Teriflunomide in the treatment of multiple sclerosis: Current evidence and future prospects

Therapeutic Advances in Neurological Disorders

Volumn 7, Issue 5, 2014, Pages 239-252

  Jo, Jiwon ^a   O'connor, Paul W ^a  

^a ST MICHAEL'S HOSPITAL   (Canada)

Author keywords

clinical trials; multiple sclerosis; review; teriflunomide

Indexed keywords

ALANINE AMINOTRANSFERASE; TERIFLUNOMIDE;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALOPECIA; ARTHRALGIA; BACKACHE; DIARRHEA; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; FOLLOW UP; HUMAN; LIMB PAIN; LIVER DYSFUNCTION; LIVER FUNCTION TEST; MULTICENTER STUDY (TOPIC); MULTIPLE SCLEROSIS; NAUSEA; NEUTROPENIA; PARESTHESIA; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PREGNANCY; REVIEW; RHABDOMYOLYSIS; SIDE EFFECT; TRIGEMINUS NEURALGIA;

EID: 84910042636     PISSN: 17562856     EISSN: 17562864     Source Type: Journal    
DOI: 10.1177/1756285614546855     Document Type: Review

References (40)

1. Bar-Or A. Freedman M.S. Kremenchutzky M. Menguy-Vacheron F. Bauer D. Jodl S. et al. (2013) Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. Neurology 81 (6): 552–8.
2. Bar-Or A. Larouche R. Legrand B. Miller B. Benamor M. Truffinet P. et al. (2013 b) Immune response to neoantigen and recall antigens in healthy subjects receiving teriflunomide. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October, Copenhagen.
3. Brent R. (2001) 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 63: 106–112.
4. Bruneau J.M. Yea C.M. Spinella-Jaegle S. Fudali C. Woodward K. Robson P.A. et al. Purification of human dihydro-orotate dehydrogenase and its inhibition by A 77 1726, the active metabolite of leflunomide. The Biochemical journal. 1998; 336 (Pt 2):299–303.
5. Cassina M. Johnson D.L. Robinson L.K. Braddock S.R. Xu R. Jimenez J.L. et al. (2012) Pregnancy outcome in women exposed to leflunomide before or during pregnancy. Arthritis and rheumatism 64 (7): 2085–94.
6. Chambers C.D. Johnson D.L. Robinson L.K. Braddock S.R. Xu R. Lopez-Jimenez J. et al. (2010) Birth outcomes in women who have taken leflunomide during pregnancy. Arthritis and rheumatism 62 (5): 1494–503.
7. Cherwinski H.M. Cohn R.G. Cheung P. Webster D.J. Xu Y.Z. Caulfield J.P. et al. (1995) The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. The Journal of pharmacology and experimental therapeutics 275 (2): 1043–9.
8. Confavreux C. Li D.K. Freedman M.S. 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. Multiple sclerosis (Houndmills, Basingstoke, England) 201.
9. Confavreux C. O'Connor P. Comi G. Freedman M.S. Miller A.E. Olsson T.P. et al. (2014) Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet neurology 13 (3): 247–56.
10. Davenport L. Czich A. Turpault S. (2013) Teriflunomide: no effects on sperm DNA. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October, Copenhagen.
11. Elder R. Xu X. Williams J. Gong H. Finnegan A. Chong A. (1997) The immunosuppressive metabolite of leflunomide, A 77 1726, affects murine T cells through two biochemical mechanisms. J Immunol 159: 22–27.
12. Fairbanks L. Bofill M. Ruckemann K. Simmonds H. (1995) 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 270: 29682–29689.
13. Fox R.I. Herrmann M.L. Frangou C.G. Wahl G.M. Morris R.E. Strand V. et al. (1999) Mechanism of action for leflunomide in rheumatoid arthritis. Clinical immunology (Orlando, Fla) 93 (3): 198–208.
14. Freedman M. Wolinsky J. Comi G. Kappos L. Olsson T. Miller A. et al. (2013) Long-term safety and efficacy of teriflunomide in patients with relapsing forms of multiple sclerosis in the TEMSO extension trial. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October, Copenhagen.
15. Freedman M. Wolinsky J. Frangin G. Confavreux C. Comi G. Byrnes W. et al. (2010) Oral teriflunomide or placebo added to glatiramer acetate for 6 months in patients with relapsing multiple sclerosis: safety and efficacy results. In: Proceedings of the 62nd Annual Meeting of the American Academy of Neurology, Toronto, abstract S21.001.
16. Freedman M.S. Wolinsky J.S. Wamil B. Confavreux C. Comi G. Kappos L. et al. (2012) Teriflunomide added to interferon-beta in relapsing multiple sclerosis: A randomized phase II trial. Neurology 78 (23): 1877–1885.
17. Fukushima R. Kanamori S. Hirashiba M. Hishikawa A. Muranaka R.I. Kaneto M. et al. (2007) Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice. Reproductive toxicology (Elmsford, NY) 24(3-4): 310–6.
18. Gold R. Wolinsky J. (2011) Pathophysiology of multiple sclerosis and the place of teriflunomide. Acta Neurol Scand 124: 75–84.
19. Hamilton L. Vojnovic I. Warner T. (1999) 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 127: 1589–1596.
20. Herrmann M. Schleyerbach R. Kirschbaum B. (2000) Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 47: 273–289.
21. Kieseier B. Stuve O. Benamor M. Delhay J. Truffinet P. (2013) Updated pregnancy outcomes from the teriflunomide clinical development programme: retrospective analysis of the teriflunomide clinical trial database. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October, Copenhagen.
22. Korn T. Magnus T. Toyka K. Jung S. (2004) Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide–mechanisms independent of pyrimidine depletion. J Leuk Biol 76: 950–960.
23. Korn T. Toyka K. Hartung H. Jung S. (2001) Suppression of experimental autoimmune neuritis by leflunomide. Brain 124: 1791–1802.
24. Leist T. Freedman M. Kappos L. Olsson T. Miller A. Wolinsky J. et al. (2013) Pooled safety data from three placebo-controlled teriflunomide studies. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October, Copenhagen.
25. Limsakun T. Menguy-Vacheron F. (2010) Pharmacokinetics of oral teriflunomide, a novel oral disease-modifying agent under investigation for the treatment of multiple sclerosis. In: Proceedings of the 62nd Annual Meeting of the American Academy of Neurology, Toronto, abstract P.05.032
26. Marriott J. O'Connor P. (2010) Emerging therapies in relapsing-remitting multiple sclerosis. Rev Recent Clin Trials 5: 179–188.
27. Mattar T. Kochhar K. Bartlett R. Bremer E. Finnegan A. (1993) Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide. FEBS Lett 334: 161–164.
28. Miller A. Wolinksy J. Kappos L. Comi G. Freedman M. Olsson T. et al. (2013) TOPIC main outcomes: efficacy and safety of once-daily oral teriflunomide in patients with clinically isolated syndrome. In: Proceedings of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October, Copenhagen.
29. O'Connor P.W. Li D. Freedman M.S. Bar-Or A. Rice G.P. Confavreux C. et al. (2006) A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology 66 (6): 894–900.
30. O'Connor P.W. Lublin F.D. Wolinsky J.S. Confavreux C. Comi G. Freedman M.S. et al. (2013) Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use. Journal of neurology 260 (10): 2472–80.
31. O'Connor P. Wolinsky J.S. Confavreux C. Comi G. Kappos L. Olsson T.P. et al. (2011) Randomized trial of oral teriflunomide for relapsing multiple sclerosis. The New England journal of medicine 365 (14): 1293–1303.
32. Osiri M. Shea B. Robinson V. Suarez-Almazor M. Strand V. Tugwell P. et al. (2003) Leflunomide for treating rheumatoid arthritis. Cochrane database of systematic reviews (Online) (1): CD002047.
33. Rahmlow M. Shuster E.A. Dominik J. Deen H.G. Jr. Dickson D.W. Aksamit A.J. Jr. et al. (2008) Leflunomide-associated progressive multifocal leukoencephalopathy. Archives of neurology 65 (11): 1538–9.
34. Ruckemann K. Fairbanks L.D. Carrey E.A. Hawrylowicz C.M. Richards D.F. Kirschbaum B. et al. (1998) Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. The Journal of biological chemistry 273 (34): 21682–91.
35. Sanofi (2012) Teriflunomide data on file at Sanofi, Sanofi S.A., Paris.
36. Siemasko K. Chong A. Jack H. Gong H. Williams J. Finnegan A. (1998) Inhibition of JAK3 and STAT 6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG 1 production. J Immunol 160: 1581–1588.
37. Tallantyre E. Evangelou N. Constantinescu C. (2008) Spotlight on teriflunomide. Int Mult Scler J 15: 6–68.
38. Vermersch P. Czlonkowska A. Grimaldi L.M. Confavreux C. Comi G. Kappos L. et al. (2014) Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Multiple sclerosis (Houndmills, Basingstoke, England) 20 (6): 705–16.
39. Warnatz K. Peter H.H. Schumacher M. Wiese L. Prasse A. Petschner F. et al. (2003) Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Annals of the rheumatic diseases 62 (1): 50–57.
40. White H. (1980) A heteroskedasticity consistent covariace matrix estimator and a direct test for heteroscedasticity. Econometrica 48: 817–830.