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.