Fingolimod (3) – Gilenya®

• Clinical trials
  • The FREEDOMS and FREEDOMS II trials were designed as three-arm studies (0.5 mg, 1.25 mg and placebo).

a) Patients with highly active relapsing-remitting multiple sclerosis with high disease activity who have not responded to a complete and appropriate course of at least one disease-modifying therapy (interferon-β), normally lasting at least one year (Duration of prior treatment with at least one disease-modifying therapy ≥ 1 year)

• For patients with highly active relapsing-remitting multiple sclerosis with high disease activity who have not responded to a complete and appropriate course of IFN-β, normally lasting at least one year, the additional benefit of fingolimod is not proven.
• An additional benefit is not proven.

b) Patients with highly active relapsing-remitting multiple sclerosis with high disease activity who have not yet received adequate disease-modifying therapy (with interferon-β) (duration of prior treatment with interferon-β < 1 year)

• For patients with highly active relapsing-remitting multiple sclerosis with high disease activity who have not yet received adequate disease-modifying therapy (duration of prior treatment with IFN-β < 1 year), there is an indication of considerable additional benefit from fingolimod.
• The G-BA classifies the extent of the additional benefit of fingolimod as considerable, 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.
• mortality
  • No deaths occurred in either treatment arm of the TRANSFORMS study.
  • Due to its size and duration, the trial was not designed to detect differences in mortality.
  • Overall, there is no additional benefit of fingolimod proven for this endpoint.
• Morbidity – relapses
  • For the relapse endpoint, the ‘annual relapse rate’ is considered the relevant measure of the endpoint.
  • There is a statistically significant difference in favour of fingolimod compared with IFN-β 1a (0.24 vs. 0.6, RR = 0.4, p = 0.017).
  • The proportion of patients experiencing a relapse was 20.4% in the fingolimod arm (79.6% relapse-free patients) and 33.9% in the interferon arm (66.1% relapse-free patients). The difference was not statistically significant.
  • When considering the overall results for the endpoint ‘disease relapses’, the additional benefit of fingolimod compared with INF-β is classified as considerable for this endpoint.
• Morbidity – Progression of disability
  • No statistically significant differences were observed between the treatment groups for either the endpoint ‘time to first confirmed disability progression’ or ‘severity of disability’ (mean change in the Multiple Sclerosis Functional Composite Standard Score (MSFC-z)).
  • An additional benefit is therefore not proven for this endpoint.
• Morbidity – Fatigue
  • The 39-item mFIS questionnaire, which is a preliminary, non-validated version of the U-FIS (Unidimensional Fatigue Impact Scale), was used to assess fatigue.
  • Due to this uncertainty, no conclusions regarding the extent of the additional benefit for this endpoint can be drawn from the data.
  • No conclusions regarding additional benefit can be drawn for the endpoint ‘fatigue’.
• Morbidity – Activities of Daily Living
  • No usable data were available for the endpoint ‘Activities of Daily Living’ (PRIMUS Activities) as, as with the mFIS, there are uncertainties as to whether the proportion of patients not included in the analysis of the questionnaire exceeds 30 per cent.
  • No conclusions regarding additional benefit can be drawn for the ‘Activities of Daily Living’ endpoint.
• Morbidity – Health status
  • For the health status endpoint, assessed using the EQ-5D visual analogue scale, no statistically significant difference (p = 0.642) was observed between the treatment groups.
  • An additional benefit of fingolimod is therefore not proven for this endpoint.
• 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, 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 – overall rate of adverse events (AEs)
  • Adverse events occurred in 92.6% of patients in the fingolimod arm and in 87.5% of patients in the INF-β arm.
  • There is no proof that fingolimod is more or less harmful than IFN-β 1a with regard to these endpoints.
• Side effects – Serious AEs and discontinuation due to AEs
  • For the endpoints of SAEs and discontinuation due to AEs, no statistically significant difference was observed between the treatment groups (p = 0.144 and p = 0.767, respectively).
  • There is not enough proof that fingolimod is more or less harmful than IFN-β 1a for these endpoints.
• Side effects – Specific adverse events – Influenza-like illness
  • For the endpoint ‘flu-like illness’, there was a statistically significant difference in favour of fingolimod compared with IFN-β 1a.
  • No flu-like symptoms were recorded with fingolimod, whilst 28.6% of patients on IFN-β 1a experienced a flu-like illness (0.03 [0.00; 0.51]; p = < 0.001).
  • It can therefore be concluded that fingolimod causes less harm than IFN-β 1a. The significant reduction in side effects is assessed as a minor additional benefit.
• Side effects – Specific adverse events – Constipation
  • Constipation occurred in 4 patients (7.4%) treated with fingolimod, whilst no such event was recorded in the IFN-β 1a group (9.33 [0.51; 169.2]; p = 0.045).
  • Thus, whilst there was a statistically significant difference to the detriment of fingolimod for the endpoint of constipation, a only minor effect cannot be ruled out due to the small number of events.
  • It is therefore not possible to conclude that fingolimod causes greater or minor harm with regard to this endpoint.
• Conclusion
  • For the endpoint ‘relapse rate’, there is a considerable additional benefit, and for the endpoint ‘flu-like illness’, a minor additional benefit of fingolimod compared with IFN-β 1a.
  • The results thus demonstrate a significant reduction in disease symptoms as well as a significant reduction in side effects.
  • Overall, for patients with highly active relapsing-remitting multiple sclerosis who have not yet received adequate disease-modifying therapy (duration of prior treatment with INF-β < 1 year), fingolimod offers additional benefit compared with INF-β 1a, as there are consistent positive effects in the endpoint categories of morbidity and side effects.
  • Overall, the G-BA concludes that there is a considerable additional benefit.

c) Patients with rapidly progressive severe relapsing-remitting multiple sclerosis

• For patients with rapidly progressing, severe relapsing-remitting multiple sclerosis, defined as two or more relapses with disability progression within one year, and with one or more gadolinium-enhancing lesions on brain MRI or with a significant increase in T2 lesions compared with a recent MRI scan, there is an indication of a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of fingolimod as minor, 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.
• On the basis of the information in the dossier and the results of the benefit assessment, the G-BA concludes that a significant improvement in treatment-related benefit, particularly with regard to the prevention of serious side effects, cannot be inferred from the data submitted.
• mortality
  • No deaths occurred in either treatment arm of the TRANSFORMS study.
  • Due to its size and duration, the trial was not designed to detect differences in mortality.
  • Overall, the additional benefit of fingolimod is not proven for this endpoint.
• Morbidity – relapses
  • For the endpoint ‘relapses’, as was also the case in patient population b), the operationalisation ‘annual relapse rate’ is considered the relevant operationalisation of the endpoint.
  • Here, there is a statistically significant difference in favour of fingolimod compared with IFN-β 1a (0.27 vs. 0.56; RR = 0.48; p = 0.031).
  • The proportion of patients experiencing a relapse was 19.6% in the fingolimod arm (80.3% relapse-free patients) and 35.4% in the interferon arm (64.6% relapse-free patients). The difference was not statistically significant.
  • The results for the endpoint ‘annual relapse rate’ are clinically relevant and are used to determine the extent of the additional benefit.
  • Overall, fingolimod shows advantages over IFN-β 1a for the endpoint ‘disease relapses’.
• Morbidity – disability progression
  • No statistically significant differences were observed between the treatment groups for either the endpoint ‘time to first confirmed disability progression’ or ‘severity of disability’ (mean change in the Multiple Sclerosis Functional Composite Standard Score (MSFC-z)).
  • An additional benefit is therefore not proven for this endpoint.
• Morbidity – Fatigue
  • The 39-item mFIS questionnaire, which is a preliminary, non-validated version of the U-FIS (Unidimensional Fatigue Impact Scale), was used to assess fatigue.
  • Due to this uncertainty, no conclusions regarding the extent of the additional benefit for this endpoint can be drawn from the data.
  • No conclusions regarding additional benefit can be drawn for the endpoint ‘fatigue’.
• Morbidity – Activities of Daily Living
  • No usable data were available for the endpoint ‘Activities of Daily Living’ (PRIMUS Activities) 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 ‘Activities of Daily Living’ endpoint.
• Morbidity – Health status
  • For the health status endpoint, assessed using the EQ-5D visual analogue scale, no statistically significant difference (p = 0.323) was observed between the treatment groups.
  • An additional benefit of fingolimod is therefore not proven for this endpoint.
• 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, 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 – overall rate of adverse events (AEs)
  • Adverse events occurred in 89.2% of patients in the fingolimod arm and in 89.3% of patients in the INF-β arm.
  • There is not enough proof of greater or minor harm from fingolimod compared with IFN-β 1a for these endpoints.
• Side effects – Serious adverse events
  • In the TRANSFORMS study, 4 (7.1%) serious adverse events (SAEs) were recorded whilst no patients experienced a SAE whilst being treated with IFN-β 1a (p = 0.029).
  • There is a statistically significant difference to the detriment of fingolimod.
  • Serious adverse events are clinically relevant and are taken into account when determining the additional benefit, whilst weighing up the greater or lesser harm caused by fingolimod.
• Side effects – discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AEs’, no statistically significant difference was observed between the treatment groups (p = 0.596).
  • There is not enough proof to show that fingolimod causes greater or minor harm compared with IFN-β 1a for this endpoint.
• Conclusion
  • Taking an overall view of the endpoints relating to morbidity and side effects, both an advantage (reduction in the annual relapse rate, minor harm for the ‘flu-like illness’ endpoint) and a disadvantage (greater harm for the ‘SAE’ endpoint) of fingolimod compared with IFN-β 1a.
  • Taken together, for patients with rapidly progressive, severe relapsing-remitting multiple sclerosis – defined as two or more relapses with disability progression in one year, and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesions compared with a recent MRI scan, there is an additional benefit of fingolimod over INF-β 1a, given the available findings on morbidity and side effects.

Courtesy translation only, please refer to the German original.