Teriflunomid (1) – Aubagio®

• Clinical trials
  • A randomised controlled trial directly comparing teriflunomide (TFN) with the appropriate comparator therapy (TENERE) was included in the assessment. The TENERE trial is an open-label, multicentre, randomised, controlled registration trial comparing TFN (at two different doses: 7 mg and 14 mg) with IFN β-1a 44 μg s.c.

Adult patients with relapsing-remitting multiple sclerosis (MS)

• The G-BA classifies the additional benefit of teriflunomide for patients with relapsing-remitting MS, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease, as lacking proof.
• In light of these considerations, based on the information in the dossier, the results of the benefit assessment and the expert opinions, the G-BA finds no proof of additional benefit from teriflunomide compared with the appropriate comparator therapy, IFN β-1a.
• mortality
  • No patients died in either the TFN arm (14 mg) or the IFN β-1a (44 µg s.c.) arm of the TENERE study.
  • Given its size and duration, the study was not designed to detect differences in mortality.
  • Overall, the additional benefit of TFN is not proven for this endpoint.
• morbidity
  • The endpoints relating to relapses and disability progression are interpreted collectively as morbidity endpoints.
  • The proportion of patients with a confirmed relapse was 23.4% for TFN and 15.4% for IFN β-1a 44 mg s.c. The probability of a relapse by week 96 was 29% for TFN and 19% for IFN β-1a. The annual relapse rate was 0.26/year for TFN and 0.22/year for IFN β-1a.
  • The proportion of patients with disability progression differed only slightly between the treatment groups; the proportion was 9.0% for TFN and 8.7% for IFN β-1a. The probability of disability progression by week 96 was 12% for TFN and 10% for IFN β-1a.
  • No statistically significant differences were observed between the treatment groups, either with regard to relapse-related endpoints or with regard to endpoints relating to disability progression.
  • With regard to relapse-related endpoints, the observed differences tend to suggest an unfavourable effect of TFN. For endpoints relating to disability progression, the differences between the treatment arms were minimal. It should be noted that, due to its short study duration, the study was not suitable for demonstrating relevant effects with regard to disability progression.
  • The additional benefit of TFN is not proven for the aforementioned morbidity endpoints.
• quality of life
  • In the TENERE study, symptoms of fatigue and their individual consequences were measured using the Fatigue Impact Scale (FIS).
  • After 48 weeks, a minor 5-point decrease in the total FIS score was observed for patients treated with TFN.
  • No statistically significant difference was observed between the treatment groups in either the total FIS score or the scores for the three subscales (cognitive, physical and psychosocial dimensions).
  • Overall, no additional benefit of TFN over IFN β-1a has been proven for the quality of life endpoint.
• Side effects
  • The proportion of patients experiencing serious adverse events was 3.6% for TFN and 5.9% for IFN β-1a. There was no significant difference between the treatment groups, and the result was not statistically significant. For this endpoint, it is not proven that TFN causes minor or major harm.
  • The proportion of patients reaching the endpoint ‘discontinuation due to adverse events’ was 6.4% for TFN and 8.9% for IFN β-1a. No statistically significant difference was observed between the treatment groups; however, discontinuation of treatment due to pregnancy or due to test results (changes in laboratory values) was not classified as a relevant event.
  • Injection-site reactions (TFN 0% vs. IFN β-1a 21.8%) and flu-like symptoms (TFN 2.7% vs. IFN β-1a 53.3%) occurred more frequently with IFN β-1a treatment than with TFN. The result was statistically significant in each case. The majority of these events were of mild or moderate severity. For both endpoints – ‘injection site reactions’ and ‘flu-like symptoms’ – there is a hint that TFN causes minor harm.
  • Nausea/vomiting (TFN 13.6% vs. IFN β-1a 5.0%), alopecia (TFN 20.0% vs. IFN β-1a 1.0%) and diarrhoea (TFN 20.9% vs. IFN β-1a 7.9%) occurred more frequently with TFN treatment than with IFN β-1a. The result was statistically significant in each case. The majority of these events were of mild or moderate severity. For each of these endpoints, there is a hint of greater harm associated with TFN.
• Overall assessment
  • For the endpoint categories of mortality, morbidity and quality of life, the additional benefit of TFN over the appropriate comparator therapy is not proven.
  • Based on side effects, there are both positive and negative effects.
  • Equivalence in terms of the efficacy of TNF compared with IFN ß-1a could not be demonstrated.

Courtesy translation only, please refer to the German original.