Teriflunomide as the gold standard in clinical trials in multiple sclerosis Review article
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Published:
Jun 30, 2022
Keywords:
multiple sclerosis, teriflunomide, clinical trial, comparator, placebo
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Abstract
Paper presents the selected features of teriflunomide that made it the most frequently chosen comparator in multiple sclerosis clinical trials. The amount of information acquired in the trials significantly strengthened the position of the drug as safe and providing reliable, comparable data. Paper briefly describes the development of clinical trials in multiple sclerosis. Food and Drug Administration approval of the first therapy influencing the long-term course of relapsing-remitting multiple sclerosis in 1993 undoubtedly become a milestone in the development of clinical trials. Research design assuming use of the placebo made a chance to demonstrate the drug’s potency. However, along with the registrations of new, effective and assessed with many parameters therapies, the placebo became gradually replaced with comparative drugs, initially injectable, then orally. From 2015 teriflunomide (dihydroorotate dehydrogenase inhibitor), once a day orally intaken, is the most commonly used comparator drug in clinical trials.
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References
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24. Ringheim GE, Wampole M, Oberoi K. Bruton’s Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures. Front Immunol. 2021; 12: 662223. http://doi.org/10.3389/fimmu.2021.662223.
25. Paik J. Teriflunomide: Pediatric First Approval. Paediatr Drugs. 2021; 23(6): 609-13. http://doi.org/10.1007/s40272-021-00471-1.
26. Gärtner J, Hauser SL, Bar-Or A et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II. Mult Scler. 2022; 28(10): 1562-75. http://doi.org/10.1177/13524585221078825.
27. Hauser SL, Bar-Or A, Cohen JA et al. ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383(6): 546-57. http://doi.org/10.1056/NEJMoa1917246.
28. Steinman L, Fox E, Hartung HP et al. ULTIMATE I and ULTIMATE II Investigators. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. 2022; 387(8): 704-14. http://doi.org/10.1056/NEJMoa2201904.
2. Pearce JM. Historical descriptions of multiple sclerosis. Eur Neurol. 2005; 54(1): 49-53. http://doi.org/10.1159/000087387.
3. Thompson AJ, Banwell BL, Barkhof F et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2): 162-73. http://doi.org/10.1016/S1474-4422(17)30470-2.
4. Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014; 27(3): 246-59. http://doi.org/10.1097/WCO.0000000000000096.
5. Ghezzi A. European and American Guidelines for Multiple Sclerosis Treatment. Neurol Ther. 2018; 7(2): 189-94. http://doi.org/10.1007/s40120-018-0112-1.
6. IFNB 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(4): 655.
7. Galetta SL, Markowitz C, Lee AG. Immunomodulatory agents for the treatment of relapsing multiple sclerosis: a systematic review. Arch Intern Med. 2002; 162(19): 2161-9. http://doi.org/10.1001/archinte.162.19.2161.
8. Hauser SL, Cree BAC. Treatment of Multiple Sclerosis: A Review. Am J Med. 2020; 133(12): 1380-90.e2. http://doi.org/10.1016/j.amjmed.2020.05.049.
9. Agencja Badań Medycznych. Słownik (access: 3.10.2022).
10. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014; 72(suppl 1): 1-5. http://doi.org/10.1159/000367614.
11. Sharma S, Mathur AG, Pradhan S et al. Fingolimod (FTY720): First approved oral therapy for multiple sclerosis. J Pharmacol Pharmacother. 2011; 2(1): 49-51. http://doi.org/10.4103/0976-500X.77118.
12. Genzyme. FDA approves Genzyme’s Aubagio® (teriflunomide), a once-daily, oral treatment for relapsing multiple sclerosis [media release]. 2012 (access: 3.10.2022).
13. Genzyme. Genzyme announces EMA accepts oral teriflunomide marketing application for treatment of multiple sclerosis [media release]. 2012 (access: 3.10.2022).
14. Foroughipour M, Gazeran S. Effectiveness and side effects of dimethyl fumarate in multiple sclerosis after 12 months of follow up: An Iranian clinical trial. Iran J Neurol. 2019; 18(4): 154-8.
15. Wray S, Bergh FT, Wundes A et al Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study. Adv Ther. 2022; 39(4): 1810-31. http://doi.org/10.1007/s12325-022-02068-7.
16. Kappos L, Fox RJ, Burcklen M et al. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial. JAMA Neurol. 2021; 78(5): 558-67. http://doi.org/10.1001/jamaneurol.2021.0405.
17. 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): 1293-303. http://doi.org/10.1056/NEJMoa1014656.
18. Confavreux C, O’Connor P, Comi G et al. TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double- blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014; 13(3): 247-56. http://doi.org/10.1016/S1474-4422(13)70308-9.
19. Comi G, Freedman MS, Meca-Lallana JE et al. Prior treatment status: impact on the efficacy and safety of teriflunomide in multiple sclerosis. BMC Neurol. 2020; 20(1): 364. http://doi.org/10.1186/s12883-020-01937-4.
20. Scott LJ. Teriflunomide: A Review in Relapsing-Remitting Multiple Sclerosis. Drugs. 2019; 79(8): 875-86. http://doi.org/10.1007/s40265-019-01135-8.
21. Miller AE. Teriflunomide in multiple sclerosis: an update. Neurodegener Dis Manag. 2017; 7(1): 9-29. http://doi.org/10.2217/nmt-2016-0029.
22. Zhang Y, Yin H, Zhang D et al. Real-world outcomes of teriflunomide in relapsing-remitting multiple sclerosis: a prospective cohort study. J Neurol. 2022; 269(9): 4808-16. http://doi.org/10.1007/s00415-022-11118-7.
23. 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.
24. Ringheim GE, Wampole M, Oberoi K. Bruton’s Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures. Front Immunol. 2021; 12: 662223. http://doi.org/10.3389/fimmu.2021.662223.
25. Paik J. Teriflunomide: Pediatric First Approval. Paediatr Drugs. 2021; 23(6): 609-13. http://doi.org/10.1007/s40272-021-00471-1.
26. Gärtner J, Hauser SL, Bar-Or A et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II. Mult Scler. 2022; 28(10): 1562-75. http://doi.org/10.1177/13524585221078825.
27. Hauser SL, Bar-Or A, Cohen JA et al. ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020; 383(6): 546-57. http://doi.org/10.1056/NEJMoa1917246.
28. Steinman L, Fox E, Hartung HP et al. ULTIMATE I and ULTIMATE II Investigators. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. 2022; 387(8): 704-14. http://doi.org/10.1056/NEJMoa2201904.