Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial

Summary

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.

Introduction

Until recently, the first-line treatment options for relapsing forms of multiple sclerosis have been mainly injectable disease-modifying therapies such as the interferon betas and glatiramer acetate. However, oral drugs are needed that are appropriate for use as first-line treatments, to avoid injection-related adverse events and potentially to improve treatment acceptance and adherence, and to provide alternative options to patients with suboptimal response or intolerance to other agents. The availability of new treatments with distinct mechanisms of action will also provide opportunities to individualise therapy for each patient. Teriflunomide is an oral, once-daily, disease-modifying therapy approved in several countries (including the USA and the European Union) for treatment of relapsing multiple sclerosis or relapsing–remitting multiple sclerosis. Teriflunomide is the principal active metabolite of leflunomide, a drug approved for treatment of rheumatoid arthritis. Teriflunomide selectively and reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme for de-novo pyrimidine synthesis required by rapidly dividing B and T lymphocytes. Through this cytostatic effect, teriflunomide has the potential to limit the immune responses that can contribute to multiple sclerosis disease activity.1, 2

In the first phase 3, placebo-controlled trial—the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial³—teriflunomide 14 mg significantly reduced the annualised relapse rate (the number of confirmed relapses per patient-year) and the risk of disability progression sustained for at least 12 weeks. Teriflunomide 7 mg also significantly reduced the annualised relapse rate, but had no significant effect on disability progression. Superiority to placebo on several MRI endpoints was also shown, with evidence of a dose effect.⁴ Moreover, extension studies showed that the effects of teriflunomide were maintained with long-term treatment (up to 8·5 years).5, 6 The safety profile of teriflunomide has been assessed in placebo-controlled clinical trials3, 7 and extension studies,5, 6 with diarrhoea, nausea, hair thinning (alopecia), and increased alanine aminotransferase concentrations being the most frequently reported adverse events.3, 7

To add to the results reported in the TEMSO trial, we undertook the phase 3 Teriflunomide Oral in People With Relapsing Multiple Sclerosis (TOWER) trial to assess the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis.