Safinamid (1) – Xadago®

• Clinical trials
  • These were randomised, placebo-controlled, double-blind trials involving adult patients with idiopathic Parkinson’s disease and motor fluctuations who were already being treated with a stable dose of levodopa.
  • The SETTLE trial comprised two treatment arms, safinamide and placebo, into which a total of 549 patients were randomised in a 1:1 ratio.
  • The studies included for the indirect comparison – CSG, NSG, PSG and UK-IESG – were randomised, placebo-controlled, double-blind trials involving patients with idiopathic Parkinson’s disease receiving a stable dose of levodopa.

Treatment of idiopathic Parkinson’s disease in the moderate to late stages as adjunctive therapy in patients with fluctuations who are on a stable dose of L-dopa, either alone or in combination with other anti-Parkinson’s medicines

• For the treatment of idiopathic Parkinson’s disease in the middle to late stages of the disease as an adjunctive therapy in patients with fluctuations who are on a stable dose of L-dopa, alone or in combination with other anti-Parkinson’s medicines, the additional benefit compared with the appropriate comparator therapy is not proven.
• mortality
  • In Study 016, there were five deaths in the safinamide group and two deaths in the placebo group. In the SETTLE study, one death occurred in the safinamide group and two in the placebo group. However, as no deaths occurred or were reported in the entacapone studies, no indirect comparison can be calculated due to the lack of data.
  • An additional benefit for safinamide in the mortality category is therefore not proven.
• Morbidity – ‘on’ time and ‘off’ time
  • An ‘off’ phase is characterised by poor mobility, muscle stiffness and/or tremor, whereas during an ‘on’ phase the patient experiences few or no Parkinson’s symptoms.
  • In the safinamide studies, changes in ‘on’ time were recorded based on diary entries whilst taking dyskinesias into account; that is, as ‘on’ phases without dyskinesias or with non-impairing dyskinesias. No such information was available for the entacapone studies; consequently, all ‘on’ phases were included in the analysis, regardless of whether dyskinesias occurred.
  • Due to the lack of information on dyskinesias in the entacapone studies, it is unclear to what extent changes in ‘on’–‘off’ time are associated with disabling dyskinesias.
  • The indirect comparison showed no significant difference between the entacapone and safinamide groups.
• Morbidity – Unified Parkinson’s Disease Rating Scale (UPDRS)
  • The Unified Parkinson’s Disease Rating Scale is used to assess the Parkinson’s-specific (long-term) course of the disease. UPDRS Part I assesses cognitive functioning, behaviour and mood; UPDRS Part II assesses activities of daily living; UPDRS Part III assesses motor function; and UPDRS Part IV assesses complications during treatment.
  • As UPDRS Part IV was not assessed in the entacapone studies, an indirect comparison of safinamide versus entacapone for this endpoint was not feasible.
  • No statistically significant differences between the treatment groups were observed in the indirect comparison for any of the individual subscales of Parts I–III of the UPDRS.
  • For the total score of Parts I to III, the entacapone studies were examined individually against the safinamide studies, as heterogeneity was observed between the individual studies on the entacapone side. These analyses also revealed no significant difference between the treatment groups.
  • However, the standardised mean comparisons reveal relatively wide confidence intervals, and the relevance threshold of 0.2 is exceeded. Furthermore, the effect estimators tend to suggest that safinamide is inferior to entacapon, meaning that, overall, the inferiority of safinamide compared with entacapon cannot be definitively ruled out.
  • As the indirect comparison did not show a significant difference between the entacapone and safinamide groups for any endpoint in the morbidity category, an additional benefit of safinamide over entacapone is therefore not proven for the morbidity endpoint category.
• Health-related quality of life
  • No usable data were available for an indirect comparison regarding health-related quality of life.
  • An additional benefit of safinamide over entacapone is therefore not proven for the quality of life endpoint category.
• Side effects – adverse events (AEs) and serious adverse events (SAEs)
  • No data suitable for an indirect comparison are available from which conclusions regarding additional benefit can be drawn.
• Overall review
  • In the overall review, within the endpoint category of non-serious side effects, there were statistically significantly fewer cases of diarrhoea with safinamide than with the COMT inhibitor entacapon.
  • Furthermore, as there is no comprehensive and complete information available for the entacapon group on all adverse events – in particular those specific to the MAO-B inhibitor safinamide – the results regarding side effects are potentially biased and can only be interpreted to a limited extent.
  • As the limited information available for the entacapon group meant that a selection had to be made of the side effects used for the benefit assessment, it is not possible to assess how the side effect profile of safinamide compared with entacapon would have looked for the unreported side effects.
  • Due to these uncertainties, the interpretability of the results on adverse events is compromised, and no valid conclusions regarding additional benefit can be drawn from the available analyses; consequently, neither an advantage nor a disadvantage of safinamide over entacapone can be inferred.
• Conclusion
  • It is not possible to conclusively assess the extent to which this impairs the interpretability of other endpoints. Furthermore, no positive effects are evident for the morbidity endpoints ‘on’ and ‘off’ times, or for the UPDRS. Furthermore, for the endpoints assessed using the UPDRS, the inferiority of safinamide compared with entacapone cannot be definitively ruled out.
  • Taking into account the lack of information on a relevant proportion of other side effects, no definitive conclusion can be drawn regarding side effects as a whole from the positive results for safinamide in relation to non-serious side effects (diarrhoea). No data on quality of life are available.
  • Thus, in view of the available data – or rather, the partially limited interpretability of the available data – and the lack of data on patient-relevant endpoints, no overall additional benefit can be established for safinamide.
  • Taking a comprehensive view of the available results for all endpoints and considering the uncertainties inherent in the indirect comparison, no added benefit can therefore be established for safinamide compared with the appropriate comparator therapy (entacapone) in patients with idiopathic Parkinson’s disease (PD) as an adjunct to a stable dose of levodopa (L-dopa) (as monotherapy or in combination with other Parkinson’s medicinal products) in patients with mid- to late-stage disease experiencing fluctuations, additional benefit is not proven.

Courtesy translation only, please refer to the German original.