Ivacaftor (24) – Kalydeco®

• Clinical trials
  • Study 106 included children aged 6 to 11 years with cystic fibrosis who were homozygous for the F508del mutation in the CFTR gene or heterozygous for the F508del mutation in the CFTR gene and who had a minimal functional mutation on the second allele, were included; depending on the study arm, they were treated with IVA/TEZ/ELX + IVA for varying durations (arm A: 15 days; arm B: 24 weeks).
  • In addition, the pharmaceutical manufacturer refers to the results of the VX18-445-109 study, which has already been assessed by the G-BA (hereinafter ‘109’) in patients aged 12 years and over with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene.

Children aged 6 to 11 years with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene

• In combination with ivacaftor/tezacaftor/elexacaftor (IVA/TEZ/ELX), there is a hint of a non-quantifiable additional benefit in children aged 6 to 11 years with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene.
• Due to the uncertainty regarding the transferability of the additional benefit to a younger population, there is a hint of a non-quantifiable additional benefit.
• mortality
  • No deaths occurred in Study 106.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
  • In Study 106, there were no pulmonary exacerbations and no hospitalisations due to pulmonary exacerbations.
• Morbidity – Symptoms measured using the Cystic Fibrosis Questionnaire – Revised (CFQ-R)
  • The CFQ-R is a questionnaire that measures patients’ subjective perceptions (known as ‘patient-reported outcomes’, PROs) or their assessment by parents/carers.
  • The endpoint ‘symptoms’ was assessed in Study 106 using the disease-specific, patient-reported CFQ-R (patient version) for the respiratory and gastrointestinal domains. In addition, the parent/carer version was administered.
  • In Study 106, the CFQ-R domains were analysed as the absolute change at week 24.
• Morbidity – forced expiratory volume in one second (FEV1%)
  • Forced expiratory volume in one second (FEV1), expressed as a percentage of the standardised normal value (FEV1%), was measured in Study 106 as the absolute change over 24 weeks of treatment. There are differing views on the clinical relevance of FEV1% to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Lung Clearance Index (LCI2.5)
  • The Lung Clearance Index is a measure used to assess ventilation heterogeneity in the lungs and is measured using the gas washout test.
  • The LCI2.5 is regarded as a surrogate endpoint. On the basis of the studies 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 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. However, as long-term data for the LCI2.5 are lacking, the interpretability of the results with regard to longer-term effects, such as on pulmonary exacerbations and symptom improvement, is limited.
  • In Study 106, the absolute change in LCI2.5 after 24 weeks of treatment was measured in comparison with baseline.
• Morbidity – Body Mass Index (BMI) and BMI z-score
  • BMI is used to assess body weight in relation to height. Body weight, or BMI, is of significance in this indication, as growth failure and impaired nutrient absorption are among the typical signs of cystic fibrosis. This endpoint is considered a patient-relevant endpoint, particularly in children with characteristic, disease-related growth disorders. Data adjusted for age and sex (z-scores) are preferred over absolute values.
  • In Study 106, the change in BMI and the age-adjusted z-score for body weight relative to height over 24 weeks were assessed as endpoints.
  • The children included in the study already had a body weight-to-height ratio at the start of the study that fell within the normal range for the healthy population of the same age and sex (z-score). However, it cannot be conclusively assessed to what extent the patients’ increasing age and development influence the result.
• quality of life
  • Health-related quality of life was assessed using the disease-specific, patient-reported CFQ-R (patient version) and encompasses the domains of physical well-being, emotional state, social limitations, body image, eating disorders and treatment burden. In addition, the parent/carer version was administered.
  • In Study 106, the CFQ-R domains were analysed as absolute change at week 24.
• Side effects
  • In Study 106, adverse events (AEs) occurred in all children; one patient (3.5%) experienced a severe adverse event (Grade 3 or 4). None of the children experienced serious SAEs, and none discontinued treatment with IVA/TEZ/ELX + IVA due to adverse events.
• Conclusion
  • Overall, the G-BA concludes that the transferability of the additional benefit of IVA/TEZ/ELX + IVA from adolescents and adults aged 12 years and over to children aged 6 to 11 years with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, is assumed, particularly given the comparable clinical presentation, the progressive course of the disease and the limitations in conducting clinical trials in this age group.
  • Taken together, based on the results of study VX19-445-106 and the results of study VX18-445-109 in adolescents and adults aged 12 years and over, IVA/TEZ/ELX + IVA demonstrates an additional benefit compared with the appropriate comparator therapy; however, the extent of this benefit is non-quantifiable due to the limited evidence available.

Courtesy translation only, please refer to the German original.