Teriflunomide for the treatment of multiple sclerosis
Introduction
Immunomodulatory therapies of the first generation, including interferon beta and glatiramer acetate, represent the standard of care in relapsing-remitting MS [1]. Their main advantage is their established positive safety profile. However, the subcutaneous or intramuscular route of application and local adverse effects at the sites of injection may impair quality of life of and long-term acceptance by patients.
Thus, there is a need for new drugs for MS therapy. Natalizumab was the first drug of a second generation of immunotherapies agents, approved by FDA and EMA for highly active MS or MS refractory to first line treatment; recently this pathway was followed by fingolimod. Much has been learned from a managing point of view in the light of natalizumab, which has been specifically designed to target a critical step of leukocyte migration into areas of inflammation within the CNS [2], [3]. Phase III clinical trials have clearly shown its advantages: high efficacy and a maximum of compliance by intravenous monthly infusion [4], [5]. Immediately after completion of a phase III trail that led to its approval, safety issues, and most notably the risk of progressive multifocal leukoencephalopathy (PML), became apparent [6], [7], [8]. Restriction of natalizumab to patients with highly active MS or patients, not responding to first line treatment, was not congruent with the inclusion criteria of these studies but based on risk-benefit considerations [9], [10]. Interestingly, this safety issue is most likely not restricted to natalizumab but is also relevant for other currently investigated drugs of the second generation, including rituximab [11], [12].
Higher specificity in MS treatment seems to go along with an increased risk of potential life threatening infectious (e.g. risk of progressive multifocal leukoencephalopathy in natalizumab or rituximab) or autoimmune (e.g. risk of autoimmune thrombocytopenia and thyroid disease in alemtuzumab) side effects [13]. As MS is a disease of low mortality in a young population and treatment primarily seems to be effective in the early inflammatory state of disease when patients suffer only from a low grade of impairment/disability, the risk-benefit consideration is crucial. Although low, the risk of a potential life threatening complication in MS population demands critical patient selection for the above discussed second generation immunomodulatory agents and high standards of safety surveillance plans.
Thus, in parallel with the sophisticated immune-selective strategies, concepts of more general immunosuppression and immunomodulation have been tested in clinical trials. In the context of these studies, oral formulations are highly appreciated by patients, improving quality of life and increasing adherence to therapy [14], [15], [16]. Oral immunomodulatory or immunosuppressant drugs characterized by a maximum of compliance combined with a good safety-benefit ratio will likely become the third category of drugs available for MS treatment in the nearer future.
Section snippets
Teriflunomide and its mode of action
Teriflunomide is the active metabolite of leflunomide, an approved therapy for rheumatoid arthritis [17], [18], [19], [20]. The ability to noncompetitively and reversibly inhibit the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH), relevant for the de novo synthesis of pyrimidine, is believed to exert the most important therapeutic effect [21], [22], [23], [24]. By inhibiting DHODH and diminishing DNA synthesis, teriflunomide has a cytostatic effect on proliferating B and T cells [25]
Pharmacokinetics
Phase two clinical trials for leflunomide showed that teriflunomide is highly protein bound in plasma (99.3%) and has a low distribution volume. Its half-life is about two weeks in humans. It is cleared by hepatic metabolism and enterohepatic circulation can be prevented by cholestyramine decreasing the half-life of the drug to one or two days [36].
Teriflunomide inhibits the cytochrome p450 2C9 isoenzyme and thereby enhances the anticoagulant effect of wafarin or phenytoin [36]. Because its
Effects of teriflunomide on experimental allergic encephalomyelitis (EAE)
Studies in Experimental Allergic Encephalomyelitis (EAE) – an animal model of MS – showed the immunomodulatory potential of leflunomide and its active metabolite and proved both leflunomide and teriflunomide to be effective in ameliorating the disease course.
In one study, the effect on disease activity was investigated in a T helper cell type 1 cell-borne monophasic disease model induced in Lewis rats by adoptive transfer of myelin basic protein (MBP)-specific T line cells. In 12 Lewis rats
Study design
In 2006, the first randomized, double-blind, placebo-controlled phase II study to assess efficacy and safety of oral teriflunomide in MS-patients with relapses was published [41].
179 patients with relapsing-remitting MS (n = 157) or secondary progressive MS with relapses (n = 22) and an Expanded Disability Status Scale (EDSS) score of <6 were randomized to receive either placebo (n = 61), teriflunomide 7 mg/day (n = 61) or teriflunomide 14 mg/day (n = 57). Patients aged 18–65 years with clinically
Study design
Two Phase III studies investigated the effect of teriflunomide 7 and 14 mg/day versus placebo on clinical endpoints, the annualized relapse rate and the accumulation of disability measured in EDSS. The first published study is the so-called TEMSO (“TEriflunomide Multiple Sclerosis Oral”) study [60]: patients with relapsing MS were randomized to receive either 7 mg (n = 365), 14 mg (n = 358) teriflunomide or placebo (n = 363) over two years. The results of the second placebo-controlled study, TOWER
Perspective: teriflunomide and its potential role in the MS treatment arena
With the approval of teriflunomide by the FDA, EMA, and the authorities in Australia and Argentina teriflunomide is becoming an enlargement of our therapeutic armentarium. The FDA, based on the statistically significant results from TEMSO, approved 7 mg as well as 14 mg teriflunomide for the treatment of relapsing forms of MS; all other authorities, however, approved, so far, the higher dose only. This seems plausible given the higher efficacy of the 14 mg dose on clinical as well as MRI measures
Conflicts of interest
Dr Kieseier has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen Idec, Genzyme/Sanofi Aventis, Grifols, Merck Serono, Mitsubishi Europe, Novartis, Roche, Talecris, and TEVA. Dr. Warnke and Dr. Stuve have nothing to declare.
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A sensitive and selective electrochemical sensor based on molecularly imprinted polymer for the assay of teriflunomide
2022, TalantaCitation Excerpt :Then, 1H-pyrrole-3-carboxylic acid (10 mmol) was added to this mixture under stirring at R.T and stirred for 2 h. The remaining precipitate (pyrrole-Bt; (1H-benzo [d] [1–3]triazol-1-yl)(1H-pyrrol-3-yl)methanone) was filtered and washed with CH2Cl2 (2 × 50 mL). Then, pyrrole-Bt (5.52 mmol) in 1,4-dioxane (25 mL) was added dropwise to an aqueous solution of l-histidine (5.52 mmol in 1.0 M NaOH), and stirring was continued at 25 °C for 20 min.
Nose-to-brain delivery of teriflunomide-loaded lipid-based carbopol-gellan gum nanogel for glioma: Pharmacological and in vitro cytotoxicity studies
2021, International Journal of Biological MacromoleculesCitation Excerpt :TFM inhibits the transformation of dihydroorotate to orotate which leads to obstruction of the biosynthetic pathway of pyrimidine (de novo) in glioma cells [13,14]. Moreover, TFM blocks the proliferation of activated microglia, astrocytes, T and B-lymphocytes by hindering the synthesis of immune-modulating agents such as cytokines [2,15–17]. The previous investigations [18], proved that TFM produced a high risk of hepatotoxicity via oral administration and thereby oral delivery is not suitable for TFM administration [18,19].
Antiviral effects of selected IMPDH and DHODH inhibitors against foot and mouth disease virus
2019, Biomedicine and PharmacotherapyMechanism of action of three newly registered drugs for multiple sclerosis treatment
2017, Pharmacological ReportsCitation Excerpt :Leflunomide, first used for the treatment of another autoimmune disease, rheumatoid arthritis, converts into teriflunomide in a non-enzymatic manner in the plasma or gut mucosa [46]. It was decided to examine teriflunomide, as the main leflunomide active metabolite, in multiple sclerosis due to its anti-inflammatory properties, and also efficiency in the treatment of autoimmune based rheumatoid arthritis [47]. Teriflunomide is an inhibitor of the mitochondrial enzyme, dihydroorotate dehydrogenase (DHODH), which is the key enzyme for the de novo pyrimidine synthesis.
Update on treatments in multiple sclerosis
2015, Presse MedicaleCitation Excerpt :However, recent guidelines suggest that high titers of Nabs 12–24 months after initiating therapy should guide to a switch from IFNβ to another class of DMT, even in the absence of significant disease activity [70,71]. Teriflunomide is an oral DMT approved for the treatment of RR-MS [72]. As inhibitor of pyrimidine synthesis, teriflunomide is known to reduce the number of circulating leukocytes, but displays a relatively good safety profile [27].