Class: Immunomodulatory agents
Name: Teriflunomide (Aubagio®)
General Dosage: Once a day oral medication.
Mechanism of Action: Inhibits the ability of all lymphocytes to grow, leads to lymphocyte death including B lymphocytes.
Effectiveness: Compared to placebo, 30% decrease relapse rate; trend in slowing disability; decreases brain atrophy by 20%; Effects on disability and brain atrophy are not statistically significant.
Possible Side Effects: Boxed warning* for hepatotoxicity (including fatal liver failure) and teratogenicity. Decreased white blood cells, increased risk of infection, peripheral neuropathy (1.4%-1.9%); increased blood pressure (3%-4%); hair thinning.
Teriflunomide, a once-daily, oral medication, was approved by the FDA in 2012 for the treatment of relapsing forms of multiple sclerosis. Made by Sanofi-Genzyme, Aubagio is the brand name the drug is marketed under.
Aubagio is chemically and functionally related to leflunomide, an FDA-approved treatment for rheumatoid arthritis. An immunomodulatory drug, Aubagio is technically an inhibitor of an enzyme known as dihydroorotate dehydrogenase. This means that Aubagio inhibits rapidly dividing cells, including activated T cells.
It is thought that Aubagio, unlike other similar drugs, has less effect on other immune functions, possibly providing patients with a decreased risk of infections and other complications linked to chemotherapy-like drugs, although an increase in infections is seen with the use of Aubagio.
The most common side effects of Aubagio experienced by patients in clinical trials included diarrhea, abnormal liver tests, nausea, and hair loss, according to the FDA. Before people begin taking Aubagio, they should have their liver enzymes tested. This testing should continue monthly for the first six months and after the first six months, patients should be monitored for signs of liver damage.
Video recorded in 2015.
* Boxed Warning: A black boxed warning is the FDA’s most stringent warning for drugs and medical devices on the market. Black box warnings, or boxed warnings, alert the public and health care providers to serious side effects, such as injury or death.
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“The true potential of this drug rests in its possible use as a combination therapy,” said Dr. Timothy Vollmer, Medical Director of the Rocky Mountain MS Center and Professor at the University of Colorado School of Medicine, in 2012. “Combination therapies ideally combine two moderately effective but safe therapies such that they can be highly effective while maintaining a good safety profile. The result is a more effective and safe treatment option for people with MS.”
PHASE III STUDIES
The most recent phase III study, TOWER, included 1,169 people with relapsing-remitting MS. Participants were randomly assigned to receive Aubagio 7 mg or 14 mg, once daily by mouth, or placebo for 48 weeks. The 14 mg dose reduced relapses by 36.3% versus placebo and a 7 mg dose reduced relapses by 22.3% versus placebo. In the 14 mg dose group, the time to disability progression was reduced by 31.5% and there was no significant reduction in the lower dose group.
Results from TEMSO, another Phase III study, found that Aubagio improved cognitive performance and reduced relapse rates in patients with relapsing forms of MS. The study enrolled 1,088 participants from 21 countries, and researchers focused on whether Aubagio was able to reduce the frequency of relapses and the progression of disability.
For the study, patients with RRMS were randomized to either placebo or once-daily Aubagio at 7 mg or 14 mg for 108 weeks. The primary objective was to evaluate the effect of Aubagio on annualized relapse rate. Treatment effects on disability progression and MRI activity were assessed as secondary endpoints.
Results were encouraging: both doses showed about a 31% reduction in annual relapse rate, and 53% to 56% of participants on Aubagio—compared to 45% on placebo—remained relapse-free during the 2-year study. Additionally, the risk of 12-week confirmed disability progression was reduced by 30% for those on 14 mg of Aubagio and 24% for those on the 7 mg dose. Participants’ MRI results were also encouraging, and demonstrated a reduction in gadolinium-enhancing T1 lesions and new active lesions.
The most commonly reported study side effects were diarrhea, nausea, liver enzyme increases (that were mainly mild and asymptomatic with no dose effect) and mild hair thinning/decreased hair density. Side effects were reported to rarely lead to treatment discontinuation. Three participants in the placebo group and one in the Aubagio 14 mg group experienced malignancies.
Results from TENERE were released in 2011. The study included 324 people from 13 countries and lasted 48 weeks. Study participants were randomized to receive oral Aubagio, 7 mg or 14 mg, once daily, or a daily injection of interferon beta-1a (Rebif). The primary endpoint of the study was the risk of failure—defined either as the first occurrence of relapse or permanent study discontinuation for any cause, whichever came first. Secondary outcomes included annualized relapse rate, participant-reported fatigue as assessed by the Fatigue Impact Scale (FIS), and participant satisfaction as assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM). A long-term extension of TENERE is ongoing.
The study found no statistical significance between Aubagio and Rebif in regards to the primary endpoint (risk of treatment failure). In the study, 48.6% of trial participants on 7 mg of Aubagio and 37.8 percent on 14 mg reached the primary endpoint, versus 42.3% in the Rebif group. The endpoint of annualized relapse rate was not distinguishable between the higher 14 mg Aubagio dose and Rebif, although it was higher in the 7 mg Aubagio group. The percentage of participants who permanently discontinued the study due to emergent adverse events was 21.8% in the Rebif group compared to 8.2% in the 7 mg Aubagio group and 10.9% in the 14 mg group.
Similarly to the TEMSO study, in the TENERE study Aubagio was safe, generally well tolerated and there were no deaths. Commonly reported side effects included nasopharyngitis, diarrhea, hair thinning, and back pain in the Aubagio groups, and increases in alanine aminotransferase levels, headache and flu-like symptoms in the Rebif group.