New and Evolving Treatment Goals in Multiple Sclerosis – the Role of Teriflunomide

European Neurological Review, 2017;12(1):37–41 DOI: https://doi.org/10.17925/ENR.2017.12.01.37

Abstract:

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.
Keywords: Teriflunomide, immunotherapy, multiple sclerosis
Disclosure: 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.
Received: February 01, 2017 Accepted March 15, 2017
Correspondence: Patrick Vermersch, University of Lille, Department of Neurology, Hôpital Roger Salengro, 59037 Lille Cedex, France. E: patrick.vermersch@univ-lille2.fr
Open Access: 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

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Keywords: Teriflunomide, immunotherapy, multiple sclerosis