
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: 894–900PubMed
21.
The IFN-beta Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655–61
22.
Jacobs LD, Cookfair DL, Rudick RA, et al., for the Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-la for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94PubMed
23.
Comi G, Abramsky O, Arbizu T, et al., for the LAQ/5062 Clinical Advisory Board and Study Group. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 9-month double-blind active extension of the multiple-center, randomized, double-blind, parallel-group placebo-controlled study [abstract no. P31]. Mult Scler 2008; 14(1 Suppl. ): S37–8
24.
Leustatin® (cladribine): US prescribing information. Raritan (NJ): Centocor Ortho Biotech, 2007
25.
Montillo M, Tedeschi A, O’Brien S, et al. Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia. Cancer 2003; 97: 114–20PubMed
26.
Astrom K, Mancall EL, Richardson EP. Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain 1958; 81: 93–111PubMed
27.
Brinkmann V. FTY720: mechanism of action and potential benefit in organ transplantation. Yonsei Med J 2004; 45: 991–7PubMed
28.
Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004; 427: 355–60PubMed
29.
Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005; 23: 127–59PubMed
30.
Yopp AC, Fu S, Honig SM, et al. FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments. J Immunol 2004; 173: 855–65PubMed
31.
Fujino M, Funeshima N, Kitazawa Y, et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003; 305: 70–7PubMed
32.
Rausch M, Hiestand P, Foster CA, et al. Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J Magn Reson Imaging 2004; 20: 16–24PubMed
33.
Webb M, Tham CS, Lin FF, et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 2004; 153: 108–21PubMed
34.
Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453–7PubMed
35.
Haghikia A, Gold R. The impact of fingolimod (FTY720) in neuroimmunologic diseases: mechanisms beyond immunomodulation. Am J Pathol 2010; 176: 2599–601PubMedPubMedCentral
36.
Bernard F, Sablone M, Sansig G, et al. Oral fingolimod (FTY720) inhibits ongoing CNS autoimmunity and promotes recovery in mice with chronic experimental autoimmune encephalomyelitis [abstract no. P228]. Mult Scler 2009; 15 Suppl. 2: S58
37.
Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355: 1124–40PubMed
38.
O’Connor P, Comi G, Montalban X, et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009; 72: 73–9PubMed
39.
Comi G, O’Connor P, Montalban X, et al., for the FTY720D2201 Study Group. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult Scler 2010; 16: 197–207PubMed
40.
Kieseier BC, Wiendl H, Hartung HP, et al. The future of multiple sclerosis therapy. Pharmacol Res 2009; 60: 207–11PubMed
41.
Seabrook TJ, Smith P, Schweitzer A, et al. Efficacy of the selective S1P 1/5 modulator, BAF312, in established experimental autoimmune encephalomyelitis and redistribution of S1P 1 and S1P5 in the inflamed human CNS tissue [poster no. P858]. 26th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis; 2010 Oct 13–16; Gothenburg
42.
Kasper LH, Due BR, ONO-4641 Study Group. A phase I study to evaluate safety, tolerability and pharmacological properties of a selective sphingosine-1-phosphate (S1P) receptor agonist ONO-4641 in patients with multiple sclerosis [poster no. P991]. 26th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis; 2010 Oct 13–16; Gothenburg
43.
Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci 2008; 29: 558–65PubMed
44.
Nayak L, Henchcliffe C. Rasagiline in treatment of Parkinson’s disease. Neuropsychiatr Dis Treat 2008; 4: 11–20
45.
Carlson NG, Rose JW. Antioxidants in multiple sclerosis: do they have a role in therapy? CNS Drugs 2006; 20: 433–41PubMed
46.
Gasperini C, Ruggieri S. New oral drugs for multiple sclerosis. Neurol Sci 2009; 30 Suppl. 2: S179–83PubMed
47.
Osburn WO, Kensler TW. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res 2008; 659: 31–9PubMed
48.
Harveya CJ, Thimmulappaa RK, Singha A, et al. Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radic Biol Med 2009; 46: 443–53
49.
Khor T, Huang M, Kwon K, et al. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 2006; 66: 11580–4PubMed
50.
Lee JM, Calkins MJ, Chan K, et al. Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 2003; 278: 12029–38PubMed
51.
Lee JM, Shih AY, Murphy TH, et al. NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J Biol Chem 2003; 278: 37948–56PubMed
52.
Johnson JA, Johnson DA, Kraft AD, et al. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci 2008; 1147: 61–9PubMedPubMedCentral
53.
Shih AY, Imbeault S, Barakauskas V, et al. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem 2005; 280: 22925–36PubMed
54.
Lukashev M, Zeng W, Goelz S, et al. Activation of Nrf2 and modulation of disease progression in EAE models by BG-12 (dimethyl fumarate) suggests a novel mechanism of action combining anti-inflammatory and neuroprotective modalities [abstract no. P503]. Mult Scler 2007; 13(2 Suppl. ): S149
55.
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: 101–7PubMedPubMedCentral
56.
Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 2006; 13: 604–10PubMed
57.
MacManus DG, Miller DH, Kappos L, et al. The effect of BG00012 on conversion of gadolinium-enhancing lesions to T1-hypointense lesions [abstract no. P459]. Mult Scler 2008; 14 Suppl. 2: S163
58.
Hoefnagel JJ, Thio HB, Willemze R, et al. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol 2003; 149: 363–9PubMed
59.
Nast A, Kopp I, Augustin M, et al. German evidence-based guidelines for the treatment of psoriasis vulgaris (short version). Arch Dermatol Res 2007; 299: 111–38PubMedPubMedCentral
60.
Andersen O, Lycke J, Tollesson PO, et al. Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis. Neurology 1996; 47: 895–900PubMed
61.
Karussis DM, Meiner Z, Lehmann D, et al. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology 1996; 47: 341–6PubMed
62.
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: 1726–33PubMed
63.
Brunmark C, Runstrom A, Ohlsson L, et al. The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis. J Neuroimmunol 2002; 130: 163–72PubMed
64.
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: 3–9PubMed
65.
Linker RA, Thöne J, Comi G, et al. Laquinimod induces up-regulation of neurotrophins in serum of patients with relapsing-remitting multiple sclerosis [abstract no. P783]. Mult Scler 2009; 15(9 Suppl. 2): S237
66.
Wegner C, Stadelmann C, Kaye J, et al. Laquinimod reduces inflammation, demyelination and axonal damage in experimental autoimmune encephalomyelitis [poster no. P836]. 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; 2007 Oct 11–14; Prague
67.
Runström A, Leanderson T, Ohlsson L, et al. Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-beta k.o. and wild type mice. J Neuroimmunol 2006; 173: 69–78PubMed
68.
Polman C, Barkhof F, Sandberg-Wollheim M, et al. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 2005; 64: 987–91PubMed
69.
Korn T, Toyka K, Hartung HP, et al. Suppression of experimental autoimmune neuritis by leflunomide. Brain 2001; 124 (Pt 9): 1791–802PubMed
70.
Korn T, Magnus T, Toyka K, et al. Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide: mechanisms independent of pyrimidine depletion. J Leukoc Biol 2004; 76: 50–60
71.
Bruneau JM, Yea CM, Spinella-Jaegle S, et al. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide. Biochem J 1998; 336 (Pt 2): 299–303PubMedPubMedCentral
72.
Cherwinski HM, Cohn RG, Cheung P, et al. The immuno-suppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J Pharmacol Exp Ther 1995; 275: 1043–9PubMed
73.
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: 2730–9PubMed
74.
Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol 1999; 162: 2095–102PubMed
75.
Merrill JE, Hanak S, Pu SF, et al. Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis. J Neurol 2009; 256: 89–103PubMed
76.
Sormani MP. The Will Rogers phenomenon: the effect of different diagnostic criteria. J Neurol Sci 2009; 287 Suppl. 1: S46–9PubMed
77.
Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Saf 2009; 32(12): 1123–34PubMed
Metadaten
Titel
Oral Therapies for Multiple Sclerosis
A Review of Agents in Phase III Development or Recently Approved
verfasst von
Prof. Ralf Gold
Publikationsdatum
01.01.2011
Verlag
Springer International Publishing
Erschienen in
CNS Drugs / Ausgabe 1/2011
Print ISSN: 1172-7047
Elektronische ISSN: 1179-1934
DOI
https://doi.org/10.2165/11539820-000000000-00000

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