Pitolisant (1) – Wakix®

• Clinical trials
  • HARMONY CTP is a randomised, double-blind trial comparing pitolisant with placebo in terms of weekly cataplexy episodes and excessive daytime sleepiness in patients with narcolepsy and cataplexy.

Adults for the treatment of narcolepsy with or without cataplexy

• In summary, the additional benefit of pitolisant is assessed as follows: for patients with narcolepsy with or without cataplexy, there is a non-quantifiable additional benefit.
• Due to the methodological limitations of the study, the overall limited evidence base and the lack of long-term results, the G-BA classifies the extent of the additional benefit for pitolisant, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition, the written submissions and the oral hearing, as non-quantifiable.
• There is an additional benefit, but it is non-quantifiable because the scientific evidence currently does not permit a quantifiable statement on the extent of the additional benefit for patient-relevant endpoints.
• mortality
  • Mortality was recorded in the HARMONY studies as part of the safety assessment. No deaths occurred.
• Morbidity – reduction in daytime sleepiness
  • Daytime sleepiness was assessed at each visit using the Epworth Sleepiness Scale (ESS) questionnaire, which was completed by the patients.
  • For the endpoint of daytime sleepiness as measured by the ESS, a statistically significant advantage of pitolisant over placebo can be inferred from the HARMONY I study: at the end of treatment, there was a 3.0-point reduction in the ESS score compared with baseline [adjusted difference pitolisant vs. placebo: -3.0 [95% CI -5.6 to -0.4]; p = 0.024].
  • Compared with modafinil, pitolisant showed neither a positive nor a negative effect on daytime sleepiness according to this scale [adjusted difference: pitolisant vs. modafinil: 0.12 [95% CI -2.5 to 2.7]].
  • Furthermore, the HARMONY Ibis study demonstrated the superiority of pitolisant over placebo in terms of daytime sleepiness [adjusted difference: pitolisant vs. placebo: -2.12 [95% CI -4.10 to -0.14]; p = 0.036].
  • Non-inferiority compared with modafinil, with a pre-specified non-inferiority margin of 2 points, could not be confirmed in this study either [adjusted difference between pitolisant and modafinil: 2.83 [95% CI 1.10 to 4.55]].
  • An ESS responder analysis (less than 10 points after completion of treatment) was presented. The results are consistent with the primary analyses for this endpoint: a clinically relevant, significant advantage for pitolisant compared with placebo was observed in both studies, whilst pitolisant showed no statistically significant difference in the responder rate compared with modafinil.
  • The supportive HARMONY CTP study also shows that, for this endpoint, a significantly higher proportion of patients treated with pitolisant had an ESS score of 10 points or less compared with the placebo group.
  • The rationale and methodology behind this are not described in a comprehensible manner, and it remains unclear whether the centres were randomly reallocated, meaning that potential bias cannot be ruled out.
  • In particular, the HARMONY Ibis study failed to demonstrate the superiority of pitolisant over placebo without cluster analysis.
  • The positive effect of pitolisant on the reduction of daytime sleepiness, as compared with placebo, cannot be assessed overall. No conclusion regarding the extent of the additional benefit can be drawn for this endpoint.
• quality of life
  • Data on quality of life were not collected in any of the studies.
  • In the indication of narcolepsy, it would be possible to assess quality of life, and it is unclear why this endpoint was not measured.
  • It is therefore not possible to draw any conclusions regarding the extent of the additional benefit in the quality of life category.
• Side effects – AEs, severe AEs, serious SAEs
  • In the HARMONY I study, more adverse events and severe adverse events occurred in the pitolisant arm (maximum dose up to 40 mg) compared with the placebo arm.
  • By contrast, when compared with the AE rates in the modafinil arm, pitolisant showed an advantage over modafinil in terms of side effects: numerically fewer events were observed in the pitolisant arm.
  • The HARMONY Ibis study showed opposite results and thus a disadvantage of pitolisant compared with modafinil. Although the maximum dose of pitolisant in this study was only 20 mg, approximately twice as many severe AEs were documented in the pitolisant arm compared with the modafinil arm [relative risk pitolisant vs. modafinil 2.13 [95% CI 1.10 to 4.12], p = 0.024].
  • The rate of AEs also showed a numerical disadvantage for pitolisant compared with modafinil.
  • The rates of serious AEs are minor overall.
  • The adverse reaction profile of pitolisant cannot be conclusively assessed on the basis of the currently available data, which involve small sample sizes and a short duration of treatment. It is not possible at this stage to draw any conclusions regarding the extent of the additional benefit.
• Overall assessment / Conclusion
  • Results on morbidity and side effects are available from the studies supporting the marketing authorisation for the assessment of the extent of the additional benefit of pitolisant.
  • The extent of the demonstrated positive effects in terms of cataplexy rates and daytime sleepiness is non-quantifiable due to methodological limitations.
  • Data on quality of life were not collected in any of the studies. However, such data would have been important, particularly for the morbidity endpoints, in order to assess the burden the symptoms place on patients and the clinical significance of a reduction in these events.
  • Against this background, it is not possible to quantify the extent of the additional benefit.
• Overall assessment / Conclusion
  • Results on morbidity and side effects are available from the studies supporting the marketing authorisation for the assessment of the extent of the additional benefit of pitolisant.
  • The positive effects demonstrated with regard to cataplexy rates and daytime sleepiness are non-quantifiable in terms of their extent due to methodological limitations.
  • Data on quality of life were not collected in any of the studies. However, such data would have been important, particularly for the morbidity endpoints, in order to assess the burden that the symptoms place on patients and the clinical significance of a reduction in these events.
  • Against this background, it is not possible to quantify the extent of the additional benefit.

Courtesy translation only, please refer to the German original.