Teriflunomide vs. Dimethyl Fumarate: Does Their Classification into Different Treatment Lines Have Merit?
Teriflunomide is one of the first-choice medications in the treatment of multiple sclerosis (MS) patients, not only in the Czech Republic. Conversely, the use of dimethyl fumarate is more limited here compared to other countries. Did the data from real-world clinical practice published this year actually demonstrate differences in the efficacy of both medications, and thus justify their classification?
Introduction
Reimbursement criteria in the Czech Republic classify oral teriflunomide as a first-line therapy for MS. The use of oral dimethyl fumarate is contingent upon the insufficient effectiveness of first-line treatment or high MS activity. Technically, dimethyl fumarate is thus classified as a higher-line treatment in our setting.
Teriflunomide
Teriflunomide belongs to the oral disease-modifying drugs (DMDs). This substance selectively inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), thereby blocking de novo pyrimidine synthesis, reducing lymphocyte proliferation, and subsequently altering their response to autoantigens. The effect of teriflunomide on T and B lymphocytes in the periphery is cytostatic but not cytotoxic.
Dimethyl Fumarate
The exact mechanism of action responsible for the therapeutic effect of dimethyl fumarate is not completely understood. However, it likely involves the activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway. This pathway is a crucial part of the response to cellular and metabolic stress, enhancing the expression of genes associated with antioxidant activity upon activation.
Study Population and Parameters
The objective of the multicenter observational study, which analyzed data from the Italian national registry, was to compare the efficacy and discontinuation rates of both modalities in patients with relapsing-remitting MS (RRMS). The primary parameters observed were the time to the first relapse and the time to confirmed disability progression. The discontinuation rate was a secondary parameter.
The study included adult patients up to 55 years old, diagnosed with RRMS based on the 2017 McDonald criteria, and who initiated treatment with teriflunomide or dimethyl fumarate between January 1, 2013, and December 31, 2017. This treatment had to last for at least 6 months.
Results
A total of 185 RRMS patients, whose first DMD was teriflunomide, and 498 patients starting with dimethyl fumarate were included in the study. Patients starting with teriflunomide had, on average, more previous relapses (2.3 vs. 1.9; p = 0.03) and higher scores on the Expanded Disability Status Scale (EDSS: 2.0 vs. 1.5; p = 0.01).
Nevertheless, no difference was observed between the two groups in the time to the first relapse (43.9 vs. 44.2 months; hazard ratio [HR] 1.004; confidence interval [CI] 0.980–1.029; p = 0.75), time to confirmed disability progression (38.9 vs. 50.7 months; HR 1.025; CI 0.880–1.066; p = 0.301), or time to treatment discontinuation (32.8 vs. 32.9 months; HR 1.049; CI 0.990–1.089; p = 0.973).
Conclusion
Both teriflunomide and dimethyl fumarate are oral medications intended for the treatment of MS. Worldwide, both are generally classified as first-line treatments or are considered foundational. This systemic setup is supported by the findings of the observational study, which demonstrated that both modalities have comparable efficacy in real-world clinical practice. The study results are consistent with findings from the Swedish registry, about which we reported last year.
(dos)
Sources:
1. Zanghì A., Avolio C., Amato M. P. et al. Real-world comparison of teriflunomide and dimethyl fumarate in naïve relapsing multiple sclerosis patients: evidence from the Italian MS register. Mult Scler Relat Disord 2022 Feb; 58: 103489, doi: 10.1016/j.msard.2022.103489.
2. Gold R., Wolinsky J. S. Pathophysiology of multiple sclerosis and the place of teriflunomide. Acta Neurol Scand 2011; 124 (2): 75–84, doi: 10.1111/j.1600-0404.2010.01444.x.
3. O'Connor P., Wolinsky J. S., Confavreux C. et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365 (14): 1293–1303, doi: 10.1056/NEJMoa1014656.
4. Scannevin R. H., Chollate S., Jung M. Y. et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 2012; 341 (1): 274–284, doi: 10.1124/jpet.111.190132.
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