Multiple Sclerosis (MS)


Aubagio (teriflunomide) is a disease-modifying therapy for multiple sclerosis (MS) by Sanofi Genzyme. It was approved by the US Food and Drug Administration (FDA) in September 2012 for the treatment of adult patients with relapsing forms of MS, including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary multiple sclerosis.1 

The treatment was also approved by the European Medicine Agency (EMA) in August 2013.2

It is available as 7 mg and 14 mg oral tablets.3

Aubagio’s Mechanism of Action

Multiple sclerosis is characterized by immune-mediated inflammation and neurodegeneration. It is a disease of unknown etiology.

Aubagio is a pyrimidine synthesis inhibitor. It acts on the dihydro-orotate dehydrogenase enzyme, inhibiting its action.2 This enzyme is involved in the oxidation of dihydroorotate to orotic acid, in de novo pyrimidine biosynthesis.4

Although the exact mechanism of action of Aubagio in MS is not fully clear, it is thought to reduce the number of lymphocytes, thereby reducing inflammation and controlling the symptoms of the disease.2 

Warnings, Precautions, and Adverse Reactions

Aubagio can have serious side effects, including a decrease in white blood cell count, allergic reactions, serious skin reactions, numbness or tingling in the hands or feet, high blood pressure, and breathing problems.5

The most common adverse reactions in patients taking Aubagio are headaches, diarrhea, nausea, hair thinning or alopecia, and abnormal liver test results.

Aubagio should not be used by patients who have severe hepatic impairment.

Aubagio should also not be used by pregnant women or women of reproductive potential who are not using effective contraception, as the treatment may harm the fetus. It also should not be taken by the male partner if a couple is trying to conceive. It is not known whether Aubagio passes into the breast milk of mothers. 

The treatment can stay in the blood for up to 2 years following discontinuation. Elimination can be accelerated by the administration of cholestyramine or activated charcoal. However, this may cause MS disease activity to return.

Get detailed prescribing information on the Aubagio monograph page at Rare Disease Advisor.

Efficacy in Clinical Trials

The safety and efficacy of Aubagio have been tested in 3 phase 3 clinical trials with 2875 patients.

The first trial, called TEMSO, was a randomized, double-blind, placebo-controlled, parallel-group design study to determine the effect of Aubagio on the frequency of relapses in patients with RRMS.6 The secondary objectives were to evaluate the effect of Aubagio on the accumulation of disability as measured by the Expanded Disability Status Scale (EDSS), the burden of disease as measured by magnetic resonance imaging (MRI), and patient-reported fatigue, as well as to assess the safety and tolerability of the treatment. 

The trial enrolled 1088 patients with MS, aged 18 to 55 years, with a score of 0 to 5.5 on the EDSS, and at least 1 relapse in the previous year or at least 2 relapses in the previous 2 years. Participants were assigned 1:1:1 to placebo, 7 mg Aubagio, or 14 mg Aubagio once daily for 108 weeks. 

The results showed that Aubagio significantly reduced relapse rates, disability progression at the higher dose, and MRI evidence of disease activity compared with placebo.7

The second clinical trial, called TOPIC, was an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study that aimed to demonstrate the effect of 7 mg and 14 mg of Aubagio compared to placebo in reducing the conversion of CIS to clinically definite MS.8 Secondary objectives included the effect of Aubagio on reducing annualized relapse rates, disease activity/progression as measured by MRI, accumulation of disability for at least 12 weeks as measured by the EDSS, participant-reported fatigue, and the proportion of disability-free participants as assessed by the EDSS compared to placebo. Other secondary measures included evaluating the safety, tolerability, and pharmacokinetics of Aubagio.

TOPIC enrolled 618 patients with CIS, aged 18 to 55 years. from 112 centers in 20 countries. Participants were randomly assigned 1:1:1 to placebo, 7 mg Aubagio, or 14 mg Aubagio daily for 108 weeks. 

Results showed that Aubagio significantly reduced the risk of relapse at both doses compared with placebo. It also reduced the risk of relapse or a new MRI lesion compared to placebo at both doses.9 

The final trial, called TOWER, was a multicenter, double-blind, parallel-group, placebo-controlled study whose primary objective was to assess the effect of 7 mg and 14 mg of Aubagio on the frequency of MS relapses in participants with relapsing MS compared to placebo.10 Secondary objectives were to assess the effect of Aubagio on disability progression, fatigue, and health-related quality of life, compared to placebo, as well as to evaluate the safety and tolerability of the treatment.

The study enrolled 1169 patients with RRMS aged 18 to 55 years with 1 or more relapses in the previous year or 2 or more relapses in the previous 2 years but no relapse in the previous month, and an EDSS score of 5.5 points or less, from 189 sites in 26 countries. Patients were randomized 1:1:1 to receive a placebo, 7 mg of Aubagio, or 14 mg of Aubagio once a day.

Results showed that 14 mg of Aubagio was associated with a lower relapse rate and less disability accumulation compared to placebo.11

References

1. Aubagio FDA approval history. Drugs.com. Accessed June 11, 2021.

2. Aubagio. European Medicines Agency. Accessed June 11, 2021.

3. Aubagio. Package insert. Sanofi Genzyme; 2016. Accessed June 11, 2021.

4. DHODH gene. MedlinePlus. Accessed June 11, 2021.

5. Aubagio (teriflunomide). Sanofi Genzyme. Accessed June 11, 2021. 

6. Study of teriflunomide in reducing the frequency of relapses and accumulation of disability in patients with multiple sclerosis (TEMSO). ClinicalTrials.gov. Updated January 4, 2013. Accessed June 11, 2021.

7. O’Connor P, Comi G, Freedman M, et al. Long-term safety and efficacy of teriflunomide: nine-year follow-up of the randomized TEMSO study. Neurology. 2016;8;86(10):920-930. doi:10.1212/WNL.0000000000002441

8. Phase III study with teriflunomide versus placebo in patients with first clinical symptom of multiple sclerosis (TOPIC). ClinicalTrials.gov. Updated March 13, 2017. Accessed June 11, 2021.

9. Miller A, Wolinsky J, Kappos L, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(10):977-986. doi:10.1016/S1474-4422(14)70191-7 

10. An efficacy study of teriflunomide in participants with relapsing multiple sclerosis (TOWER). ClinicalTrials.gov. Updated July 7, 2016. Accessed June 11, 2021.11. Confavreux C, O’Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247-256. doi:10.1016/S1474-4422(13)70308-9

Reviewed by Kyle Habet, MD, on 7/1/2021.