Major Finding: Patients taking 7 mg/day or 14 mg/day of teriflunomide experienced a statistically significant 31% reduction in the annualized relapse rate.
Data Source: A randomized, placebo-controlled phase III study (TEMSO) involving 1,088 patients with relapsing MS.
Disclosures: Sanofi-Aventis sponsored the trial. The investigators disclosed financial relationships with many companies that manufacture drugs for MS, including Sanofi-Aventis.
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 significant reduction of 31% compared with placebo. The 14-mg group also showed 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 TEMSO 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. The teriflunomide group had 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, he said.
TEMSO participants were adults aged 18–55 years with relapsing MS and a score of 5.5 or lower on the Expanded Disability Status Scale, and had experienced at least one relapse in the year prior to enrollment, or two relapses in the prior 2 years.
The availability of an oral agent for the treatment of this complex and progressively disabling disease is very good news for MS patients, Dr. Giancarlo Comi said during the press briefing.
“Of course it is central in the management of these patients to have available drugs to modify the disease course … we are literally entering a period where we can provide patients with much better support than ever before,” said Dr. Comi of Clinica Neurologica, Ospedale San Raffaele, Milan, Italy.
Indeed, other ongoing research is also demonstrating the safety and efficacy of teriflunomide, both as monotherapy and in combination with other treatments, said Dr. Mark Freedman of the Multiple Sclerosis Research Clinic at Ottawa Hospital. Dr. Freedman and Dr. Comi are investigators in the TEMSO trial.
For example, an open-label extension of a phase II trial of teriflunomide showed that teriflunomide was well tolerated during 8 years of continuous use following a 36-week double-blind portion of the study.
Dr. Freedman said that the results from a second phase III study of teriflunomide are expected to be reported in 2012.