Danicopan (1) – Voydeya®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the completed, randomised, controlled, double-blind Phase III ALPHA trial for the benefit assessment.

Adults with paroxysmal nocturnal haemoglobinuria (PNH) who have residual haemolytic anaemia

• Consequently, for Danicopan as an add-on therapy to Ravulizumab or Eculizumab for the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH), who have residual haemolytic anaemia, as the scientific evidence does not permit quantification of the additional benefit.
• The strength of the evidence is classified as ‘hint’.
• mortality
  • Overall survival was not assessed as an independent endpoint in the ALPHA study. Deaths were recorded as part of the adverse event monitoring. No deaths occurred in any study arm during TP1.
  • Nevertheless, due to the uncertainties of the ALPHA study outlined above, the results cannot be evaluated and are therefore not suitable for quantifying the extent of the additional benefit.
• Morbidity – Change in haemoglobin (Hb) levels from baseline to week 12
  • The endpoint ‘change in haemoglobin (Hb) level from baseline to week 12’ was the primary endpoint of the ALPHA study.
  • This endpoint represents a laboratory parameter with no direct relation to symptoms and is not, in itself, relevant to patients. As it is the primary endpoint, it is presented here for the sake of completeness.
• Morbidity – Freedom from transfusion
  • The endpoint ‘transfusion-free status’ during TP1 describes the proportion of patients who did not require a transfusion from baseline to week 12.
  • PNH is a chronic condition. Consequently, no conclusions regarding the long-term avoidance of transfusions can be drawn from the absence of transfusions after only 12 weeks, as reported in the comparative data from TP1.
  • The results for the endpoint ‘transfusion-free status’ cannot therefore be assessed in this case and are thus unsuitable for quantifying the extent of the additional benefit. The endpoint is presented for supplementary information only.
• Morbidity – Fatigue (FACIT-Fatigue)
  • In the ALPHA study, fatigue as perceived by patients was assessed using the FACIT-Fatigue questionnaire.
  • In its written statement on the FACIT-Fatigue (as well as on the other patient-reported endpoints), the pharmaceutical manufacturer presents responder analyses for both improvement and worsening.
  • The responder analysis for improvement shows no statistically significant difference. The responder analysis for deterioration shows a statistically significant difference between the treatment arms in favour of danicopan.
  • Nevertheless, due to the uncertainties of the ALPHA study outlined at the outset, the results cannot be evaluated and are therefore not suitable for quantifying the extent of the additional benefit.
• Morbidity – Symptoms (EORTC QLQ-C30)
  • Patients’ symptoms were assessed in the ALPHA study using the symptom scales of the EORTC-QLQ-C30 questionnaire.
  • The EORTC QLQ-C30 is a generic measurement tool for assessing symptoms and quality of life in patients with oncological diseases. The relevance of individual items in the questionnaire to the symptoms in the present therapeutic indication is unclear. The symptom scales of the EORTC QLQ-C30 are therefore not used for this assessment.
• Morbidity – General health status (EQ-5D Visual Analogue Scale)
  • Patients’ health status was assessed in the ALPHA study using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The responder analysis for improvement shows no statistically significant difference. The responder analysis for deterioration shows a statistically significant difference between the treatment arms in favour of Danicopan.
  • Nevertheless, due to the uncertainties of the ALPHA study outlined at the outset, the results cannot be evaluated and are therefore not suitable for quantifying the extent of the additional benefit.
• quality of life
  • Data on health-related quality of life from the ALPHA study are available based on the functional scales and the global health status scale of the EORTC QLQ-C30.
  • In the responder analyses for improvement, a statistically significant difference in favour of Danicopan is evident on the physical functioning scale. In the responder analyses for deterioration, statistically significant differences between the treatment arms in favour of Danicopan were observed on the scales for physical functioning, role functioning and emotional functioning.
  • However, due to the uncertainties of the ALPHA study outlined above, the results cannot be evaluated and are therefore not suitable for quantifying the extent of the additional benefit.
• Side effects – Total adverse events (AEs)
  • AEs occurred in approximately 75% of patients in the intervention arm and approximately 62% of patients in the comparator arm. The results are presented here for supplementary information only.
• Overall assessment
  • Results from the ALPHA study are available for the benefit assessment of Danicopan as an add-on therapy to Ravulizumab or Eculizumab for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH) who have residual haemolytic anaemia. During the 12-week, double-blind, randomised controlled phase (TP1) of the study, Danicopan was compared with placebo (in each case with stable background therapy with Ravulizumab or Eculizumab).
  • PNH is a chronic condition. Accordingly, as previously noted in the G-BA’s resolutions on ravulizumab and pegcetacoplan, a comparative study duration of at least 24 weeks is generally regarded as necessary for the therapeutic indication of PNH. Against this background, the total duration of 12 weeks for TP1 of the ALPHA study is considered too short to allow reliable conclusions to be drawn from the available data regarding the extent of the additional benefit.
  • Furthermore, additional uncertainties arise because TP1 was terminated prematurely, meaning that data collection for some patients in the intervention and control arms was carried out in an unblinded manner towards the end of TP1. Furthermore, the possibility of unintended unblinding of the study staff cannot be ruled out, as the treating study staff were aware of the patients’ haemoglobin levels.
  • In summary, the available data on mortality, morbidity, quality of life and side effects do not allow for a quantification of the extent of the additional benefit of Danicopan, particularly given the short duration of TP1 (12 weeks).

Courtesy translation only, please refer to the German original.