Mepolizumab (5) – Nucala®

• Clinical trials
  • Study 200622 was a randomised, double-blind trial in which mepolizumab was compared with placebo, in each case in addition to standard therapy for the treatment of HES.

Adults with inadequately controlled hypereosinophilic syndrome without an identifiable, non-haematological secondary cause

• There is a hint of considerable additional benefit for mepolizumab as an adjunctive treatment in adult patients with inadequately controlled hypereosinophilic syndrome without an identifiable, non-haematological secondary cause.
• Overall, there is a hint of considerable additional benefit.
• mortality
  • In study 200622, one death occurred in the mepolizumab arm by week 32.
  • This result is not statistically significant.
• Morbidity – Clinically manifest HES relapses
  • For the present benefit assessment, analyses of the proportion of patients with ≥ 1 clinically manifest HES flare-up are used, as these events are associated with symptoms that are noticeable to patients.
  • A statistically significant advantage was observed for mepolizumab compared with placebo, in each case in combination with standard therapy.
• Morbidity – Fatigue: Brief Fatigue Inventory (BFI)
  • Fatigue was assessed in the 200622 study using BFI Item 3 (most severe fatigue) and the BFI total score (intensity of fatigue / impairment due to fatigue).
  • For the fatigue endpoint, no statistically significant differences were observed between the treatment arms at week 32.
• Morbidity – Severity of HES symptoms (HES-DS)
  • In the 200622 study, the severity of symptoms affecting various organ systems was assessed using an electronic diary (HES-DS).
  • Muscle/joint pain; nasal or sinus symptoms; skin symptoms
  • Based on the differences in mean scores, no statistically significant difference was observed between the two treatment arms.
  • Chills or sweating; abdominal pain or bloating; respiratory symptoms
  • The analyses based on mean differences each revealed a statistically significant advantage in favour of mepolizumab plus standard therapy compared with placebo plus standard therapy.
  • However, the 95% confidence interval for the standardised mean difference does not lie entirely outside the irrelevance range of −0.2 to 0.2 in either case. It cannot therefore be concluded that the effect is clinically relevant.
• Morbidity – Work Productivity and Activity Impairment (WPAI)
  • The Work Productivity and Activity Impairment (WPAI) scale used in the 200622 study is a tool designed primarily to assess health economic aspects relating to the impairment of work productivity and activities over the past 7 days.
  • For the benefit assessment, the WPAI scores for absenteeism and presenteeism are not taken into account. However, the impairment of daily activities due to the disease (question 6) addresses an aspect relevant to patients.
  • For this endpoint, operationalised as the mean change at week 32, a statistically significant advantage was observed in the mepolizumab arm compared with the placebo arm.
  • The result is considered a clinically relevant effect, as the 95% confidence interval of the standardised mean difference lies entirely outside the non-significant range of −0.2 to 0.2.
• Morbidity – Patient-reported treatment response (RTS) and patient-reported symptom severity (SSR)
  • No data suitable for benefit assessment are available for the endpoints patient-reported treatment response (RTS) and patient-reported symptom severity (SSR).
• Morbidity – PROMIS and modified MSAS-SF
  • The endpoint ‘physical functioning and sleep’, as assessed in the 200622 study using the Patient Reported Outcome Measurement Information System (PROMIS), could not be used in the benefit assessment, as the study-specific operationalisation was not sufficiently validated in the dossier.
  • The same applies to the endpoint ‘burden of symptoms’, which was assessed using a modified version of the Memorial Symptom Assessment Scale-Short Form (MSAS-SF).
• Quality of life – SF-36v2 – physical and mental health summary scores
  • The Health Survey Short Form 36 (SF-36) is a generic instrument for measuring health-related quality of life, comprising eight domains and a total of 36 questions.
  • For the benefit assessment, the analyses of improvement by 15% of the scale range at week 32 are used.
  • For the physical composite score (PCS) of the SF-36v2, based on the responder analysis for an improvement of ≥ 9.4 points, there is a statistically significant advantage in favour of mepolizumab + standard therapy compared with placebo + standard therapy.
  • For the mental health summary score (MCS) of the SF-36v2, based on the responder analysis for an improvement of ≥ 9.6 points, there was no statistically significant difference between the treatment groups.
  • In terms of health-related quality of life, mepolizumab showed advantages over placebo in the physical summary score, whilst there were no differences in the mental health summary score.
• Side effects – severe adverse events (SUEs), discontinuation due to adverse events (UEs)
  • For the endpoints assessed – SUEs and discontinuation due to AEs – no statistically significant differences were observed between the treatment groups in either case.
  • In the endpoint category of side effects, there was neither an advantage nor a disadvantage for treatment with mepolizumab plus standard therapy compared with placebo plus standard therapy.
• Overall review
  • The benefit assessment is based on the randomised controlled trial 200622, in which mepolizumab was compared with placebo, in each case in addition to standard therapy for the treatment of HES.
  • Data are available for the endpoint categories of mortality, morbidity, quality of life and side effects.
  • In the overall review, the positive effects of mepolizumab on the morbidity endpoints of clinically manifested HES flare-ups and impairment of activity, as well as on health-related quality of life (physical summary score of the SF-36) compared with the appropriate comparator therapy are assessed as a significant improvement in treatment-related benefit that has not been achieved to date.
  • The extent of the additional benefit is classified as considerable.
  • Consequently, it can be concluded that, overall, mepolizumab offers considerable additional benefit as an adjunctive treatment compared with standard medical management in adult patients with inadequately controlled hypereosinophilic syndrome without an identifiable, non-haematological secondary cause.

Courtesy translation only, please refer to the German original.