Teriflunomide: A New Oral Agent for the Treatment of Multiple Sclerosis

Abstract & Commentary

By Susan Gauthier, DO, MS, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Gauthier reports no financial relationships relevant to this field of study.

Synopsis: Teriflunomide, an orally administered inhibitor of dihydro-orotate dehydrogenase, was found to be superior to placebo in reducing relapses in a 2-year, Phase 3 clinical trial in patients with multiple sclerosis.

Source: O'Connor P, et al. Randomized trial of oral teraflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-1303.

An active search is ongoing for the perfect "pill" to treat multiple sclerosis (MS). Patients with relapsing forms of MS typically are treated with one of four first-line injectable treatments. The major limitations related to these agents include partial efficacy (~30% reduction in relapse rate), limited data on long-term disability, and multiple side effects related to injection. Clinicians caring for patients with MS spend much time counseling patients through challenges such as injection anxiety, injection site pain/irritation, and injection fatigue. Fingolimod (Gilenya®), an oral agent recently approved by the FDA for treating MS, has limited use as a first-line agent due to a complicated safety profile. Teriflunomid is the first of a series of new oral agents in the pipeline for MS. All of these newer agents have the potential to replace the current injection therapy.

Teriflunomide is an active metabolite of leflunomide, which is used to treat patients with rheumatoid arthritis; however, teriflunomide has a distinct mechanism of reversibly inhibiting dihydro-orotate dehydrogenase. As a result, there is a reduction in pyrimidine synthesis and a subsequent reduction in T- and B-cell activation and proliferation. In the study by O'Connor et al, patients with active relapsing-remitting MS were randomized (1:1:1) to receive either placebo, teriflunomide 7.0 mg, or teriflunomide 14.0 mg, and were followed for 108 weeks. Progressive patients with intervening relapses also were enrolled; however, these patients made up a small minority. The primary outcome for the study was a reduction in relapse rate, and secondary objectives included a delay in sustained disability progression as well as a reduction in number of standard MRI measures. The dropout rate for this study was high (between 25%-29%), yet similar across all treatment groups. There was a 31.2% (P < 0.001) and 31.5% (P < 0.001) relative risk reduction in annualized relapse rate in patients treated with 7.0 mg and 14.0 mg of teriflunomide, respectively, compared to placebo. A significant benefit on sustained disability was found only within the high-dose group (30% reduction at 2 years, P = 0.03). There was a 39.4% (P = 0.03) and 67.4% (P < 0.001) relative risk reduction in new T2 lesions and a 57% (P < 0.001) and 80% (P < 0.001) relative reduction in new gadolinium-enhanced lesions per scan in the low- and high-treatment groups, respectively, compared to placebo. There was no significant benefit of teriflunomide on the rate of brain atrophy. The most common adverse events related to teriflunomide (with a dose-response effect) were diarrhea, nausea, hair thinning or decreased hair density, and elevated alanine aminotransferase. The rate of mildly elevated alanine aminotransferase was very common (> 1 times occurred in 54.0% and 57.3%, respectively), but the incidence of > 3 times was similar across placebo and treatment groups (6.3%, 6.7%, and 6.7%, respectively). There was only a slight reduction in lymphocyte counts in teriflunomide-treated patients that stabilized after 3 months. Importantly, the rate of serious infections was similar among all groups (2.2%, 1.6%, and 2.5%, respectively).


This was a well-designed study that demonstrated a beneficial effect of teriflunomide in relapsing forms of MS. Surprisingly, infections were not found to be higher in the active treatment cohort and the drug appears to be fairly well tolerated. The results from this study are similar to those of the pivotal trials for the current injectable therapies; therefore, it doesn't appear that an efficacy advantage has been gained with teriflunomide. Is there a side effect advantage of teriflunomide over the injections? Considering the gastrointestinal side effects and hair thinning associated with teriflunomide, we will need "real world" patient experience to answer this question. Thus, it has yet to be determined if teriflunomide will be the "pill to end injections" for patients with MS or if other agents in the pipeline are better candidates.