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Background: In the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported., Methods: All patients who entered the extension (N = 751) were assigned to teriflunomide 14 mg and assessed for long-term safety and efficacy., Results: Of 751 patients in the TOWER extension study, 253, 265, and 233 patients received placebo/teriflunomide 14 mg, teriflunomide 7 mg/14 mg, and teriflunomide 14 mg/14 mg, respectively. Median teriflunomide exposure was 4.25 years (maximum 6.3 years). The overall frequency of adverse events (AEs) was comparable across treatment groups, but a higher proportion of patients in the teriflunomide 7 mg/14 mg (12.4%) and 14 mg/14 mg (12.4%) groups had serious AEs compared with the placebo/teriflunomide 14 mg group (6.4%). Alanine aminotransferase increase and hair thinning occurred at a higher frequency in the placebo/teriflunomide 14 mg group (11.2% and 14.3%, respectively) compared with the teriflunomide 7 mg/14 mg (3.0% and 4.5%, respectively) and 14 mg/14 mg groups (5.2% and 4.3%, respectively). The incidences of AEs of interest (hematologic and hepatic effects, peripheral neuropathy, hypertension, and malignancy) were low and comparable across treatment arms. Disability worsening and adjusted annualized relapse rates were low and stable over time, and mean Expanded Disability Status Scale scores were unchanged over time, for all treatment groups., Conclusion: In the TOWER extension study, the efficacy of teriflunomide 14 mg was maintained in patients with RMS. No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile in the extension that was consistent with the core trial. These findings support the positive benefit:risk profile of teriflunomide as a long-term immunomodulatory therapy., (Copyright © 2020. Published by Elsevier B.V.)

Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.

Background: Two pivotal phase 3 teriflunomide studies provided data on relapses, fatigue, and health-related quality of life (HRQoL) in patients with relapsing forms of multiple sclerosis (MS)., Objectives: Using pooled data from the TEMSO (NCT00134563) and TOWER (NCT00751881) studies, we investigated the association between relapse severity, and changes from baseline to Week 108 in fatigue and HRQoL outcomes., Methods: Four definitions of relapse severity were applied in this analysis: sequelae post-relapse; relapse leading to hospitalization; relapse requiring intravenous corticosteroids; and intense relapse. We assessed the association between relapse severity and changes in Fatigue Impact Scale score (n=959), physical and mental health component summary scores from the Short Form (SF)-36 questionnaire (n=904), and SF-6D utility index scores (n=820)., Results: Irrespective of the definition of relapse severity applied, in patients experiencing severe relapse(s), fatigue was increased and HRQoL was decreased; these changes were statistically significant (p<0.0001), and were also clinically significant in many cases. The greatest worsening in fatigue and HRQoL was observed in patients with relapses leading to hospitalization., Conclusions: Given that severe relapses adversely affect patient-reported fatigue and HRQoL, prevention of severe relapses should be an important therapeutic aim in the treatment of patients with MS., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Teriflunomide, a once-daily oral immunomodulator for the treatment of relapsing-remitting multiple sclerosis, has demonstrated consistent efficacy on clinical and MRI parameters in clinical trials., Objective: To summarize the safety and tolerability profile of teriflunomide based on data from four placebo-controlled trials., Methods: Safety and tolerability were assessed using two teriflunomide clinical program data pools. Pool 1 contained 3044 patients randomized to teriflunomide (14 mg or 7 mg) or placebo in the core studies of one phase 2 trial and three phase 3 trials, with cumulative treatment exposure >1500 patient-years per group. Pool 2 comprised 2338 patients who received teriflunomide treatment in the above trials, including those continuing in extension studies, with a duration of treatment up to 12 years, representing >6800 patient-years. Safety assessments included adverse events, laboratory parameters, and physical examinations., Results: In Pool 1, the number of patients experiencing adverse events and serious adverse events was similar in the three treatment groups. Common events occurring in ≥ 10% of patients in either teriflunomide group, and with an incidence ≥ 2% compared with placebo, were alanine aminotransferase (ALT) increase, headache, diarrhea, hair thinning, and nausea. Overall, the nature of events observed in Pool 2 was similar to Pool 1. The majority of events in both pools were of mild-to-moderate intensity, were self-limiting, and infrequently resulted in discontinuation of therapy. The most common reason for treatment discontinuation in all treatment groups was ALT elevation, reflecting the protocol requirement to discontinue treatment on confirmation of ALT > 3 × the upper limit of normal., Conclusions: No new or unexpected safety signals beyond those detected in individual trials were identified in this pooled analysis with treatment duration exceeding 12 years and a cumulative exposure to teriflunomide exceeding 6800 patient-years. Overall, both doses of teriflunomide had consistent and manageable safety profiles., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

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 14 mg, or subcutaneous IFNβ-1a 44 µg. 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.

Multiple sclerosis (MS) relapses impose a substantial clinical and economic burden. Teriflunomide is a new oral disease-modifying therapy approved for the treatment of relapsing MS. We evaluated the effects of teriflunomide treatment on relapse-related neurological sequelae and healthcare resource use in a post hoc analysis of the Phase III TEMSO study. Confirmed relapses associated with neurological sequelae [defined by an increase in Expanded Disability Status Scale/Functional System (sequelae-EDSS/FS) ≥ 30 days post relapse or by the investigator (sequelae-investigator)] were analyzed in the modified intention-to-treat population (n = 1086). Relapses requiring hospitalization or intravenous (IV) corticosteroids, all hospitalizations, emergency medical facility visits (EMFV), and hospitalized nights for relapse were also assessed. Annualized rates were derived using a Poisson model with treatment, baseline EDSS strata, and region as covariates. Risks of sequelae and hospitalization per relapse were calculated as percentages and groups were compared with a χ(2) test. Compared with placebo, teriflunomide reduced annualized rates of relapses with sequelae-EDSS/FS [7 mg by 32 % (p = 0.0019); 14 mg by 36 % (p = 0.0011)] and sequelae-investigator [25 % (p = 0.071); 53 % (p < 0.0001)], relapses leading to hospitalization [36 % (p = 0.015); 59 % (p < 0.0001)], and relapses requiring IV corticosteroids [29 % (p = 0.001); 34 % (p = 0.0003)]. Teriflunomide-treated patients spent fewer nights in hospital for relapse (p < 0.01). Teriflunomide 14 mg also decreased annualized rates of all hospitalizations (p = 0.01) and EMFV (p = 0.004). The impact of teriflunomide on relapse-related neurological sequelae and relapses requiring healthcare resources may translate into reduced healthcare costs.

Objective: The purpose of this study was to determine the effects of oral teriflunomide on multiple sclerosis (MS) pathology inferred by magnetic resonance imaging (MRI)., Methods: Patients (n=1088) with relapsing MS were randomized to once-daily teriflunomide 7 mg or 14 mg, or placebo, for 108 weeks. MRI was recorded at baseline, 24, 48, 72 and 108 weeks. Annualized relapse rate and confirmed progression of disability (sustained ≥12 weeks) were the primary and key secondary outcomes. The principal MRI outcome was change in total lesion volume., Results: After 108 weeks, increase in total lesion volume was 67.4% (p=0.0003) and 39.4% (p=0.0317) lower in the 14 and 7 mg dose groups versus placebo. Other measures favoring teriflunomide were accumulated enhanced lesions, combined unique activity, T2-hyperintense and T1-hypointense component lesion volumes, white matter volume, and a composite MRI score; all were significant for teriflunomide 14 mg and most significant for 7 mg versus placebo., Conclusions: Teriflunomide provided benefits on brain MRI activity across multiple measures, with a dose effect evident on several markers. These effects were also consistent across selected subgroups of the study population. These findings complement clinical data showing significant teriflunomide-related reductions in relapse rate and disease progression, and demonstrate containment of MRI-defined disease progression.

Background: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients., Objective: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups., Methods: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately., Results: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance., Conclusion: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO.

Objective: To evaluate teriflunomide as add-on therapy to ongoing stable-dosed interferon-β (IFNβ) in patients with relapsing forms of multiple sclerosis (RMS)., Methods: A total of 118 patients with RMS were randomly assigned 1:1:1 to receive oral placebo or teriflunomide, 7 or 14 mg, once daily for 24 weeks; 86 patients entered the 24-week extension. The primary objective was to evaluate safety; secondary objectives were to evaluate the effects of treatment on disease activity assessed by MRI and relapse rate., Results: Teriflunomide was well tolerated with a low and similar incidence of treatment-emergent adverse events (TEAEs) across the 3 groups; TEAEs led to treatment discontinuation of 4.9%, 8.1%, and 7.9% of patients in the placebo, 7-mg, and 14-mg groups, respectively. The number of gadolinium-enhancing T1 (T1-Gd) lesions was reduced in both teriflunomide groups, with relative risk reductions (RRRs) of 84.6% (p = 0.0005) and 82.8% (p < 0.0001) for 7 and 14 mg, respectively, compared with IFNβ alone at 48 weeks. T1-Gd lesion volume was also reduced in the 7-mg group (RRR 72.1%, p = 0.1104) and 14-mg group (RRR 70.6%, p = 0.0154). A trend toward dose-dependent reduction in annualized relapse rate was also noted (RRRs 32.6% [p = 0.4355] and 57.9% [p = 0.1005] for 7 and 14 mg, respectively)., Conclusion: Teriflunomide as add-on therapy to IFNβ had acceptable safety and tolerability and reduced MRI disease activity compared with IFNβ alone., Classification of Evidence: This study provides Class II evidence that teriflunomide, 7 and 14 mg, added to IFNβ, is safe. The T1-Gd lesion burden was significantly reduced with both teriflunomide doses.

Background: Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis., Methods: We concluded a randomized trial involving 1088 patients with multiple sclerosis, 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years. Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks. The primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks., Results: Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P<0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P=0.08), and 20.2% with teriflunomide at 14 mg (P=0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI). Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase levels (≥1 times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred., Conclusions: Teriflunomide significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity, as compared with placebo. (Funded by Sanofi-Aventis; TEMSO ClinicalTrials.gov number, NCT00134563.).

Uptake and retrograde axonal transport of intravenously injected horseradish peroxidase (HRP) was studied during regeneration after a crush injury of the facial nerve of the mouse. The circulation time of HRP was 12 to 24 h. HRP injected immediately after the crush diffused into injured axons in the crushed region and accumulated subsequently in perikarya of facial neurons in the brain stem. After a time interval of 1 h or 5 days between the crush and the injection only a faint HRP accumulation occurred in a few facial neurons. After an interval of 7 days a moderate number of neurons had incorporated the tracer, while after more than 9 days the HRP activity in the regenerating neurons was more pronounced than in the contralateral neurons. Ultrastructurally, muscles of the vibrissae showed denervated subneural apparatuses 6 days after the crush. 8 days after the crush regenerating axon terminals containing small clusters of synaptic vesicles, dense cored vesicles and some HRP-labelled vesicles, were found over some gutters and after 10 to 13 days all examined gutters contained axon terminals with large numbers of synaptic vesicles and some HRP-containing vesicles. More than one axon terminal profile was seen in the same synaptic gutter. 32 and 64 days after the crush the neuromuscular junctions had regained a more mature appearance. The calibre spectra of the crushed facial nerves still showed a shift towards smaller diameters 134 days after the crush, at a time when a slight increase in HRP activity in the facial neurons persisted.