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Teriflunomide in the treatment of multiple sclerosis: Current evidence and future prospects

SAGE Publications Inc
Therapeutic Advances in Neurological Disorders
Authors:
Jiwon Oh at Johns Hopkins Medicine
Jiwon Oh
Paul W. O’Connor
Paul W. O’Connor
Paul W. O’Connor
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A number of novel oral agents are now approved for use in relapsing multiple sclerosis (MS). Among these agents, teriflunomide has shown promise with respect to clinical efficacy and safety in relapsing MS patients. In this review we aim to clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing relevant points on the use of teriflunomide in MS, with a discussion of teriflunomide's pharmacologic properties, pivotal clinical trials, and safety and tolerability.
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... As an oral immunomodulator, terif lunomide is approved for the treatment of multiple sclerosis (MS) [13]. It inhibits proliferation and reduces the number of activated T and B cells [14] by inhibiting dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in the synthesis of pyrimidines in rapidly proliferating cells, thereby decreasing the inflammatory response to antigens [15]. Teriflunomide can impair some cellular functions, including cell surface molecular expression, cytokine production, and cellular migration [16]. ...
... As the mechanism of action of terif lunomide differs from that of mogamulizumab, we can also use teriflunomide as an add-on therapy in patients with HAM/ TSP, as teriflunomide has immunomodulatory effects [15] and mogamulizumab is able to eliminate CCR4-expressing cells through antibody-dependent cellular cytotoxic effects [35]. Therefore, the concomitant use of teriflunomide with newly introduced drugs in the treatment of patients with HAM/TSP can prevent disease progression. ...
Safety and efficacy of teriflunomide on clinical course, and laboratory findings in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis: a triple-blind study
Article
Full-text available
  • May 2025
  • J NEUROL
Background HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the central nervous system (CNS). Teriflunomide is an oral agent developed for the treatment of multiple sclerosis (MS) by suppressing the proliferation of autoreactive lymphocytes. This study was conducted to evaluate the efficacy of teriflunomide in HAM/TSP patients in Northeast Iran. Methods This study was a triple-blind, randomized, placebo-controlled trial involving 22 patients with HAM/TSP. The intervention group (n = 11) received one tablet of teriflunomide (14 mg daily), while the control group (n = 11) received one placebo tablet for 12 months. Muscle strength, spasticity, motor disability, urinary disorders, walking speed, laboratory factors, and drug complications were examined during the study. Results In the intervention group, consumption of teriflunomide decreased the duration of walking according to the T25FW test (p = 0.01). The severity of OMDS disability also significantly decreased (P < 0.001). Additionally, the total score of UDS in the intervention group decreased. The levels of HTLV-1 proviral load significantly decreased (p = 0.003). No adverse effects were observed, and the increase in liver enzyme levels was tolerable and controllable. Conclusions Teriflunomide effectively reduced the proviral load, improved the severity of disability and walking speed, and better controlled urinary and constipation symptoms without any adverse effects. Therefore, teriflunomide can be considered a disease-modifying therapy for patients with HAM/TSP. However, further studies with a large number of patients and longer duration, along with the determination of specific HAM/TSP-associated biomarkers, are needed to validate the results of the present study. Trial registration IRCT20180618040127N3; November 19, 2021.
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... Based on the classification of current treatment methods for MS, disease-modifying therapy was analyzed from three angles: e-DMT, t-DMT, and I-DMT. Drugs developed based on conventional therapies, i.e., t-DMT, include the following 13 drugs in this paper: Dimethyl fumarate (DMF) [18][19][20][21][22], Teriflunomide [23][24][25], Interferon beta (IFN-β) [26,27], Glatiramer acetate [28,29], mitoxantrone [30,31], cladribine [32,33], diroximel fumarate (DRF) [34,35], Ozanimod [36,37], Oral Myelin [38,39], Nanocrystalline gold (CNM-AU8) [40], CS-0777 [41,42], Ibudilast [43,44], Vidofludimus (IMU-838) [45,46]. The drugs classified as part of the emerging disease treatment strategies for e-DMTs were the following 18: Ocrelizumab, Natalizumab, Fingolimod, natalizumab, alemtuzumab, rituximab, ofatumumab, Siponimod, daclizumab, Masitinib, Ublituximab, Evobrutinib, Tolebrutinib, Fenebrutinib, Orelabrutinib, The Venn diagram is a widely recognized visualization method to find the intersection content of different datasets. ...
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... It has an oral bioavailability of 100%, and peak levels are achieved within 2 h of intake. Due to known teratogenic effects in animal studies, strict contraception is recommended in all reproductive-age females, and males are advised not to father a child while on therapy due to possible seminal transmission (Vukusic et al., 2020;Kieseier and Benamor, 2014;Oh and O'Connor, 2014). ...
Disease modifying therapy and pregnancy outcomes in multiple sclerosis: A systematic review and meta-analysis
Article
  • Aug 2023
  • J NEUROIMMUNOL
Objectives: To report pregnancy outcomes among multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs). Methods: We performed a retrospective chart review of articles published from June 1996 to May 2023. Additional information was acquired from the drug registries of individual pharmaceutical companies. A comparison was also made with pregnancy data of the general population using the World Health Organization database. Summary analysis was achieved using R statistical software (v3.6), and the overall prevalence of outcomes was estimated using a random effects model. Results: A meta-analysis of 44 studies was conducted. Dimethyl fumarate had the highest prevalence of premature births at 0.6667% (SD:0.5236-0.7845). The highest rates of stillbirths and infant deaths (perinatal and neonatal) were observed with interferons at 0.004% (SD:0.001-0.010) and 0.009% (SD:0.005-0.0015), respectively. Cladribine had the majority of ectopic pregnancies (0.0234%, SD:0.0041-1217), while natalizumab had the highest prevalence of spontaneous abortions (0.1177%, SD:0.0931-0.1477) and live birth defects (0.0755%, SD:0.0643-0.0943).None of the outcomes were significantly different from those of the general population (p > 0.05), except ectopic pregnancy and spontaneous abortion (p < 0.001), where the odds were 0.665 (0.061-0.886) and 0.537(0.003-0.786), respectively. The pooled prevalence of MS relapses was 221% for a single episode (SD:0.001-0.714), 0.075% for more than one episode (SD:0.006-0.167), and 0.141% for at least one episode requiring steroids (SD:0.073-0.206) none of these reached clinical significance. Conclusion: Existing research suggests that DMT use in MS patients during pregnancy is generally considered safe. This study supports their utilization on a case-by-case basis. However, further primary research on this topic with clinical trials is warranted.
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... This medicine inhibits pyrimidines de novo synthesis in T lymphocytes and B lymphocytes as well as protein tyrosine kinases and cyclo-oxygenase-2, leading to the suppression of inflammatory responses to auto-antigens. This drug has shown modest activity in relapsing MS, comparable with other first-line agents with an acceptable safety profile [34]. ...
S1PR1 modulators in multiple sclerosis: Efficacy, safety, comparison, and chemical structure insights
Article
  • Feb 2023
Multiple sclerosis (MS) is a neurological disease that leads to severe physical and cognitive disabilities. Drugs used in the treatment of MS vary from small synthetic molecules to large macromolecules such as antibodies. Sphingosine 1-phosphate receptor modulators are frequently used for the treatment of MS. These medicines prevent the egress of lymphocytes from secondary lymphoid organs leading to immune system suppression. Currently, four S1PR modulators are on the market and several potential drug candidates are in clinical trials for the treatment of MS. These compounds differ in chemical structure, adverse effects, and efficacy points of view. The current article reviews the latest studies on S1PR1 modulators and compares them with other MS drugs in terms of efficacy, tolerability, and safety. A special focus was dedicated to discussing the structure-activity relationships of these compounds and performing a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to gain better insight into the ligand-receptor interaction mode.
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... Teriflunomide is a selective dihydroorotate dehydrogenase inhibitor interfering with DNA synthesis, targeting especially lymphocytes and thus potentially causing slight lymphopenia [58][59][60]. However, teriflunomide has not been associated with significant immunosuppression and phase III clinical trials did not indicate an increased risk for infections [59]. ...
Navigating the landscape of COVID-19 for Multiple Sclerosis patients and clinicians
Article
Full-text available
  • Feb 2023
The purpose of this literature review was to summarise relevant findings regarding the clinical management of multiple sclerosis (MS) in the COVID-19 pandemic, with the focus on patient risks, and the implications of disease-modifying treatment, both on COVID-19 severity and on the response to the SARS-CoV-2 vaccinations. Although MS per se does not seem to put patients at risk for more severe COVID-19, alongside the risk factors known to apply to the general population, progressive disease course, higher disability status, and B-cell depleting therapies may all negatively affect infection severity. The question of COVID-19 sequelae in patients with MS (pwMS) remains unresolved, challenging researchers to further explore this area. The safety profile of COVID-19 vaccinations in pwMS is similar to that of the general population. The efficacy of the vaccination might be affected by B-cell depletion, as well as by S1PR-modulating medications that attenuate humoral responses to the COVID-19 vaccination. Future research should focus on gathering evidence regarding the clinical course of MS following COVID-19 infection and vaccination in larger studies, as well as on establishing the safest and most efficient schedule of COVID-19 vaccination in pwMS on cell-depleting therapies.
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Optic Neuritis in the New Millennium
Article
  • Jun 2024
Optic neuritis (ON) is a common cause of acute visual loss due to optic neuropathy in adults. Although typical demyelinating ON usually recovers, some forms of autoimmune inflammatory ON may result in permanent disability. The relatively recent discovery of novel autoantibodies and their roles in the pathogenesis of ON, including aquaporin 4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody in MOG-associated disease (MOGAD) has led to paradigm shifts in both the acute and chronic management of ON. We performed a comprehensive literature review to assess current and upcoming perspectives on ON by searching for contemporary articles (from 2015 to 2024) for articles that reported updates in diagnostic tools and methods, such as antibody testing. This monograph reviews these recent advances in the evaluation and management of ON.
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Brain Health: Translating Scientific Evidence Into Clinical Practice in Multiple Sclerosis
Article
Full-text available
  • Jul 2016
Brain volume loss (BVL) progresses more rapidly in patients with multiple sclerosis (MS) than in healthy individuals, and brain atrophy begins early in the course of the disease. The objective of this symposium was to emphasise the importance of care and preservation of the brain within treatment protocols for MS so that early and appropriate management can be initiated to preserve brain volume and function. Prof Per Solberg Sørensen chaired the symposium and welcomed the speakers. Prof Heinz Wiendl gave a presentation on BVL in MS and described its underlying pathophysiology. Dr Andreas Lysandropoulos illustrated how information on BVL is clinically relevant and can be taken from clinical studies to assist clinical practice and decision-making. The final presentation was given by Prof Andrew Chan who highlighted the important role of brain atrophy in decision-making for early treatment and presented recent data for two treatments for MS: teriflunomide and the monoclonal antibody alemtuzumab. The symposium was concluded by a short question and answer session.
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Drug repurposing of ilepcimide that ameliorates experimental autoimmune encephalomyelitis via restricting inflammatory response and oxidative stress
Article
  • Nov 2022
  • TOXICOL APPL PHARM
Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that remains incurable. Herein, we demonstrated that ilepcimide (Antiepilepsirine), an antiepileptic drug used for decades, protects mice from experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Our studies found that ilepcimide treatment effectively ameliorates demyelination, blood-brain barrier leakage and infiltration of CD4⁺ and CD8⁺ T cells in EAE mice. On the one hand, ilepcimide can inhibit dihydroorotate dehydrogenase (DHODH), an important therapeutic target for MS. Computer molecular docking, thermal shift and fluorescence quenching assay demonstrated the directly interaction between ilepcimide and DHODH. Accordingly, ilepcimide observably repressed T cell proliferation in mixed lymphocyte reaction (MLR) assay and concanavalin A (Con-A) model in a DHODH-dependent manner. On the other hand, ilepcimide exhibited neuroprotective effect possibly through activating NRF2 antioxidant pathway in mouse neural crest-derived Neuro2a cells. Collectively, our findings have revealed the therapeutic potential of ilepcimide in EAE mouse model via restricting inflammatory response and oxidative stress, offering a potential opportunity for repurposing existing drug ilepcimide for MS therapy.
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Suppression of experimental autoimmune neuritis by leflunomide
Article
Full-text available
  • Sep 2001
  • BRAIN
Leflunomide is a new immunosuppressive drug whose active metabolite, A77 1726, impairs cellular nucleotide metabolism by inhibiting the dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme of de novo pyrimidine synthesis. Furthermore, A77 1726 suppresses tyrosine kinases involved in signal transduction pathways. We investigated the immunosuppressive effects of leflunomide in experimental autoimmune neuritis (EAN) in rats, which is a model of immune-mediated neuropathies. In EAN that was actively induced by subcutaneous injection of peripheral nerve myelin, leflunomide completely prevented paraparesis if applied orally from the day of immunization. Leflunomide was much more effective than azathioprine, which did not mitigate EAN at all. Even when leflunomide was administered therapeutically after the appearance of the first neuropathical signs, it halted the progression and markedly reduced the severity and duration of EAN. Inflammatory infiltrates, demyelination and axonal degeneration in sciatic nerve sections of leflunomide-treated EAN rats were strongly reduced. Leflunomide-treated rats did not mount autoantibodies as specified by ELISA (enzyme-linked immunosorbent assay) with a mixture of peripheral myelin proteins, including P2 and myelin basic protein. In EAN that was adoptively transferred by injection of neuritogenic cells of a P2-specific T-helper line, application of leflunomide also clearly reduced signs of disease. Additional injection of uridine did not neutralize the effect of leflunomide. Similarly, transfer of neuritogenic P2-specific T cells, which were activated in the presence of A77 1726 plus uridine in vitro , still resulted in reduced severity of adoptive transfer EAN in vivo , although proliferation of these cells in vitro was identical to that of control cells. The T-cell receptor-mediated in vitro activatability of a P2-specific T-cell hybridoma was diminished by high concentrations of A77 1726, as evidenced by reduced Ca2+ flux into the cytosol. Together with the findings in adoptive transfer EAN, this indicates that the antiproliferative effect is probably not the only mechanism of immunosuppressive action by leflunomide. In summary, leflunomide suppresses EAN efficiently and may constitute a promising therapy for immune-mediated neuropathies.
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Importance of Ribonucleotide Availability to Proliferating T-lymphocytes from Healthy Humans
Article
Full-text available
  • Dec 1995
Sensitive high performance liquid chromatography techniques, which differentiate between purine and pyrimidine ribonucleoside and deoxyribonucleoside triphosphates, were used to quantify pools in phytohemagglutinin-stimulated T-lymphocytes (98% CD4 and CD8) from healthy volunteers. The importance of de novo synthesis and salvage was evaluated by incubating the cells with C-radiolabeled precursors (40 μM), azaserine (20 μM; a glutamine antagonist), and ribavirin (50 μM; an IMP dehydrogenase inhibitor). We confirmed that resting T-lymphocytes meet their metabolic requirements by salvage. Noteworthy observations were as follows. First, nucleotide pool expansion over 72 h is disproportionate, with that for purines (ATP and GTP) being 2-fold compared with up to 8-fold for pyridine (NAD) or pyrimidine (UTP, UDP-Glc, and CTP) pools. This supports an additional role for the latter in membrane lipid biosynthesis, protein glycosylation, and strand break repair. Second, intact de novo pathways are essential for such expansion. Azaserine not only inhibited purine synthesis (confirmed by N-formylglycinamide polyphosphate accumulation), but also reduced expansion of pyrimidine and NAD pools by 70%. Ribavirin depleted GTP pools by 40% and reduced pyrimidine pool expansion by 40% at 72 h. These findings underline the importance of pyrimidine ribonucleotide availability as well as GTP synthesis de novo to proliferating T-lymphocytes. They also demonstrate an absence of coordinate regulation between de novo purine and pyrimidine biosynthesis.
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Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial
Article
Full-text available
  • Oct 2013
Background In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression. Objective This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNβ-1a). Methods Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14mg, or subcutaneous IFNβ-1a 44µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised. Results Some 324 patients were randomised (IFNβ-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNβ-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNβ-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings. Conclusion Effects on time to failure were comparable between teriflunomide and IFNβ-1a. There was no difference between teriflunomide 14 mg and IFNβ-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.
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The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms.
Article
  • Jul 1997
The immunosuppressive metabolite of leflunomide, A77 1726, inhibits the enzymatic activity of protein tyrosine kinases and of dihydro-orotic acid dehydrogenase, an enzyme involved in pyrimidine biosynthesis. Here murine CTLL cell lines were studied to determine which of the biochemical targets of A77 1726 was responsible for the observed inhibition of proliferation and cytotoxic activity. At low concentrations of A77 1726, pyrimidine biosynthesis is the target, since inhibition of proliferation correlates with a reduction in pyrimidine NTP levels and is reversed by uridine. At higher concentrations of A77 1726, uridine no longer reverses the inhibition of proliferation even though pyrimidine NTP levels are restored. This second mechanism for inhibiting proliferation is probably inhibition of protein tyrosine kinases, since these higher concentrations of A77 1726 inhibit IL-2-induced tyrosine phosphorylation of Jak1 and Jak3, the protein tyrosine kinases initiating signaling by the IL-2R. Tyrosine phosphorylation of the beta-chain of the IL-2R, which is required for IL-2-driven proliferation, is also inhibited by A77 1726. Cytotoxicity of a CTLL line that overexpresses the Lck protein tyrosine kinase is inhibited by A77 1726; this inhibition is not affected by uridine, but does correlate with inhibition of an Lck in vitro kinase reaction. These studies establish that inhibition of pyrimidine biosynthesis and that of protein tyrosine kinase both contribute to the effects of A77 1726 on CTLL cell lines.
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Inhibition of JAK3 and STAT6 Tyrosine Phosphorylation by the Immunosuppressive Drug Leflunomide Leads to a Block in IgG1 Production
Article
  • Feb 1998
Leflunomide is an immunosuppressive drug capable of inhibiting T and B cell responses in vivo. A number of studies demonstrate that leflunomide functions both as a pyrimidine synthesis inhibitor and as a tyrosine kinase inhibitor. We previously reported that leflunomide inhibits LPS-stimulated B cell proliferation, cell cycle progression, and IgM secretion. This inhibition can be reversed by the addition of exogenous uridine, suggesting that leflunomide functions as a pyrimidine synthesis inhibitor in B cells. We report here that while the addition of uridine restored proliferation and IgM secretion to leflunomide-treated LPS-stimulated B cells, as determined by metabolic labeling and immunoprecipitation, it did not completely restore secretion of IgG Ab. We hypothesized that leflunomide inhibits LPS-induced IgG secretion by inhibiting tyrosine kinase activity required for isotype switch. We tested this hypothesis in a well-defined model of isotype switch, LPS plus IL-4 induction of IgG1. Leflunomide inhibited IgG1 secretion in this model in a dose-dependent manner. The signal transduction pathway utilized by IL-4 to induce IgG1 involves tyrosine phosphorylation of the IL-4 receptor, JAK1, JAK3, and STAT6 proteins induced by IL-4 binding to the IL-4R. Leflunomide diminished the tyrosine phosphorylation of JAK3 and STAT6 in the absence or presence of uridine. In gel mobility shift studies, STAT6 binding to the STAT6 DNA binding site in the IgG1 promoter decreased in the presence of leflunomide or leflunomide plus uridine. Taken together, these data suggest that leflunomide acts as a tyrosine kinase inhibitor to block IgG1 production.
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Therapy and management of relapsing-remitting multiple sclerosis
Article
  • Jan 2015
In 2012, our expert group formulated treatment goals for the immunomodulatory therapy of relapsing-remitting MS (RRMS): the primary aim is the best achievable control of disease activity, as measured by the absence of clinical and MRI-detectable disease activity. Treatment of RRMS should therefore be initiated early with an effective medication. Prompt adaptation is required in the case of insufficient disease suppression. Accordingly, the sensitive clinical and MRI-based detection of disease activity is essential for individually optimized treatment decisions. In a second workshop in 2014, the expert group discussed criteria and procedures for the monitoring and management of RRMS patients. Relapse episodes should be detected by carefully taking patient history at regular neurologic visits. Changes in the disability status should be monitored clinically and supplemented by sensitive quantitative tools at least annually, or better in 6 months intervals. Monitoring should cover relevant functional systems, neurocognition, fatigue, and depression. MRI becomes increasingly important in providing early evidence of disease activity. It remains currently focused on the detection of new or enlarging lesions. Global brain atrophy cannot be reliably quantified in routine care to date. Patient- reported outcomes such as quality of life, personal goals and factors affecting life-style requirements should be represented in monitoring and treatment decisions. Standardized patient management systems can improve the consistency and benefit of long-term care. Cooperation in multi-sector and interdisciplinary networks with MS centers working as the hubs will also likely contribute to the quality of care.
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Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): A randomised, double-blind, placebo-controlled, phase 3 trial
Article
  • Mar 2014
  • LANCET NEUROL
Background Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing–remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis. Methods This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18–55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5·5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881. Findings Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0·50 [95% CI 0·43–0·58]) than in those assigned to teriflunomide 14 mg (0·32 [0·27–0·38]; p=0·0001) or teriflunomide 7 mg (0·39 [0·33–0·46]; p=0·0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0·68 [95% CI 0·47–1·00]; log-rank p=0·0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0·95 [0·68–1·35]; log-rank p=0·7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group). Interpretation Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis. Funding Genzyme, a Sanofi company.
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