Teriflunomide for the Treatment of Multiple Sclerosis

Abstract

Several novel oral agents are emerging for use in multiple sclerosis (MS). Among these oral agents, teriflunomide is showing promise with respect to clinical efficacy and safety in relapsing MS patients. In this review, the authors clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing salient points on the use of teriflunomide in MS, with a discussion of teriflunomide's development, pharmacologic properties, preclinical and clinical trials, and safety and tolerability.

Keywords

teriflunomide - multiple sclerosis - clinical trials

• References

• 1 Marriott JJ, O'Connor PW. Emerging therapies in relapsing-remitting multiple sclerosis. Rev Recent Clin Trials 2010; 5 (3) 179-188
• 2 Osiri M, Shea B, Robinson V , et al. Leflunomide for treating rheumatoid arthritis. Cochrane Database Syst Rev 2003; (1) CD002047
• 3 Bartlett RR, Schleyerbach R. Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity—I. Disease modifying action on adjuvant arthritis of the rat. Int J Immunopharmacol 1985; 7 (1) 7-18
• 4 Korn T, Magnus T, Toyka K, Jung S. Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide—mechanisms independent of pyrimidine depletion. J Leukoc Biol 2004; 76 (5) 950-960
• 5 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) 299-303
• 6 Cherwinski HM, Cohn RG, Cheung P , et al. The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J Pharmacol Exp Ther 1995; 275 (2) 1043-1049
• 7 Fox RI, Herrmann ML, Frangou CG , et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol 1999; 93 (3) 198-208
• 8 Rückemann K, Fairbanks LD, Carrey EA , et al. Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. J Biol Chem 1998; 273 (34) 21682-21691
• 9 Herrmann ML, Schleyerbach R, Kirschbaum BJ. Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 2000; 47 (2-3) 273-289
• 10 Fairbanks LD, Bofill M, Ruckemann K, Simmonds HA. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. J Biol Chem 1995; 270 (50) 29682-29689
• 11 Elder RT, Xu X, Williams JW, Gong H, Finnegan A, Chong AS. The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. J Immunol 1997; 159 (1) 22-27
• 12 Korn T, Toyka K, Hartung HP, Jung S. Suppression of experimental autoimmune neuritis by leflunomide. Brain 2001; 124 (Pt 9) 1791-1802
• 13 Siemasko K, Chong AS, Jäck HM, Gong H, Williams JW, Finnegan A. Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. J Immunol 1998; 160 (4) 1581-1588
• 14 Xu X, Williams JW, Bremer EG, Finnegan A, Chong AS. Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J Biol Chem 1995; 270 (21) 12398-12403
• 15 Hoskin DW, Taylor RM, Makrigiannis AP, James H, Lee TD. Dose-dependent enhancing and inhibitory effects of A77 1726 (leflunomide) on cytotoxic T lymphocyte induction. Int J Immunopharmacol 1998; 20 (9) 505-513
• 16 Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol 1999; 162 (4) 2095-2102
• 17 González-Alvaro I, Ortiz AM, Domínguez-Jiménez C, Aragón-Bodi A, Díaz Sánchez B, Sánchez-Madrid F. Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway. Ann Rheum Dis 2009; 68 (10) 1644-1650
• 18 Mattar T, Kochhar K, Bartlett R, Bremer EG, Finnegan A. Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide. FEBS Lett 1993; 334 (2) 161-164
• 19 Manna SK, Mukhopadhyay A, Aggarwal BB. Leflunomide suppresses TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis. J Immunol 2000; 165 (10) 5962-5969
• 20 Hamilton LC, Vojnovic I, Warner TD. A771726, the active metabolite of leflunomide, directly inhibits the activity of cyclo-oxygenase-2 in vitro and in vivo in a substrate-sensitive manner. Br J Pharmacol 1999; 127 (7) 1589-1596
• 21 Jankovic V, Samardzic T, Stosic-Grujicic S, Popadic D, Trajkovic V. Cell-specific inhibition of inducible nitric oxide synthase activation by leflunomide. Cell Immunol 2000; 199 (2) 73-80
• 22 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 (9) 2730-2739
• 23 Layseca-Espinosa E, Pedraza-Alva G, Montiel JL , et al. T cell aggregation induced through CD43: intracellular signals and inhibition by the immunomodulatory drug leflunomide. J Leukoc Biol 2003; 74 (6) 1083-1093
• 24 Dimitrova P, Skapenko A, Herrmann ML, Schleyerbach R, Kalden JR, Schulze-Koops H. Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation. J Immunol 2002; 169 (6) 3392-3399
• 25 Déage V, Burger D, Dayer JM. Exposure of T lymphocytes to leflunomide but not to dexamethasone favors the production by monocytic cells of interleukin-1 receptor antagonist and the tissue-inhibitor of metalloproteinases-1 over that of interleukin-1beta and metalloproteinases. Eur Cytokine Netw 1998; 9 (4) 663-668
• 26 Cutolo M, Sulli A, Ghiorzo P, Pizzorni C, Craviotto C, Villaggio B. Anti-inflammatory effects of leflunomide on cultured synovial macrophages from patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62 (4) 297-302
• 27 Kraan MC, de Koster BM, Elferink JG, Post WJ, Breedveld FC, Tak PP. Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients. Arthritis Rheum 2000; 43 (7) 1488-1495
• 28 Kraan MC, Reece RJ, Barg EC , et al. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis Rheum 2000; 43 (8) 1820-1830
• 29 Fuentealba RA, Marasa J, Diamond MI, Piwnica-Worms D, Weihl CC. An aggregation sensing reporter identifies leflunomide and teriflunomide as polyglutamine aggregate inhibitors. Hum Mol Genet 2012; 21 (3) 664-680
• 30 Limsakun TM-VF. Pharmacokinetics of oral teriflunomide, a novel oral disease-modifying agent under investigation for the treatment of multiple sclerosis. In: Neurology. Minneapolis, MN: American Academy of Neurology; 2010
• 31 Tallantyre E, Evangelou N, Constantinescu CS. Spotlight on teriflunomide. Int MS J 2008; 15 (2) 62-68
• 32 Storch MK, Stefferl A, Brehm U , et al. Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 1998; 8 (4) 681-694
• 33 Weissert R, Wallström E, Storch MK , et al. MHC haplotype-dependent regulation of MOG-induced EAE in rats. J Clin Invest 1998; 102 (6) 1265-1273
• 34 Korn T, Mitsdoerffer M, Kuchroo VK. Immunological basis for the development of tissue inflammation and organ-specific autoimmunity in animal models of multiple sclerosis. Results Probl Cell Differ 2010; 51: 43-74
• 35 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 (1) 89-103
• 36 Styren SD, Barbier AJ, Selk DE, Wettstein JG. Beneficial effects of teriflunomide in experimental allergic encephalomyelitis. Abstract presented at: 34th Annual Meeting of the Society for Neuroscience; October 23–27, 2004; San Diego, CA
• 37 O'Connor PW, Li D, Freedman MS , et al; Teriflunomide Multiple Sclerosis Trial Group; University of British Columbia MS/MRI Research Group. A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 2006; 66 (6) 894-900
• 38 Confavreux C, Li DK, Freedman MS , 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) 1278-1289
• 39 Freedman MS, Wolinsky JS, Wamil B , et al; Teriflunomide Multiple Sclerosis Trial Group and the MRI Analysis Center. Teriflunomide added to interferon-β in relapsing multiple sclerosis: a randomized phase II trial. Neurology 2012; 78 (23) 1877-1885
• 40 Freedman MS WJ, Frangin GA, Confavreaux C , et al. Oral teriflunomide or placebo added to glatiramer acetate for 6 months in patients with relapsing multiple sclerosis: safety and efficacy results. In: Neurology. Minneapolis, MN: American Academy of Neurology; 2010
• 41 U.S. National Institutes of Health. Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta (TERACLES). Available at: http://clinicaltrials.gov/ct2/show/NCT01252355?term=teriflunomide&rank=3 . Accessed July 23, 2012
• 42 U.S. National Institutes of Health. Long Term Safety of Teriflunomide When Added to Interferon-Beta or Glatiramer Acetate in Patients With Multiple Sclerosis. Available at: http://clinicaltrials.gov/ct2/show/NCT00811395?term=teriflunomide&rank=4 . Accessed July 23, 2012
• 43 O'Connor P, Wolinsky JS, Confavreux C , et al; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365 (14) 1293-1303
• 44 U.S. National Institutes of Health. Long Term Safety and Efficacy Study of Teriflunomide 7 mg or 14 mg in Patients With Relapsing-Remitting Multiple Sclerosis. Available at: http://clinicaltrials.gov/ct2/show/NCT00803049?term=teriflunomide&rank=13 . Accessed July 23, 2012
• 45 Genzyme. Genzyme Reports Positive Top-Line Results of TOWER, a Pivotal Phase III Trial for AUBAGIOTM* (teriflunomide) in Relapsing Multiple Sclerosis. Available at: http://www.businesswire.com/news/home/20120531006926/en/Genzyme-Reports-Positive-Top-Line-Results-TOWER-Pivotal . Accessed July 23, 2012
• 46 Genzyme. Genzyme Reports Top-line Results for TENERE Study of Oral Teriflunomide in Relapsing Multiple Sclerosis. Available at: http://www.businesswire.com/news/home/20111219006550/en/Genzyme-Reports-Top-line-Results-TENERE-Study-Oral . Accessed July 23, 2012
• 47 U.S. National Institutes of Health. Phase III Study With Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC). Available at: http://clinicaltrials.gov/ct2/show/NCT00622700?term=TOPIC&rank=1 . Accessed July 23, 2012
• 48 Brent RL. Teratogen update: reproductive risks of leflunomide (Arava); a pyrimidine synthesis inhibitor: counseling women taking leflunomide before or during pregnancy and men taking leflunomide who are contemplating fathering a child. Teratology 2001; 63 (2) 106-112
• 49 Fukushima R, Kanamori S, Hirashiba M , et al. Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor leflunomide in mice. Reprod Toxicol 2007; 24 (3-4) 310-316
• 50 Chambers CD, Johnson DL, Robinson LK , et al; Organization of Teratology Information Specialists Collaborative Research Group. Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis Rheum 2010; 62 (5) 1494-1503
• 51 Cassina M, Johnson DL, Robinson LK , et al; Organization of Teratology Information Specialists Collaborative Research Group. Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis Rheum 2012; 64 (7) 2085-2094
• 52 White DH, Lynskey NV, Jones PB. Leflunomide use in New Zealand. A national prospective post-marketing study. Intern Med J 2009; 39 (2) 95-102
• 53 Warnatz K, Peter HH, Schumacher M , et al. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Ann Rheum Dis 2003; 62 (1) 50-57
• 54 Gold R, Wolinsky JS. Pathophysiology of multiple sclerosis and the place of teriflunomide. Acta Neurol Scand 2011; 124 (2) 75-84