Teriflunomide, the active metabolite of leflunomide, is an oral immunomodulator with anti-inflammatory properties that reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in pyrimidine synthesis for DNA replication. Although the exact mechanism by which teriflunomide exerts its therapeutic effects in MS is not fully understood, it is thought to be mediated by a reduced number of lymphocytes.1,2
Phase II study
The safety and efficacy of teriflunomide were assessed in a 36-week phase II study involving 179 patients with MS and a score of ≤6 on the Expanded Disability Status Scale (EDSS). Patients had experienced two relapses in the previous three years and one relapse during the preceding year.3
Patients randomised to receive teriflunomide 7mg or 14mg daily showed significant reductions in the median number of combined unique active lesions per scan compared with those receiving placebo (0.2 [p<0.03] and 0.3 [p<0.01], respectively, versus 0.5). In addition, patients receiving teriflunomide had significantly fewer T1 enhancing lesions and new or enlarging T2 lesions per scan compared with placebo. Patients receiving teriflunomide 14mg also had a significantly lower T2 disease burden than those given placebo (p=0.1016).3
Teriflunomide was well tolerated with a similar incidence of adverse events, including serious events, observed in all three groups.3 The results of an open-label extension to this study demonstrated a favourable safety profile for teriflunomide for up to 8.5 years.4
The TEMSO study evaluated the efficacy and safety of teriflunomide in reducing the frequency of relapses and progression of physical disability in 1,086 patients with relapsing-remitting MS, with or without progression. Patients included in the phase III double-blind study had a score of ≤5.5 on the EDSS and had experienced at least one relapse during the preceding year or two relapses in the previous two years.2
Annualised relapse rate reduced
Patients were randomised to receive a once-daily dose of teriflunomide 7mg (n=365) or 14mg (n=358) or placebo (n=363) for 108 weeks. Teriflunomide significantly reduced the annualised relapse rate (ARR) (0.37 for either dose of teriflunomide versus 0.54 for placebo, p<0.001 for both), with relative risk reductions of 31.2% and 31.5% for the 7mg and 14mg teriflunomide groups, respectively (p<0.001 for both).2
The proportion of patients with confirmed progression of disability was lower in the 7mg teriflunomide group and significantly lower in the 14mg teriflunomide group than in the placebo group (relative risk reductions of 23.7% [p=0.08] and 29.8% [p=0.03], respectively).2
Improvements in MRI measures
In addition, both doses of teriflunomide improved several MRI measures of disease activity, including change in total lesion volume from baseline, compared with placebo.2
Common adverse events which occurred more frequently in the teriflunomide groups and which had an observed dose effect included diarrhoea, nausea, hair thinning and elevated alanine aminotransferase levels.2
The TOWER study (n=1,169), which was similar in design and patient inclusion criteria to the TEMSO study, reported similar findings. Teriflunomide 14mg significantly reduced the ARR compared with placebo (0.32 versus 0.50, p<0.0001) and a significantly lower proportion of patients in the teriflunomide 14mg group had sustained disability progression at three months than in the placebo group (15.8% versus 19.7%, p<0.05).1
Efficacy, safety and tolerability of teriflunomide were compared with interferon beta-1a in the phase III TENERE study, which included 324 patients with relapsing MS with or without progression and an EDSS score ≤5.5.5
Patients were randomised to receive oral teriflunomide 7mg or 14mg once daily or interferon beta-1a as a subcutaneous injection three times a week (starting dose 8.8 microgram titrating up to 44 microgram over four weeks).5
No difference was found between either teriflunomide dose or interferon beta-1a in terms of time to failure (defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any reason). In addition, no difference was observed between teriflunomide 14mg and interferon beta-1a in terms of ARR (0.26 versus 0.22, p=0.6) although the ARR was significantly higher in the teriflunomide 7mg group (0.41 versus 0.22 for interferon beta-1a, p=0.03).5
Patients reported greater satisfaction and less fatigue with teriflunomide than with interferon beta-1a. The overall incidence of adverse effects was similar across all three treatment groups.5
- Aubagio Summary of Product Characteristics, August, 2013.
- O’Connor P et al. N Engl J Med 2011; 365: 1293–303.
- O'Connor P et al. Neurology 2006; 66: 894–900.
- Confavreux C et al. Mult Scler 2012; 18: 1278–89.
- Vermersch P et al. Mult Scler 2013; DOI:10.1177/1352458513507821.
Further information: Genzyme