Teriflunomide is an oral immunotherapy agent that acts primarily as an inhibitor of dihydroorotate-dehydrogenase (DHODH), a key
mitochondrial enzyme involved in the synthesis of pyrimidines in rapidly proliferating cells such as T lymphocytes and B lymphocytes,
thus attenuating the inflammatory response to auto-antigens. The TEMSO and TOWER phase III clinical studies have demonstrated
the efficacy and safety of teriflunomide in the first-line treatment of patients with relapsing multiple sclerosis (MS), with long-term follow-up
data available up to 9 years. Teriflunomide has also been shown to decrease the risk of conversion to clinically definite MS (CDMS) in patients
with a first clinical sign of MS or risk of conversion to CDMS after a clinically isolated syndrome. In addition to reducing disability progression
and relapse rate, teriflunomide has also been found to decrease imaging activity and is associated with significant reductions in brain volume
loss. The convenience of administration of teriflunomide should establish its role within the growing number of treatment options for MS.
Patrick Vermersch has received honoraria and consulting fees from Biogen, Sanofi-Genzyme, Bayer, Novartis, Teva, Merck-Serono, Roche, Medday and Almirall. He has also received research support from Biogen, Bayer, Novartis, Sanofi-Genzyme, Roche and Merck-Serono. There were no publication fees associated with the publication of this article. Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Acknowledgements: Medical writing support was provided by Katrina Mountfort, Freelance Writer, and was supported by Touch Medical Media. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
February 01, 2017 Accepted
March 15, 2017
Patrick Vermersch, University of Lille, Department of Neurology, Hôpital Roger Salengro, 59037 Lille Cedex, France. E: email@example.com
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Multiple sclerosis (MS) is a chronic, progressive disease of the central nervous system (CNS), resulting from inflammatory lesions that become sites of demyelination and axonal injury. These lesions are associated with infiltrating T cells and monocytes, as well as B cells and plasma cells.1 Treatment of MS presents a challenge, since disease-modifying treatments (DMTs) must limit immune responses associated with disease initiation and propagation while also minimising any adverse effect on normal protective immune function. Enhanced understanding of the roles of T and B lymphocytes in the pathophysiology of relapsing MS have facilitated new approaches to managing MS with markedly improved efficacy.2,3 Treatment goals have changed: halting disability progression and promoting some degree of functional improvement are becoming achievable for many patients.3–5 The burden of treatment has also been decreased with the approval of a number of oral DMTs for relapsing-remitting MS (RRMS).6 Teriflunomide (Aubagio® Sanofi-Genzyme, Massachusetts, US) is an oral immunomodulatory agent that selectively targets T and B cells and has been approved both in the US and in Europe for the treatment of RRMS.7,8 This article will discuss the clinical evidence for the efficacy and safety of teriflunomide in MS, as well as clarifying the role of teriflunomide in the context of current and emerging MS treatment options.
Teriflunomide in the treatment of multiple sclerosis
Teriflunomide is the active metabolite of the parent drug, leflunomide, which has been in clinical use for many years as a treatment for rheumatoid arthritis.9 Following oral ingestion, leflunomide is rapidly converted almost entirely into teriflunomide. The latter has been found to have highly effective immunomodulatory and anti-inflammatory properties.7 Its precise effect of reducing T and B cells on the pathophysiology of MS has not been fully elucidated but is related to its action on the proliferation of activated lymphocytes. Teriflunomide selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase in de novo pyrimidine synthesis, halting cell division in cells such as autoreactive T- and B-lymphocytes in MS and limiting their involvement in the inflammatory processes underlying MS.10-15 Mean reductions of white blood cell counts of around 15% occur during the first 6 weeks of teriflunomide initiation and persist during treatment, although mean absolute counts remain within the normal range for most patients.18 A similar reduction has been reported for dimethyl fumarate (DMF).16 Cells that do not proliferate in response to activation, e.g. resting lymphocytes, can divide through homeostatic proliferation in which pyrimidines are synthesised by means of the salvage pathway.10,11 As a result of teriflunomide action, fewer autoreactive T- and B-lymphocytes cross the blood– brain barrier into the CNS but there is no apparent effect on the viability of stimulated T or B cells, a limited impact on lymphocyte activation and no direct effects on DNA.10,17,18
The impact of teriflunomide on adaptive immune cell subsets in humans was recently demonstrated in the TERI-DYNAMIC study:19 patients (n=39) with RRMS received teriflunomide 14 mg once daily for 24 weeks. From baseline to week 12 and week 24, the proportion of CD19+
B cells and absolute counts of Th1 cells decreased and the proportion of CD4+ cells versus CD8+ cytotoxic cells increased. Results also showed that teriflunomide decreases clonal diversity, which provides an immunomodulatory action without impairing immune function.19
Clinical evidence for the efficacy of teriflunomide
Two multicentre, multinational, randomised double-blind parallel-arm, placebo-controlled studies, TEMSO20 and TOWER,21 have examined the efficacy and safety of teriflunomide 14 mg and 7 mg/day in patients with MS. The study designs and baseline characteristics were similar in both trials; patients had relapsing MS, were between the ages of 18 and 55 years old, had Expanded Disability Status Scale (EDSS) scores ≤5.5, and at least two clinical relapses in the preceding 2 years, or at least one relapse in the previous year. Patients were randomised to teriflunomide 14 mg or 7 mg/day or placebo once daily for 108 weeks (Table 1). In the TEMSO and TOWER studies, compared with placebo, teriflunomide reduced the annualised relapse rate (ARR) relative risk by 32% (p<0.001) and 36% (p=0.0001), for 14 mg and 7 mg respectively. Results showed 29.8% (p=0.028) and 31.5% (p=0.044) relative risk reductions for 14 mg teriflunomide versus placebo for confirmed disability progression in the TEMSO and TOWER studies, respectively (Figure 1).20,21 In the TEMSO study, teriflunomide 14 mg treatment resulted in a 67.4% relative reduction in new T2 lesion volume (p<0.001)20,24 and an 80.4% reduction in the number of gadolinium (Gd)-enhancing T1 lesions per scan at week 108.24
Recently, long-term data from TEMSO has been released: no new or unexpected adverse events (AEs) occurred in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide.25
In the TOWER study extension, the improvement in disability progression has been sustained up to 5.5 years. A mean change in EDSS from baseline
of <0.15 points26 and the median EDSS was in the range 2.0–2.5 at all time points.27 Similar control of disability progression has also been observed in the TEMSO long-term extension study.28
1. McFarland HF, Martin R, Multiple sclerosis: a complicated picture of autoimmunity, Nat Immunol, 2007;8:913–9.
2. Oh J, O’Connor PW, Novel and imminently emerging treatments in relapsing-remitting multiple sclerosis, Curr Opin Neurol, 2015;28:230–6.
3. Sorensen PS, New management algorithms in multiple sclerosis, Curr Opin Neurol, 2014;27:246–59.
4. Feinstein A, Freeman J, Lo AC, Treatment of progressive multiple sclerosis: what works, what does not, and what is needed, Lancet Neurol, 2015;14:194–207.
5. Fox EJ, Rhoades RW, New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis, Curr Opin Neurol, 2012;25 Suppl:S11–9.
6. Marriott JJ, O’Connor PW, Emerging therapies in relapsingremitting multiple sclerosis, Rev Recent Clin Trials, 2010;5:179–88.
7. Genzyme Therapeutics, Aubagio, Summary of Product Characteristics. Available at: www.medicines.org.uk/emc/ medicine/28533 (accessed 14 March 2017).
8. Genzyme Corporation. US Prescribing Information. Available at: http://products.sanofi.us/aubagio/aubagio.pdf (accessed 14 March 2017).
9. Osiri M, Shea B, Robinson V, et al., Leflunomide for treating rheumatoid arthritis, Cochrane Database Syst Rev, 2003;CD002047.
10. Bar-Or A, Pachner A, Menguy-Vacheron F, et al., Teriflunomide and its mechanism of action in multiple sclerosis, Drugs, 2014;74:659–74.
11. Genc K, Dona DL, Reder AT, Increased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy, J Clin Invest, 1997;99:2664–71.
12. Gold R, Wolinsky JS, Pathophysiology of multiple sclerosis and the place of teriflunomide, Acta Neurol Scand, 2011;124:75–84.
13. Rawls J, Knecht W, Diekert K, et al., Requirements for the mitochondrial import and localization of dihydroorotate dehydrogenase, Eur J Biochem, 2000;267:2079–87.
14. Warnke C, Meyer zu Horste G, Hartung HP, et al., Review of teriflunomide and its potential in the treatment of multiple sclerosis, Neuropsychiatr Dis Treat, 2009;5:333–40.
15. Knecht W, Bergjohann U, Gonski S, et al., Functional expression of a fragment of human dihydroorotate dehydrogenase by means of the baculovirus expression vector system, and kinetic investigation of the purified recombinant enzyme, Eur J Biochem, 1996;240:292–301.
16. Gold R, Kappos L, Arnold DL, et al., Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis, N Engl J Med, 2012;367:1098–107.
17. Kaplan J, Cavalier S, Turpault S, Biodistribution of teriflunomide in naive rats vs rats with experimental autoimmune encephalomyelitis, Presented at: 31st Congress of the European Committee for Research in Multiple Sclerosis (ECTRIMS), Barcelona, Spain, 7–10 October 2015, P354.
18. Li L, Liu J, Delohery T, et al., The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro, J Neuroimmunol, 2013;265:82–90.
19. Wiendl H, Gross C, Lindman M, et al., TERI-DYNAMIC: exploring the impact of teriflunomide on immune cell population size, receptor repertoire, and function in patients with RRMS, Neurology, 2016;86:Suppl. P5.282.
20. O’Connor P, Wolinsky JS, Confavreux C, et al., Randomized trial of oral teriflunomide for relapsing multiple sclerosis, N Engl J Med, 2011;365:1293–303.
21. Confavreux C, O’Connor P, Comi G, et al., Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Neurol, 2014;13:247–56.
22. McDonald WI, Compston A, Edan G, et al., Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis, Ann Neurol, 2001;50:121–7.
23. Polman CH, Reingold SC, Edan G, et al., Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”, Ann Neurol, 2005;58:840–6.
24. Wolinsky JS, Narayana PA, Nelson F, et al., Magnetic resonance imaging outcomes from a phase III trial of teriflunomide, Mult Scler, 2013;19:1310–9.
25. O’Connor P, Comi G, Freedman MS, et al., Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study, Neurology, 2016;86:920–30.
26. Kappos LF, Freedman MS, Comi G, et al., Teriflunomide efficacy on annualized relapse rate and expanded disability status scale scores: 2.5-year follow-up in the TOWER extension study in patients with relapsing MS, Presented at: 31st Congress of the European Committee for Research in Multiple Sclerosis (ECTRIMS), Barcelona, Spain, 7–10 October 2015, P1099.
27. Genzyme - a Sanofi company, Cambridge, Massachusetts, United States. Data on file, 2015.
28. Freedman MS, Wollinsky J, Comi G, et al., Safety and efficacy of teriflunomide for up to 9 Years in relapsing forms of multiple sclerosis: update of the TEMSO extension trial, Neurology, 2014;82:Supplement P3.150.
29. Kappos L, Pooled efficacy data from two phase 3 placebocontrolled trials of oral, once-daily teriflunomide, Abstract 34098. Presented at: Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Copenhagen, Denmark, 2-5 October, 2013.
30. Miller AE, Wolinsky JS, Kappos L, et al., Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Neurol, 2014;13:977–86.
31. Cook RJ, Sackett DL, The number needed to treat: a clinically useful measure of treatment effect, BMJ, 1995;310:452–4.
32. Freedman MS, Montalban X, Miller AE, et al., Comparing outcomes from clinical studies of oral disease-modifying therapies (dimethyl fumarate, fingolimod, and teriflunomide) in relapsing MS: Assessing absolute differences using a number needed to treat analysis, Mult Scler Relat Disord, 2016;10:204–12.
33. Gold R, Kappos L, Arnold DL, et al., Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis, N Engl J Med, 2012;367:1098–107.
34. Fox RJ, Miller DH, Phillips JT, et al., Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis, N Engl J Med, 2012;367:1087–97.
35. Leist T, Freedman M, Miller A, et al., Assessing comparative outcomes from teriflunomide and dimethyl fumarate studies in relapsing MS: use of “number needed to treat” analysis, Neurology, 84:Suppl. P3.245.
36. O’Connor PW, Lublin FD, Wolinsky JS, et al., Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use, J Neurol, 2013;260:2472–80.
37. Wolinsky JS, Freedman MS, Thangavelu K, et al., Efficacy of teriflunomide treatment in achieving no evidence of disease activity in the TEMSO long-term extension study, Presented at: 31st Congress of the European Committee for Research in Multiple Sclerosis (ECTRIMS), Barcelona, Spain, 7–10 October 2015, P1047.
38. Coyle PK, LaGanke C, Khatri B, et al., Improvements in patient reported outcomes with teriflunomide: week 24 interim results from the US cohort of the Teri-PRO phase 4 study, Presented at: 31st Congress of the European Committee for Research in Multiple Sclerosis (ECTRIMS), Barcelona, Spain, 7–10 October 2015, P562.
39. Radue. E-W, Sprenger T, Gaetano L, et al., Teriflunomide slows brain volume loss in relapsing MS: a SIENA analysis of the TEMSO MRI dataset, Neurology, 2016;86:Suppl. P3.089.
40. Comi G, Freedman MS, Kappos L, et al., Effect of teriflunomide on lymphocyte and neutrophil counts: pooled analyses from four placebo-controlled studies, Presented at: Joint ECTRIMS– ACTRIMS Meeting, Boston, MA, USA, 10–13 September 2014, P060.
41. Comi G, Freedman MS, Kappos L, et al., Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions, Mult Scler Relat Disord, 2016;5:97–104.
42. Leist TP, Freedman M, Kappos L, et al., Pooled safety analyses from teriflunomide clinical studies, Neurology, 2015;84:Suppl. P7.268.
43. Singer B, Comi G, Miller A, et al., Teriflunomide Treatment Is Not Associated with Increased Risk of Infections: Pooled Data from the Teriflunomide Development Program, Neurology, 2014;82:Supple P2.194.
44. Kremenchutzky M, Freedman M, Bar-Or A, et al., 12-year clinical efficacy and safety data for teriflunomide: results from a Phase 2 extension study, Presented at: American Academy of Neurology (ANN) 67th Annual Meeting, Vancouver, BC, Canada, 23 April 2015, P7.223,
45. Bar-Or A, Freedman MS, Kremenchutzky M, et al., Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis, Neurology, 2013;81:552–8.
46. European Agency for the Evaluation of Medicinal Products (EMA) - Committee for Proprietary Medicinal Products (CPMP), Note for Guidance on Harmonization of Requirements for Influenza Vaccines, 1997. Available at: http://www.ema. europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003945.pdf
47. Kieseier BC, Benamor M, Pregnancy outcomes following maternal and paternal exposure to teriflunomide during treatment for relapsing-remitting multiple sclerosis, Neurol Ther, 2014;3:133–8.
48. Garcia-Enguidanos A, Calle ME, Valero J, et al., Risk factors in miscarriage: a review, Eur J Obstet Gynecol Reprod Biol, 2002;102:111–9.
49. Bar-Or A, Wiendl H, Miller B, et al., Randomized study of teriflunomide effects on immune responses to neoantigen and recall antigens, Neurol Neuroimmunol Neuroinflamm, 2015;2:e70.