Lumacaftor / Ivacaftor (2) – Orkambi®

• Clinical trials
  • Study 109 was a randomised, double-blind, placebo-controlled Phase 3 trial that was decisive for the extension of the marketing authorisation for lumacaftor/ivacaftor.

a) Patients aged 6 years and over who are homozygous for the F508del mutation in the CFTR gene

• Taken together, on the basis of the criteria in Section 5(7) of the AM-NutzenV, and given the described uncertainty regarding the LCI2.5 endpoint in relation to the current scientific evidence on its validity, the G-BA has determined, at most, a hint of a non-quantifiable additional benefit of lumacaftor/ivacaftor compared with the best available symptomatic treatment in the present therapeutic indication for children aged between 6 and 11 years.
• mortality
  • No deaths occurred in the study.
• Morbidity – Pulmonary exacerbations and hospitalisations due to pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
  • There were 24 pulmonary exacerbations per 50 patient-years in the lumacaftor/ivacaftor arm and 18 exacerbations per 49.8 patient-years in the control arm.
  • There were 8 hospitalisations due to pulmonary exacerbations per 50 patient-years in the lumacaftor/ivacaftor arm and 6 hospitalisations per 49.8 patient-years in the control arm.
  • These data show no statistically significant difference between the treatment groups.
  • The study shows that pulmonary exacerbations are not very common events in children aged 6 to 11 years.
• Quality of life – Health-related quality of life measured using the CFQ-R
  • Quality of life was assessed using the validated, disease-specific quality-of-life instrument CFQ-R, employing two versions (the patient version and, supplementarily, the parent/carer version).
  • In the self-assessment using the patient version, the difference – averaged over the course of the study – showed no statistically significant improvement with lumacaftor/ivacaftor compared with the control group.
  • Overall, no additional benefit of lumacaftor/ivacaftor compared with best-possible symptomatic treatment can be inferred for health-related quality of life as measured by the patient version of the CFQ-R.
• Side effects – Serious adverse events (SAEs)
  • For the SAE endpoint, IQWiG carried out its own calculations based on the information in the study report in order to assess the influence of the concurrent recording of exacerbation events on the result for the SAE endpoint.
  • This resulted in 5 to 7 children with at least one SAE in the lumacaftor/ivacaftor arm and 6 to 9 children with at least one SAE in the control arm.
  • In summary, for the SAE endpoint, there is no indication of greater or minor harm from lumacaftor/ivacaftor compared with best-possible symptomatic treatment.
• Overall assessment
  • For the benefit assessment of lumacaftor/ivacaftor for the treatment of cystic fibrosis (CF, cystic fibrosis) in patients aged 6 years and over who are homozygous for the F508del mutation in the CFTR gene, results from Study 109 are available regarding morbidity, quality of life and side effects.
  • Based on the data in the dossier and the information submitted by the pharmaceutical manufacturer during the commenting procedure, it can be assumed that the standard of care in Study 109 corresponds to an adequate implementation of the best possible symptomatic treatment, in line with the appropriate comparator therapy as determined by the G-BA.
  • For the children aged 6 to 11 years examined here, who are homozygous for the F508del mutation in the CFTR gene, there are no statistically significant differences with regard to the endpoints of pulmonary exacerbations and hospitalisations due to pulmonary exacerbations, symptoms (measured using the CFQ-R questionnaire), BMI and BMI z-score, health-related quality of life (measured using the CFQ-R questionnaire) and side effects, no statistically significant differences were observed between the lumacaftor/ivacaftor arm and the control arm.
  • With regard to the lung function parameters LCI2.5 and FEV1 %, statistically significant differences were observed in favour of lumacaftor/ivacaftor compared with best-possible symptomatic treatment.
  • In the present therapeutic indication for children aged between 6 and 11 years, disease progression and, consequently, organ damage are not yet at an advanced stage. In practice, it is evident that the quality of life among these children is largely good to near-normal, and that there is no high rate of exacerbations in this patient population.
  • As the aim of treatment in this young patient group is to slow the progression of the disease, the LCI2.5 endpoint is regarded as a diagnostic and potential prognostic parameter for the clinical assessment of disease progression in the early stages of cystic fibrosis.
  • Given the progressive nature of the disease, particular importance is attached to the therapeutic goal of slowing progression when assessing the additional benefit in the present patient population, namely children aged 6 to 11 years.
  • Given the largely absent symptoms in children aged 6 to 11 years, it appears difficult to demonstrate this advantage. In the G-BA’s view, the lung function parameter LCI2.5 can be used in this regard to derive an additional benefit of lumacaftor/ivacaftor for patients aged 6 years and over, compared with the best possible symptomatic treatment.
  • However, in view of the uncertainties outlined and the limitations in assessing the direct significance of the observed effect, the extent of the advantage cannot be quantified for the overall assessment of additional benefit.
• Conclusion
  • To assess the additional benefit of lumacaftor/ivacaftor compared with the best available symptomatic treatment in patients aged 6 to 11 years with cystic fibrosis (CF, cystic fibrosis) who are homozygous for the F508del mutation in the CFTR gene, the pharmaceutical manufacturer submitted Study 109.

Courtesy translation only, please refer to the German original.