FDA approves oral disease-modifying drug for multiple sclerosis

On September 12, 2012, FDA approved teriflunomide (Aubagio, Genzyme, a Sanofi-Aventis company), a pyrimidine synthesis inhibitor, for the treatment of patients with relapsing forms of multiple sclerosis (MS). This is the second oral disease-modifying treatment approved for MS with the first being fingolimod (Gilenya, Novartis) approved in 2010.

In a clinical trial, the relapse rate was 30% lower for individuals who received teriflunomide than for those taking placebo.

Patients considering taking teriflunomide should be evaluated for liver function before starting and periodically during treatment as this drug has a risk of liver toxicity. In addition, teriflunomide is labeled as pregnancy category X, so all women of childbearing age must have a negative pregnancy test prior to starting this drug treatment and must continue to use birth control while taking this agent.

Efficacy

FDA approval for teriflunomide was based on the data from the TEriflunomide Multiple Sclerosis Oral (TEMSO) trial, a phase 3 study that enrolled 1088 patients with relapsing forms of MS . Patients were randomized to receive teriflunomide at a dose of 7 mg, 14 mg, or placebo. Neurological examinations were performed every 12 weeks until 108 weeks and at unscheduled visits for suspected relapse. MRI was also performed at screening and at weeks 24, 48, 72, and 108.

The primary end point was the annualized relapse rate (ARR) which was significantly reduced by 31% in patients treated with 7 mg or 14 mg of teriflunomide compared with the placebo-treated patients. There was also a statistically significant reduction in the time to disability progression, sustained for 12 weeks, by 30% in the 14-mg dose group compared to placebo.

MRI outcomes demonstrated a significantly lower change in total lesion volume from baseline in the 7-mg and 14-mg groups compared with the placebo group.

Safety

The most common adverse reactions for teriflunomide in the 14-mg and 7-mg groups, respectively, during the clinical trials were headache (19% and 22%), ALT increase (14% and 12%), alopecia (13% and 10%), diarrhea (18% and 15%), influenza (12% and 9%), nausea (14% and 9%), and paresthesia (10% and 9%). Alopecia was the most common cause of discontinuation in the clinical trials.

Teriflunomide carries a black-box warning of the risk of hepatotoxicity and teratogenicity. Because fatal liver failure has been reporting in patients treated with leflunomide, a similar risk is expected with teriflunomide. Clinicians should evaluate patients’ liver function within 6 months before teriflunomide initiation and monitor ALT levels monthly for 6 months after starting the drug.

Based on animal trials, teriflunomide may cause major birth defects if used during pregnancy. It is contraindicated in pregnant women or women of childbearing age who are not using reliable contraception.

Dosage

The recommended dose of teriflunomide is 7 mg or 14 mg orally once daily, with or without food. Within 6 months of initiating therapy, the clinician should obtain transaminase, bilirubin levels, and a complete blood count. Patients should also be screened for latent tuberculosis infection with a tuberculin skin test prior to initiation of therapy. Blood pressure should also be checked prior to treatment and periodically during treatment. Due to prolonged elimination of  teriflunomide (8 months to 2 years) upon treatment discontinuation, accelerated elimination procedures including administration of cholestyramine 8 g every 8 hours for 11 days or 50 g of oral activated charcoal powder every 12 hours for 11 days can be used.

Diana M. Sobierajis assistant professor of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.