Mepolizumab (1) – Nucala®

• Clinical trials
  • For the benefit assessment of mepolizumab in adult patients with severe refractory eosinophilic asthma, the pharmaceutical manufacturer draws on the two randomised controlled trials, MENSA and SIRIUS.
  • In the multicentre, randomised, double-blind MENSA trial, patients with severe refractory eosinophilic asthma were treated with mepolizumab in the intervention arms or with placebo in the comparator arm (in each case in addition to therapy with ICS and LABA).
  • The multicentre, randomised, double-blind SIRIUS study investigated patients with severe refractory eosinophilic asthma who received either 100 mg s.c. mepolizumab or placebo s.c. (in each case in addition to treatment with ICS, LABA and OCS) over a 24-week treatment period.

a) Patients with severe refractory eosinophilic asthma who are not being treated with oral corticosteroids, or who are only being treated with them during acute exacerbations

• The additional benefit is not proven.
• As only the MENSA study was submitted for patient population a), and this cannot be used for assessment for the reasons described, additional benefit is therefore not proven for this patient population.

b) Patients with severe refractory eosinophilic asthma who are treated regularly with oral corticosteroids, even beyond the treatment of acute exacerbations

• There is a hint of a minor additional benefit.
• Based on these considerations, the information in the dossier, the results of the benefit assessment and the addendum, as well as the statements submitted, the G-BA concludes that, for adult patients with severe refractory eosinophilic asthma who are treated regularly with OCS even beyond the treatment of acute exacerbations, there is a hint of a minor additional benefit of mepolizumab compared with the appropriate comparator therapy.
• mortality
  • For the patient-relevant endpoint of all-cause mortality, the SIRIUS study showed no statistically significant difference between the treatment groups, as there were no deaths at all in the intervention arm receiving mepolizumab and only one death in the control arm.
  • An additional benefit in terms of overall survival is not proven.
• Morbidity – Clinically significant exacerbations
  • As part of the reduction in OCS dose, the annual rate of exacerbations was reduced in both study arms in the SIRIUS trial.
  • The overall rates of exacerbations show a statistically significant advantage of mepolizumab over placebo (RR 0.60 [95% CI: 0.44; 0.84]; p=0.002).
• Morbidity – OCS reductions to ≤ 5 mg/day
  • For the endpoint ‘OCS reduction to ≤ 5 mg/day’, a statistically significant advantage of mepolizumab over placebo was observed (RR 1.71 [95% CI: 1.13; 2.58]; p=0.008), whereas the endpoint ‘reduction in OCS to 0 mg/day’ showed no statistically significant difference between the treatment groups.
  • Reducing the dose of oral glucocorticoids in the treatment of severe, refractory asthma is a recognised therapeutic goal.
  • The endpoint ‘reduction in OCS to ≤ 5 mg/day’ is therefore used as a valid surrogate endpoint for assessing additional benefit.
• Morbidity – episodes of night-time awakening requiring the use of rescue medication
  • The analysis of the endpoints ‘episodes of night-time awakening requiring the use of rescue medication’ and ‘asthma symptom score’ showed no statistically significant difference between the treatment groups.
• Morbidity – Asthma symptom score
  • The analysis of the endpoints ‘episodes of night-time awakening with use of rescue medication’ and ‘asthma symptom score’ showed no statistically significant difference between the treatment groups.
• Health-related quality of life – SGRQ (St George’s Respiratory Questionnaire) – Responder
  • In the SIRIUS study, no statistically significant advantage of mepolizumab over placebo was observed for the SGRQ responder endpoint.
  • Consequently, there is no hint of any additional benefit of mepolizumab compared with placebo.
  • An additional benefit for quality of life is therefore not proven.
• Side effects – discontinuation due to adverse events (AEs)
  • There is no hint of additional benefit.
  • An additional benefit in terms of avoiding side effects is therefore not proven.
• Conclusion
  • Taking into account the overall results on mortality, morbidity, quality of life and side effects, the SIRIUS study shows that, for patient group b), mepolizumab offers no added benefit compared with the appropriate comparator therapy “Patients with severe refractory eosinophilic asthma who are treated regularly with oral corticosteroids, even beyond the treatment of acute exacerbations” (in accordance with the GINA Report 2016, Level 5), no previously unachieved significant improvement in treatment-related benefit, in particular no alleviation of serious symptoms, no moderate prolongation of life expectancy, no relevant reduction in serious side effects or no significant reduction in other side effects.
  • Therefore, classification as a considerable additional benefit is not justified.
  • The G-BA classifies the extent of the additional benefit of mepolizumab for this patient population 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.
  • In doing so, account is taken of the endpoint ‘reduction in OCS to ≤ 5 mg/day’, which shows a statistically significant improvement with mepolizumab compared with the control arm.

Courtesy translation only, please refer to the German original.