Lumacaftor / Ivacaftor (3) – Orkambi®

Patients aged 2 to 5 years with cystic fibrosis who are homozygous for the F508del mutation

• For LUM/IVA for the treatment of cystic fibrosis in children aged 2 years and over who are homozygous for the F508del mutation in the CFTR gene, there is a hint of additional benefit compared with the appropriate comparator therapy, based on the extrapolation of evidence to the paediatric population aged 2–5 years; however, this additional benefit is non-quantifiable because the current scientific evidence does not permit this.
• Given the limitations of the available evidence, a hint of a non-quantifiable additional benefit can be inferred in terms of the certainty of the conclusion.
• Taking into account the lack of alternative treatments for children aged 2–5-year-old children, the severity of the condition, the progressive course of the disease and the therapeutic aim of the treatment, there is, despite the clear limitations of the available evidence, a hint of a non-quantifiable additional benefit for one of the endpoints ‘LCI2.5’ compared with the appropriate comparator therapy, best supportive care; however, this is non-quantifiable because the scientific data do not permit it.
• mortality
  • In the study, none of the 115 children aged 2–5 years died whilst receiving treatment with LUM/IVA.
• Morbidity – Lung Clearance Index (LCI2.5)
  • For the endpoint Lung Clearance Index (LCI2.5; absolute change), there was no statistically significant difference between LUM/IVA and baseline based on the mean difference (MWD [95% CI]: -0.58 [-1.17; 0.02]; p=0.056).
  • In a patient population of children aged 2–5 years with a body weight of ≥ 14 kg, a statistically significant advantage was observed for LUM/IVA at week 24 compared with baseline for the LCI2.5 endpoint (MWD [95% CI]: -0.76 [-1.45; -0.08]; p=0.032).
  • LUM/IVA demonstrated comparable efficacy in the studies of children aged 2 years and older and those aged 6 years and older, based on the results for the Lung Clearance Index (LCI2.5) endpoint.
  • For the population of children aged 2–5 years, although the same direction of effect was demonstrated for the LCI2.5 from baseline to week 24, this did not reach statistical significance.
  • The LCI2.5 is regarded as a surrogate endpoint. Based on the study submitted by the pharmaceutical manufacturer, it cannot be concluded that the LCI2.5 is a valid surrogate parameter for patient-relevant endpoints.
  • However, in the very young patient population under consideration here, which still exhibits relatively few symptoms, any influence on the course of the disease can only be measured to a very limited extent.
  • During the commenting procedure, it became clear that the LCI2.5 endpoint is established in clinical practice for monitoring early changes in cystic fibrosis within this therapeutic area. Against this background, LCI2.5 is used as a relevant endpoint for the benefit assessment in the age group of patients with cystic fibrosis under consideration here.
  • There is a lack of long-term data for the LCI2.5, and the interpretability of the results with regard to longer-term effects, such as on pulmonary exacerbations and symptom improvement, is limited.
• Morbidity – Forced expiratory volume in one second (FEV1 %)
  • For the endpoint forced expiratory volume in one second (FEV1 %), no statistically significant difference was observed in Study 115 between LUM/IVA and baseline.
• Morbidity – Body Mass Index (BMI) and BMI z-score
  • In Study 115, a statistically significant difference was observed for LUM/IVA compared with baseline (MWD [95% CI]: 0.29 [0.14; 0.45]; p<0.001); however, it cannot be conclusively assessed to what extent the observed improvement in the BMI z-score is attributable to the patients’ increasing age and development.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are considered to be of clinical significance to patients.
  • In Study 115, 25 pulmonary exacerbations occurred per 29 patient-years during treatment with LUM/IVA.
  • The study shows that pulmonary exacerbations are not very common events in children aged 2 to 5 years.
  • Both in study 115 involving 2–5-year-old children and in study 109 involving 6–11-year-olds, it was found that pulmonary exacerbations are not frequent events in the very young patient population (2–5 years and 6–11 years), which still exhibits relatively few symptoms.
• Morbidity – hospitalisations due to cystic fibrosis
  • In Study 115, there were 4 hospitalisations due to CF per 29 patient-years.
• Health-related quality of life
  • Data on health-related quality of life were not recorded in Study 115.
  • Endpoints in the health-related quality of life category were not investigated in study 115.
• Side effects
  • Adverse events occurred in 59 patients (98.3%) in Study 115; 4 patients (6.7%) experienced serious adverse events, severe adverse events (≥ Grade 3) occurred in 5 patients (8.3 per cent).
  • A total of 3 patients (5.0 %) discontinued treatment with LUM/IVA due to adverse events.
  • LUM/IVA in children aged 2–5 years exhibits an acceptable adverse reaction profile comparable to that seen in the populations of children aged 6–11 years and patients aged ≥ 12 years.
• Overall assessment/Conclusion
  • Based on the extrapolation of evidence from studies involving children aged 6–11 years and patients aged 12 years and over to the population of 2–5, the G-BA concludes that LUM/IVA provides additional benefit for children aged 2 years and over with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene.
  • Based on the criteria in Section 5(7) of the AM-NutzenV, the G-BA classifies the extent of the non-quantifiable additional benefit.
  • Taking into account the lack of alternative treatments for children aged 2–5-year-old children, the severity of the disease, its progressive course and the therapeutic aim of the treatment, there is, despite the clear limitations of the available evidence, a hint of a non-quantifiable additional benefit for the endpoint ‘LCI2.5’ compared with the appropriate comparator therapy, ‘best supportive care’; however, this is non-quantifiable because the scientific evidence does not permit it.

Courtesy translation only, please refer to the German original.