Teriflunomide Tablets (Aubagio®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a second oral drug for the treatment of multiple sclerosis (MS). Teriflunomide, a metabolite of leflunomide and a pyrimidine synthesis inhibitor, is an immunomodulatory agent. It is marketed by Sanofi Aventis as Aubagio.
Teriflunomide is indicated for the treatment of the relapsing form of MS.1
The recommended dose is 7 mg or 14 mg once daily with or without food.1 Liver transaminase levels, bilirubin levels, and blood counts should be obtained within 6 months before initiation of therapy. Patients should be screened for latent tuberculosis and blood pressure before initiation and monitored periodically during therapy.
Teriflunomide is available as 7 mg and 14 mg tablets.
Teriflunomide provides another option for relapsing MS. It has a different mechanism of action than fingolimod and both are dosed once daily.
Teriflunomide carries a box warning for hepatotoxicity.1 Severe liver hepatic injury, including fatal liver failure, has been reported with leflunomide, the prodrug of teriflunomide.1 The drug is teratogenic and is contraindicated in pregnant women or in women of child-bearing age without reliable contraception.1
Teriflunomide is believed to exert its immunomodulating effect by reducing T- and B-cell activation, proliferation, and function in the central nervous system (CNS).1 The efficacy and safety of teriflunomide was evaluated in a double-blind, placebo-controlled study in MS patients with relapsing MS with at least one relapse in the previous year or two over the prior 2 years and a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS).1,2 Patients had not received interferon-beta for at least 4 months prior to study entry. These patients (n = 1088) were randomized at the ratio of 1:1:1 to teriflunomide 7 mg, 14 mg, and placebo once daily for 108 weeks. The primary endpoint was the annualized relapse rate. Secondary endpoints included confirmed percentage of patients with progression of disability for at least 12 weeks, change in total lesion volume based on magnetic resonance imaging (MRI), and mean number of new active (gadolimium-enhanced T1) lesions per scan. Progession of disability was defined as at least a 1-point increase from baseline EDSS of ≤ 5.5 and a 0.5-point increase if the baseline value was > 5.5. The annualized relapse rates were 0.54 for placebo and 0.37 for the 7 mg and 14 mg strengths. This represented a relative risk reduction of 31.2% and 31.5%, respectively. The percent disability progression at week 108 was 20.2% (14 mg), 21.7% (7 mg), and 27.3% (placebo). The 7 mg dose was not statistically significant different than placebo. The median changes from baseline in total lesion volume at week 108 were 1.127, 0.753, and 0.345 for placebo, 7 mg, and 14 mg, respectively. Mean number of gadolinium-enhancing lesions per scan were 1.331, 0.570, and 0.261. All MRI effects were statistically different from placebo (P < 0.05). Adverse events compared to placebo included diarrhea (15-18% vs 9%), nausea (9-14% vs 7%), alopecia (10-13% vs 3%), increase in ALT (12-14% vs 7%), and neutropenia (2-4% vs 0.3%).
There are currently no published comparative studies involving teriflunomide and the other oral agent, fingolimod, or injectable drugs (e.g., interferon-beta, glatiramer acetate). In a Phase 2, 24-week study (n = 118), teriflunomide (7 mg or 14 mg) or placebo were added to interferon-beta.3 Both active arms reduced the number of gadolinium-enhanced T1 lesions compared to interferon-beta alone at week 24 and 48. Lesion volume was significantly reduced with the 14 mg dose at both time points. The annualized relapse rates were numerically in favor of teriflunomide at at week 48, but did not reach statistical significance.
MS is an inflammatory disease of the CNS. There are an estimated 400,000 Americans with MS,4 and the disease is two to three times more common in women. The majority of patients (approximately 85%) have the relapsing form (relapsing-remitting). Current FDA-approved therapy includes interferon-beta, glatiramer acetate, natalizumab, mitoxantrone, and fingolimod. Fingolimod and teriflunomide are the only drugs that are effective orally.
1. Aubagio Prescribing Information. Bridgewater, NJ: Sanofi; September 2012.
2. O'Connor P, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-1303.
3. Freedman MS, et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: A randomized phase II trial. Neurology 2012;78:1877-1885.
4. National MS Society. Multiple Sclerosis: Just the Facts. 2011. Available at: www.nationalmssociety.org/about-multiple-sclerosis/index.aspx. Accessed Oct. 13, 2012.