Benralizumab (1) – Fasenra®

• Clinical trials
  • In the multicentre, randomised, double-blind CALIMA and SIROCCO trials, patients with severe refractory eosinophilic asthma were treated with benralizumab in the intervention arms and with placebo in the comparator arm.
  • The multicentre, randomised, double-blind ZONDA trial investigated patients with severe eosinophilic asthma who received either 30 mg benralizumab s.c. (every 4 weeks, or initially every 4 weeks and then every 8 weeks after the first 3 doses) or placebo subcutaneously (in each case in addition to treatment with ICS, LABA and OCS) over a 28-week treatment period.

a) Adult patients with severe eosinophilic asthma that is inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists, and for whom further options for treatment escalation have not yet been exhausted

• The additional benefit is not proven.
• The data from the ZONDA study only include data from patients who can be considered to have reached the limits of current treatment options. There are therefore no data available to assess any additional benefit for patient group a).

b) Adult patients with severe eosinophilic asthma that is inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists, and for whom further options for treatment escalation have already been exhausted

• In light of these considerations, based on 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 eosinophilic asthma, which is inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists and for whom further options for treatment escalation have already been exhausted, there is a hint of a minor additional benefit of benralizumab compared with the appropriate comparator therapy.
• mortality
  • No statistically significant difference was observed between the treatment groups for the patient-relevant endpoint of overall mortality. An additional benefit in terms of overall survival is therefore not proven.
• morbidity
  • In the ZONDA study, morbidity was assessed using the patient-relevant endpoints of asthma exacerbations, asthma control, reductions in OCS to ≤ 5 mg/day and reductions in OCS to 0 mg/day.
  • The endpoint ‘asthma exacerbations’ was defined as a worsening of asthma symptoms leading to the administration of OCS (or an increase in the dose of existing OCS therapy) for at least 3 days, a visit to an A&E department requiring treatment with OCS, or hospitalisation due to asthma.
  • As the aim of the ZONDA study was to reduce the dose of oral corticosteroids and asthma symptoms were used to guide the reduction in OCS dosage, the results for the endpoints ‘asthma exacerbations’ and ‘asthma control’ cannot be used to assess any additional benefit.
  • For the endpoints ‘OCS reduction to ≤ 5 mg/day’ (RR 1.77 [95% CI: 1.22; 2.57]; p=0.003) and ‘OCS reduction to 0 mg/day’ (RR 2.83 [95% CI: 1.34; 5.94]; p=0.006), benralizumab demonstrated statistically significant advantages compared with the control group.
  • Reducing the dosage of oral glucocorticoids in the treatment of severe, refractory asthma is a recognised therapeutic goal. The use of oral glucocorticoids, particularly at higher doses over prolonged periods, can lead to frequent side effects. In the G-BA’s view, reducing the glucocorticoid dose below the so-called Cushing’s threshold in severe refractory eosinophilic asthma is regarded as a relevant surrogate for the avoidance of glucocorticoid-induced side effects. The endpoint ‘reduction in OCS to ≤ 5 mg/day or 0 mg/day’ is therefore used as a valid surrogate endpoint for the assessment of additional benefit.
  • Although the morbidity endpoints of asthma exacerbations and asthma control cannot be used to assess additional benefit, their results support the endpoint ‘reduction in OCS to ≤ 5 mg/day or 0 mg/day’, as there was no increased incidence of exacerbations in the benralizumab arm despite the reduction in OCS.
  • However, the remaining uncertainties regarding the full utilisation of all therapeutic escalation options in the control group of the ZONDA study are taken into account, as these may have a direct influence on the possibility of reducing OCS whilst maintaining at least the same level of asthma control. In this context, particular reference is made to the new escalation option, mepolizumab, for which additional benefit in terms of OCS reduction has already been established. As mepolizumab could not be used in the comparator arm, there remains a degree of uncertainty in the sense that the result for the endpoint ‘reduction in OCS to ≤ 5 mg/day and reduction in OCS to 0 mg/day’ may be weakened. Based on these considerations, the advantage of benralizumab in the ‘morbidity’ category results in a minor additional benefit of benralizumab compared with the appropriate comparator therapy.
• quality of life
  • Quality of life was assessed using the standardised and validated Asthma Quality of Life Questionnaire AQLQ(S)+12 for patients aged 12 years and over, which comprises 32 questions across four domains: symptoms, activity limitation, emotional functioning and environmental triggers.
  • For the quality of life endpoint, as measured by the AQLQ(S)+12, there was no statistically significant advantage of benralizumab compared with the control group.
  • An additional benefit for quality of life is therefore not proven.
• Side effects
  • With regard to side effects, adverse events (AEs) and serious adverse events (SAEs), as well as discontinuations due to adverse events (AEs), although asthma symptoms were not excluded in advance as ‘disease-related events’ when evaluating the AEs.
  • The study showed no statistically significant advantage of benralizumab over the control group.
  • An additional benefit in terms of avoiding side effects is therefore not proven.
• Conclusiveness (probability of additional benefit)
  • For the patient population in the ZONDA study, the G-BA considers the appropriate comparator therapy to have been implemented sufficiently adequately.
  • The probability of additional benefit is therefore classified as a hint.
• Conclusion
  • In summary, data were available for the benefit assessment of benralizumab from the ZONDA study, an OCS reduction study, and from a patient population of the CALIMA and SIROCCO studies selected on the basis of their maintenance therapy.
  • The ZONDA study demonstrates advantages of benralizumab in terms of a statistically significant improvement, as compared with the control arm, for the endpoint ‘OCS reduction to ≤ 5 mg/day or to 0 mg/day’. The results for the endpoints of asthma control and asthma exacerbations cannot be taken into account, as patients’ symptoms were used as a measure of OCS reduction.
  • No advantage of treatment with benralizumab could be demonstrated for the endpoints of mortality, quality of life and side effects.
  • The G-BA classifies the extent of the additional benefit of benralizumab 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.

Courtesy translation only, please refer to the German original.