The efficacy of teriflunomide in patients who received prior disease-modifying treatments: Subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies.

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.

Multiple sclerosis relapses are associated with increased fatigue and reduced health-related quality of life - A post hoc analysis of the TEMSO and TOWER studies.

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.

Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions.

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.

Canadian Expert Panel Recommendations for MRI Use in MS Diagnosis and Monitoring.

BACKGROUND: A definitive diagnosis of multiple sclerosis (MS), as distinct from a clinically isolated syndrome, requires one of two conditions: a second clinical attack or particular magnetic resonance imaging (MRI) findings as defined by the McDonald criteria. MRI is also important after a diagnosis is made as a means of monitoring subclinical disease activity. While a standardized protocol for diagnostic and follow-up MRI has been developed by the Consortium of Multiple Sclerosis Centres, acceptance and implementation in Canada have been suboptimal. METHODS: To improve diagnosis, monitoring, and management of a clinically isolated syndrome and MS, a Canadian expert panel created consensus recommendations about the appropriate application of the 2010 McDonald criteria in routine practice, strategies to improve adherence to the standardized Consortium of Multiple Sclerosis Centres MRI protocol, and methods for ensuring effective communication among health care practitioners, in particular referring physicians, neurologists, and radiologists. RESULTS: This article presents eight consensus statements developed by the expert panel, along with the rationale underlying the recommendations and commentaries on how to prioritize resource use within the Canadian healthcare system. CONCLUSIONS: The expert panel calls on neurologists and radiologists in Canada to incorporate the McDonald criteria, the Consortium of Multiple Sclerosis Centres MRI protocol, and other guidance given in this consensus presentation into their practices. By improving communication and general awareness of best practices for MRI use in MS diagnosis and monitoring, we can improve patient care across Canada by providing timely diagnosis, informed management decisions, and better continuity of care.

Novel and imminently emerging treatments in relapsing-remitting multiple sclerosis.

PURPOSE OF REVIEW: To summarize mechanisms of action, efficacy, and safety of novel and imminently emerging disease-modifying treatments (DMTs) intended to be used in relapsing-remitting multiple sclerosis (RRMS). RECENT FINDINGS: Novel and imminently emerging DMTs for the treatment of RRMS include alemtuzumab, daclizumab, ocrelizumab, pegylated interferon-ß-1a, and three times weekly glatiramer acetate. These DMTs have substantially different mechanisms of action, efficacy, and safety and tolerability profiles, which are summarized concisely in this article. SUMMARY: The treatment landscape of RRMS is evolving rapidly as the available treatment options have doubled in recent years, and a number of novel DMTs will likely become available in the near future. Choosing the optimal DMT for patients is becoming an increasingly complex process, and the care of patients with MS will likely require regular input from neurologists subspecializing in the care of patients with MS. As the use of novel DMTs with unknown long-term safety profiles increases, postmarketing surveillance and vigilance with regards to safety monitoring will be essential to confirm the safety and clinical efficacy of these DMTs for patients with RRMS.

Established disease-modifying treatments in relapsing-remitting multiple sclerosis.

PURPOSE OF REVIEW: The purpose of this review is to summarize mechanisms of action, efficacy and safety of established disease-modifying treatments (DMTs) that have been widely approved for use in relapsing-remitting multiple sclerosis (RRMS). RECENT FINDINGS: Established and widely used DMTs for the treatment of RRMS include the interferon-ß agents, glatiramer acetate, natalizumab, fingolimod, teriflunomide and dimethyl fumarate. These DMTs have quite different mechanisms of action, efficacy and safety and tolerability profiles, which are summarized concisely in the article below. SUMMARY: The treatment algorithm for RRMS is becoming increasingly complex with the ever-expanding armamentarium of DMTs. The choice of DMT will become an increasingly individual decision, based on a number of factors, including disease activity and severity, safety/tolerability profile and patient preference. Neurologists treating patients with multiple sclerosis (MS) will need a thorough knowledge of efficacy, safety and tolerability of the spectrum of DMTs available for treatment of RRMS to provide comprehensive clinical care.

Multiple sclerosis in 2014. Progress in MS--classification, mechanisms and treatment.

Scientific progress in multiple sclerosis (MS) research spanned a number of areas in 2014, including therapeutics, disease classification, risk management, and disease mechanisms. Advances were particularly notable in the field of progressive MS. Altogether, the findings move us one step closer to a better understanding of this complex disease.

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

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.

Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. METHODS: In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18-55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700. FINDINGS: Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379-0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416-0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515-0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540-0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). INTERPRETATION: TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. FUNDING: Genzyme, a Sanofi company.

Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: results from the TOWER study.

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % (p = 0.0021); 7 mg, 31.3 % (p = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % (p = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % (p = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % (p = 0.0002); 7 mg, 21.5 % (p = 0.0337)], and intense relapses [14 mg only, 52.5 % (p = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse (p = 0.009) and had lower annualized rates of all hospitalizations (p = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs.

Defining the clinical course of multiple sclerosis: the 2013 revisions.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Disease-modifying agents in multiple sclerosis.

Over the past two decades, major advances have been made in the development of disease-modifying agents (DMAs) for multiple sclerosis (MS), and nine agents are now licensed for use in the treatment of MS in the United States. Clinical trials have demonstrated that a number of investigational agents have beneficial effects on clinical and radiographic measures of disease activity, thus the repertoire of available DMAs in MS will likely continue to expand moving forward. Although many of the first-line DMAs have the benefits of established long-term safety and tolerability, in some patients, treatment with one of the more potent novel agents may be appropriate. However, the use of novel agents must be approached with caution, since short-term clinical trials give little information on the long-term efficacy and safety of novel DMAs in MS patients. This chapter will consider the efficacy and safety of both established and investigational agents for the treatment of MS.

Teriflunomide.

Teriflunomide is a novel disease-modifying agent that was recently approved for use in the treatment of multiple sclerosis (MS). Teriflunomide has demonstrated clinical efficacy and safety in a number of large, multicenter, phase III clinical trials and is an attractive agent to add to the growing repertoire of available treatments for MS, as it has the benefit of oral administration. Furthermore, existing clinical experience with its parent drug, leflunomide, provides indirect long-term safety data. This review summarizes teriflunomide's pharmacologic properties, pivotal clinical trials, and safety profile, and ends with a discussion of the role of teriflunomide in the context of current and emerging MS treatment options.

Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis.

OBJECTIVE: To investigate the effect of teriflunomide on the efficacy and safety of seasonal influenza vaccine. METHODS: The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n = 41) or 14 mg (n = 41), or interferon-ß-1 (IFN-ß-1; n = 46). The primary endpoint was the proportion of patients with influenza strain-specific antibody titers ≥40, 28 days postvaccination. RESULTS: More than 90% of patients achieved postvaccination antibody titers ≥40 for H1N1 and B in all groups. For H3N2, titers ≥40 were achieved in ≥90% of patients in the 7 mg and IFN-ß-1 groups, and in 77% of the 14-mg group, respectively. A high proportion of patients already had detectable antibodies for each influenza strain at baseline. Geometric mean titer ratios (post/prevaccination) were ≥2.5 for all groups and strains, except for H1N1 in the 14-mg group (2.3). The proportion of patients with a prevaccination titer <40 achieving seroprotection was ≥61% across the 3 treatment groups and 3 influenza strains. However, fewer patients in the 14-mg than the 7-mg or IFN-ß-1 groups exhibited seroprotection to H3N2 (61% vs. 78% and 82%, respectively). CONCLUSION: Teriflunomide-treated patients generally mounted effective immune responses to seasonal influenza vaccination, consistent with preservation of protective immune responses. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that teriflunomide generally does not adversely impact the ability of patients with RMS to mount immune responses to influenza vaccination.

Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use.

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.

An update of teriflunomide for treatment of multiple sclerosis.

There are a number of oral agents emerging as potential disease-modifying agents in multiple sclerosis (MS). Among these investigational agents, teriflunomide has shown promise in large, multicenter, phase III clinical trials with respect to safety and efficacy in relapsing MS patients, and is the latest disease-modifying agent approved for use in MS patients in the United States. This review will summarize teriflunomide's historical development, clinical pharmacology, studies in animals, clinical trials, and safety data, and will end with a discussion of the role of teriflunomide in MS in the context of existing treatment options.

Safety, tolerability, and efficacy of oral therapies for relapsing-remitting multiple sclerosis.

Treatment options for relapsing-remitting multiple sclerosis (RRMS) have been continuously expanding in recent years, and the emergence of a number of oral disease-modifying agents (DMAs) has significantly changed the landscape of therapeutic options for MS patients. Many of these oral DMAs have demonstrated satisfactory safety and tolerability profiles in clinical trial settings, but the long-term safety of these agents is an important concern. This review discusses salient points on the safety and clinical efficacy of the approved and emerging novel oral therapies in RRMS, including fingolimod, teriflunomide, dimethyl fumarate, laquinimod, and cladribine.

Teriflunomide for the treatment of multiple sclerosis.

Several novel oral agents are emerging for use in multiple sclerosis (MS). Among these oral agents, teriflunomide is showing promise with respect to clinical efficacy and safety in relapsing MS patients. In this review, the authors clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing salient points on the use of teriflunomide in MS, with a discussion of teriflunomide's development, pharmacologic properties, preclinical and clinical trials, and safety and tolerability.

Clinical effects of natalizumab on multiple sclerosis appear early in treatment course.

In clinical practice natalizumab is typically used in patients who have experienced breakthrough disease during treatment with interferon beta (IFNß) or glatiramer acetate. In these patients it is important to reduce disease activity as quickly as possible. In a phase II study, differences between natalizumab and placebo in MRI outcomes reflecting inflammatory activity were evident after the first infusion and maintained through a 6-month period, suggesting a rapid onset of natalizumab treatment effects. To explore how soon after natalizumab initiation clinical effects become apparent, annualized relapse rates per 3-month period and time to first relapse were analyzed in the phase III AFFIRM study (natalizumab vs. placebo) and in the multinational Tysabri(®) Observational Program (TOP). In AFFIRM, natalizumab reduced the annualized relapse rate within 3 months of treatment initiation compared with placebo in the overall population (0.30 vs. 0.71; p < 0.0001) and in patients with highly active disease (0.30 vs. 0.94; p = 0.0039). The low annualized relapse rate was maintained throughout the 2-year study period, and the risk of relapse in AFFIRM patients treated with natalizumab was reduced [hazard ratio against placebo 0.42 (95 % CI 0.34-0.52); p < 0.0001]. Rapid reductions in annualized relapse rate also occurred in TOP (baseline 1.99 vs. 0-3 months 0.26; p < 0.0001). Natalizumab resulted in rapid, sustained reductions in disease activity in both AFFIRM and in clinical practice. This decrease in disease activity occurred within the first 3 months of treatment even in patients with more active disease.