TOPIC: Teriflunomide Delays Clinically Definite MS

Topline results of a phase 3 trial confirm that treatment of clinically isolated syndrome, a first attack suggestive of multiple sclerosis (MS), with teriflunomide (Aubagio, Genzyme/Sanofi) delayed conversion to clinically definite MS.

The results, from the TOPIC trial, show patients with clinically isolated syndrome (CIS) treated with teriflunomide, 14 mg and 7 mg, were less likely to progress to clinically definite MS, defined as a second clinical attack, the primary endpoint of the trial, than those receiving placebo.

This benefit of early treatment has been previously shown with the injectable agents, interferon β-1a and glatiramer acetate, but teriflunomide is the first of the oral agents to show this effect, Aaron E. Miller, MD, medical director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, New York, New York, told Medscape Medical News. Dr. Miller is a member of the steering committee for the development of teriflunomide and was an investigator in the TOPIC trial.

"So the fact that the results of this trial are very positive gives us a legitimate use to use an oral agent at this early stage potentially," he said.

"More and more patients are coming to the attention of neurologists at the time that they have their very first event, and the availability of effective treatments that decrease the likelihood of conversion to definite MS is very important," he added.

The company confirmed it will seek a supplemental approval for this indication. Teriflunomide is already approved in the United States, as well as for the treatment of relapsing-remitting MS — 1 of 3 oral agents now approved for this use. The others are fingolimod (Gilenya, Novartis), first to the market and approved in September 2010, and dimethyl fumarate, also known as BG-12 (Tecfidera, Biogen Idec), approved in March 2013.

Full results of the TOPIC trial will be presented at an upcoming medical meeting not specified.

High Conversion

Previous studies have shown that the likelihood of people with CIS converting to clinically definite MS in the absence of treatment is "extraordinarily high," he said — in 1 study, over 90% by 14 years. "So as a result, we're very interested in treatments administered at the very earliest stage, before one can actually make a diagnosis of MS," Dr. Miller said.

The double-blind, multicenter TOPIC trial compared treatment with teriflunomide in doses of 14 mg or 7 mg per day against placebo in 618 patients with CIS. Patients were included if they experienced a first acute or subacute well-defined neurologic event consistent with demyelination, onset of MS symptoms within 90 days of randomization, and MRI showing 2 or more characteristics of MS. The average duration of exposure to teriflunomide in this study was 16 months.

During 2 years of treatment, patients receiving teriflunomide, 14 mg, had a 43% reduction in the risk for conversion to clinically definite MS vs placebo (P = .0087). In those receiving 7 mg per day, there was a 37% reduction in the risk for conversion vs placebo (P = .0271).

Adverse events observed in the trial were consistent with those in previous clinical trials with teriflunomide for MS. The most common types of adverse events reported more frequently in the treated groups were alanine aminotransferase elevations, nasopharyngitis, headache, alopecia, diarrhea, and paresthesia. No deaths were reported in either teriflunomide group during the study. One patient in the placebo group died of suicide.

The rate of treatment discontinuation due to adverse events was similar across treatment groups (9.1% for placebo compared with 12.1% for 7 mg of teriflunomide and 8.3% for 14 mg).

The US label for teriflunomide includes a boxed warning citing the risk for hepatotoxicity and teratogenicity (based on animal data). The drug is contraindicated in pregnant women and women of childbearing potential who are not using reliable contraception.

The TOPIC trial is part of a program of investigation with teriflunomide that includes previously reported trials TEMSO (Teriflunomide Multiple Sclerosis Oral), TOWER (Teriflunomide Oral in people With relapsing-remitting MultiplE ScleRosis), and TENERE. Another phase 3 trial, TERACLES, investigating teriflunomide as an adjunct to interferon, is still ongoing.

Full prescribing information for teriflunomide is available at www.genzyme.com.

The TOPIC trial was supported by Genzyme, a Sanofi company.