Fingolimod (4) – Gilenya®

• Clinical trials
  • In its dossier, the pharmaceutical manufacturer refers to the direct comparative TRANSFORMS trial. The study design of this trial is multicentre, randomised, double-blind, parallel-group and actively controlled (double-dummy).
  • The trial comprised three treatment arms: fingolimod 0.5 mg, administered orally (431 patients), fingolimod 1.25 mg, administered orally (426 patients), and INF-β 1a 30 μg, administered intramuscularly (435 patients).

a) Patients with highly active RRMS who had not responded to a complete and appropriate course of at least one disease-modifying therapy, for whom, following an individual patient assessment taking into account the overall clinical situation, in particular the severity of severe relapses, a change in basic therapy depending on prior treatment or, where appropriate, continuation or adjustment of the previous therapy

• Taken together, for patients with highly active RRMS who have not responded to a full and appropriate course of treatment with at least one disease-modifying therapy, and for whom, following an individual patient assessment taking into account the overall clinical situation, in particular the severity of relapses, a change in basic therapy depending on previous treatment or, where appropriate, continuation of the previous therapy may be considered, in view of the available findings on morbidity and side effects, the additional benefit of fingolimod compared with the appropriate comparator therapy is not proven.
• mortality
  • No deaths occurred in either treatment arm of the TRANSFORMS study. Due to its size and duration, the study was not designed to detect differences in mortality. Overall, the additional benefit of fingolimod is not proven for this endpoint.
• morbidity
  • For all endpoints listed under the category of morbidity, there were no statistically significant differences were observed between the two study arms in the patient population.
  • The benefit assessment did not reveal any statistically significant differences between the study arms with regard to the endpoints‘time to first confirmed relapse’, ‘patients with a confirmed relapse’, ‘annual relapse rate’,‘severity of relapses’or‘disability progression’.
  • The endpoints ‘severity of disability’ (assessed using the MSFC-z score), fatigue (assessed using the mFIS), activities of daily living (assessed using PRIMUS Activities) and health status (assessed using the EQ-5D-VAS) were determined using questionnaires. Due to the significant difference in the proportion of missing values between the two study arms (actual or potential non-response rate greater than 15 per cent) in this analysis, these results cannot be interpreted validly and therefore cannot be used for the benefit assessment in this patient group.
  • For the endpoint category of morbidity, there is a statistically significant difference in favour of switching to fingolimod compared with continuing IFN-β 1atherapy, for RRMS patients with high disease activity who have received less than one year of prior treatment with IFN-beta.
  • For patients who switched therapies within their standard of care after one year of prior treatment, the difference between the treatment arms is not significant. No evaluable data are available regarding a switch to fingolimod in patients who have received a complete and appropriate course of treatment lasting less than 12 months.
  • Due to the lack of individual patient-specific decisions regarding the timing and therapeutic consistency, the impact of the statistically significant advantage observed in a patient population on the overall group cannot be estimated. The additional benefit of fingolimod in the morbidity category is therefore not proven.
• Conclusion on the morbidity endpoint category
  • For the ‘morbidity’ endpoint category, there is a statistically significant difference in favour of switching to fingolimod compared with continuing IFN-β 1atherapy, for RRMS patients with high disease activity who have received less than one year of prior treatment with IFN-beta.
  • For patients who switched therapies within the context of their basic treatment, following one year of prior treatment, the difference between the treatment arms is not significant. No evaluable data are available regarding a switch to fingolimod in patients who have received a complete and appropriate course of treatment lasting less than 12 months.
  • Due to the lack of individual patient-specific decisions regarding the timing and therapeutic consistency, the impact of the statistically significant advantage observed in a patient population on the overall group cannot be estimated. The additional benefit of fingolimod in the morbidity category is therefore not proven.
• Health-related quality of life
  • For the health-related quality of life endpoint, assessed using the PRIMUS Qol and EQ-5D questionnaires, only the PRIMUS Qol is considered a suitable instrument for measuring health-related quality of life for the benefit assessment in this indication.
  • However, no usable data were available either for the patient group ‘RRMS patients with high disease activity who have received prior treatment with IFN-beta for less than 1 year’ or for patients who had not completed a full and appropriate course of at least 1 year with at least one DMT (other than IFN-beta), as, as with the mFIS, there are uncertainties as to whether the proportion of patients not included in the questionnaire analysis exceeds 30 per cent.
  • No conclusions regarding additional benefit can be drawn for the endpoint ‘health-related quality of life’.
• Side effects
  • No statistically significant differences were observed between the treatment arms in any of the patient groups with regard to the overall rates of AEs, SAEs and therapy discontinuations due to AEs.
  • A comprehensive review of the results on side effects does not allow any conclusions to be drawn regarding greater harm or additional benefit for fingolimod. The statistically significant advantage in the endpoint ‘influenza-like events’ is present exclusively in the patient population (patients who had received prior treatment with IFN-β for less than 1 year) and cannot be extrapolated to the entire patient population a). The additional benefit is therefore classified as not proven.

b) Patients with highly active RRMS who have not responded to a complete and appropriate course of at least one disease-modifying therapy, for whom, following an individual patient assessment taking into account the overall clinical situation, in particular the severity of severe relapses, a switch to an escalation therapy is the recommended course of treatment

• No data are available regarding a comparison with a patient-specific escalation therapy that takes into account prior treatment and the marketing authorisation. An additional benefit of fingolimod compared with the appropriate comparator therapy is not proven.

Courtesy translation only, please refer to the German original.