Teriflunomide, a novel oral disease-modifying drug, significantly reduced the annualized relapse rate and the risk of disability progression in relapsing multiple sclerosis by about 30% in a 2-year, phase III trial.
The study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO), which was sponsored by Sanofi-Aventis, randomized 1,088 patients to receive a single daily dose of 7 mg or 14 mg of teriflunomide or placebo.
The primary end point – the annualized relapse rate – was significantly lower among the 7-mg and 14-mg groups (0.370 and 0.369, respectively) than it was in placebo-treated patients (0.539). These rates represented a statistically significant reduction of 31% compared with placebo. Patients in the 14-mg group also experienced a significant 30% reduction in the risk of disability progression, Dr. Paul O'Connor reported at the congress.
Teriflunomide is the active metabolite of leflunomide, a synthetic, low-molecular-weight drug that was approved by the Food and Drug Administration in 1998 for the treatment of rheumatoid arthritis.
The metabolite is a reversible inhibitor of the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH) that exerts anti-inflammatory, antiproliferative, and immunosuppressive effects, but the mechanisms by which it does so are not yet completely understood. Inhibition of pyrimidine biosynthesis (via suppression of DHODH) and interference with tyrosine kinase activity both appear to be involved.
The treatment groups also experienced a significant reduction in brain disease activity as measured by magnetic resonance imaging (MRI). The burden of disease as determined by total lesion volume, for example, was reduced by 39% and 67% in the 7-mg and 14-mg dose groups, respectively, compared with placebo, said Dr. O'Connor of St. Michael's Hospital, Toronto. He is the principal investigator for TEMSO.
“In my view, teriflunomide is a safe and effective new monotherapy, and it represents a potential first-line treatment for patients with relapsing MS,” he said during a press briefing on the findings.
The safety profile of teriflunomide in this study was a particularly strong, positive point, he added.
The overall adverse event rates were the same in the placebo and treatment groups, as were the rates of adverse events leading to permanent discontinuation of treatment. Patients in the teriflunomide group experienced more nausea, diarrhea, increases in alanine transferase, and hair thinning than did those in the placebo group, but these effects were mild. Treatment was generally very well tolerated, and no opportunistic infections occurred.
Dr. Mark Freedman of the Multiple Sclerosis Research Clinic at Ottawa (Canada) Hospital said the results from a second phase III study of teriflunomide are expected to be reported in 2012. He and Dr. Comi are investigators in the TEMSO trial.