Oral Teriflunomide Comparable to Interferon in MS

Allison Shelley

December 20, 2011

December 20, 2011 — New topline results released today suggest that oral teriflunomide (Aubagio, Sanofi) has similar efficacy and safety to interferon beta-1a (Rebif, Merck Serono) in the treatment of multiple sclerosis (MS).

Sanofi hopes its new oral agent will soon join fingolimod (Gilenya, Novartis) on the market. Analysts say that if the new oral agent can show it is noninferior to another commonly used therapy, such as interferon, it will improve the drug's chances of approval.

Sanofi filed with the US Food and Drug Administration in October and is planning an application with the European Medicines Agency in the first quarter of 2012.

The new phase 3 clinical trial, known as TENERE, included 324 patients with relapsing forms of MS. The trial is funded by Genzyme, a Sanofi company.

Investigators saw no statistical superiority between teriflunomide and interferon on risk for treatment failure, which is the primary composite endpoint of the study. Risk for treatment failure was defined as the occurrence of a confirmed relapse or permanent treatment discontinuation for any cause, whichever came first.

The higher daily dose of teriflunomide and interferon were not distinguishable on the endpoint of estimated annual relapse rate. There were more annual relapses in the lower-dose teriflunomide group.

The rate of permanent treatment discontinuation to a treatment-emergent adverse event was worse in the interferon group.

Table. High- and Low-Dose Teriflunomide vs Interferon

Outcome Teriflunomide 7 mg (n = 109) Teriflunomide 14 mg (n = 111) Interferon Beta (n = 104)
Treatment failure risk 48.6% 37.8% 42.3%
Estimated annual relapse 0.410 0.259 0.216
Treatment discontinuation 8.2% 10.9% 21.8%

There were no deaths in the trial. Most adverse events observed in the teriflunomide groups were mild in severity and included nasopharyngitis, diarrhea, hair thinning, and back pain. The most common adverse events seen in the interferon group were increases in alanine aminotransferase levels, headache, and influenza-like symptoms.

This is the second completed trial of 5 efficacy studies of teriflunomide in MS. The first was the Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients with Multiple Sclerosis (TEMSO), which showed a significant reduction in annualized relapse rates.

The TEMSO trial was first presented at the European Committee for Treatment and Research in Multiple Sclerosis and reported by Medscape Medical News at the time. The results of the trial were published in October in the New England Journal of Medicine (2011;365:1293-1303).

The randomized, double-blind, placebo-controlled, multinational study included 1088 patients with MS. The reduction in annualized relapse rates was more than 30% vs placebo with both doses of the drug.

Teriflunomide is a novel disease-modifying therapy that reversibly inhibits dihydroorotate dehydrogenase, a key enzyme involved in de novo pyrimidine synthesis. This reportedly reduces T- and B-cell proliferation and function in response to autoantigens, but preserves the replication and function of cells living on their pyrimidine pool, including hematopoietic cells or memory T cells, through the so-called salvage pathway.

Imaging Data

In April, investigators presented new magnetic resonance imaging (MRI) data from TEMSO at the American Academy of Neurology 63rd Annual Meeting.

"Teriflunomide was superior to placebo across a range of MRI measures," Jerry Wolinsky, MD, from the University of Texas in Houston, said at the meeting. This included change from baseline in total lesion volume, number of gadolinium-enhancing T1 lesions per scan, proportion of patients free from gadolinium-enhancing T1 lesions, and number of unique active lesions.

"As more oral agents emerge, we will have to balance the different potencies and safety issues," Dr. Cohen said during an interview after the meeting. "Each agent is promising, but different. The magnitude of efficacy for teriflunomide appears to be less than for other agents, such as fingolimod; however, there are fewer potential side effects."

Dr. Cohen says the challenge moving forward will be in patient selection. "Ultimately, we'll need more experience with each of these agents."

Genzyme says detailed results from this latest study will be presented at an upcoming medical meeting.

This study was funded by Genzyme, a Sanofi company.

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