Dupilumab (10) – Dupixent®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted results from the BOREAS and NOTUS studies, two double-blind, randomised, controlled trials comparing dupilumab with placebo.
  • The BOREAS trial was conducted between May 2019 and May 2023, and the NOTUS trial between July 2020 and May 2024, at approximately 300 centres worldwide (including Europe and Germany) in each case.

a) Adults with COPD characterised by an elevated eosinophil count in the blood, whose condition is inadequately controlled despite combination therapy comprising ICS, LABA and LAMA, or – where ICS is not appropriate – combination therapy comprising LABA and LAMA, with a post-bronchodilator (BD) FEV1 ≥ 50 per cent of the target

• In the overall assessment, dupilumab as add-on maintenance therapy is found to offer a minor additional benefit compared with maintenance therapy comprising LABA and LAMA and, where appropriate, ICS.
• However, taking into account the availability of a meta-analysis of two RCTs, the certainty of the evidence is overall classified as an indication.
• mortality
  • For the endpoint of all-cause mortality, the meta-analysis shows no statistically significant difference between the treatment groups.
• Morbidity – exacerbations (adjudicated)
  • In the BOREAS and NOTUS studies, exacerbations were documented by the investigator and confirmed by an external adjudication committee, and were defined as follows: “An acute event involving a worsening of respiratory symptoms beyond normal daily variation, leading to a change in medication. This usually involves an acute change in one or more of the following cardinal symptoms: i) an increase in cough (frequency and severity), ii) an increase in sputum volume and/or a change in the nature of the sputum, and iii) an increase in dyspnoea”.
  • For both the endpoint of moderate or severe exacerbations and the endpoint of severe exacerbations, the meta-analysis shows a statistically significant advantage for dupilumab compared with placebo.
  • Overall, however, only a small number of severe exacerbations occurred (in the BOREAS study, 2.1% and 4.3% respectively, and in the NOTUS study, 1.8% and 4.7% of patients in the intervention and control arms respectively). Consequently, the reduction in the number of patients with severe exacerbations shows an absolute difference of only 2.2% and 2.9%, respectively.
• Morbidity – Respiratory symptoms (E-RS:COPD)
  • The 11 questions in the EXACT questionnaire on respiratory symptoms form a standalone instrument (E-RS:COPD) that measures changes in respiratory symptoms.
  • For the endpoint of respiratory symptoms, measured using the total score of the E-RS:COPD, there is heterogeneity between the results from the BOREAS and NOTUS studies (p = 0.049).
  • In the meta-analysis (as in the individual studies), there is no statistically significant difference between the treatment groups.
• Morbidity – Health status
  • For the health status endpoint, measured using the EQ-5D VAS, the NOTUS study shows no statistically significant difference between the treatment groups. No data are available for the BOREAS study.
• Quality of life – St George’s Respiratory Questionnaire (SGRQ)
  • Health-related quality of life was assessed using the SGRQ. The SGRQ comprises the domains of symptoms, activity and daily living. A reduction in the score indicates an improvement.
  • For the SGRQ endpoint, measured using the total SGRQ score, the meta-analysis shows a statistically significant advantage for dupilumab compared with placebo.
  • At the individual study level, a significant difference was observed only in the BOREAS study; the absolute difference in the number of patients showing an improvement in quality of life was 8.2%.
• Side effects – severe adverse events (SUEs)
  • For the SUE endpoint, the meta-analysis shows no statistically significant difference between the treatment groups.
• Side effects – Discontinuation due to adverse events (AEs)
  • For the endpoint ‘discontinuation due to AEs’, the meta-analysis shows no statistically significant difference between the treatment groups.
• Side effects – Specific adverse events
  • No data are available for the relevant patient population for the endpoints of eye diseases (SOC, AEs) and pneumonia (PT, AEs).
  • For the endpoint ‘cardiovascular events’ (MACE), the meta-analysis showed no statistically significant difference between the treatment groups.
• Overall assessment
  • For the endpoint ‘all-cause mortality’, the meta-analysis shows no statistically significant difference between the treatment groups.
  • For the endpoint ‘respiratory symptoms’, as measured by the E-RS:COPD, and for the health status endpoint, measured using the EQ-5D VAS, the meta-analysis (E-RS:COPD) and the NOTUS study (health status), respectively, show no statistically significant differences between the treatment groups.
  • In the quality of life category, the meta-analysis showed a statistically significant advantage of dupilumab compared with placebo for the SGRQ endpoint. A significant difference is evident at the individual study level only in the BOREAS study; the absolute difference in the number of patients showing an improvement in quality of life is 8.2%. The advantage is therefore considered moderate.
  • In the category of side effects, there were no statistically significant differences between the treatment groups.
  • In the overall assessment, dupilumab as an add-on maintenance therapy is therefore found to offer a minor additional benefit for the present patient population of patients with a post-BD FEV1 ≥ 50% of predicted, compared with maintenance therapy comprising LABA and LAMA and, where applicable, ICS.

b) Adults with COPD characterised by an elevated blood eosinophil count who, despite combination therapy comprising ICS, LABA and LAMA, or – where ICS is not appropriate – combination therapy comprising LABA and LAMA, and who have a post-BD FEV1 < 50% of the target

• An additional benefit is not proven.
• For patients with a post-BD FEV1 < 50% of the target value, no data are available for comparison with the appropriate comparator therapy. Therefore, additional benefit is not proven.

Courtesy translation only, please refer to the German original.