Ivacaftor (9) – Kalydeco®

• Clinical trials
  • For the benefit assessment of ivacaftor in children aged 2 to 5 years with cystic fibrosis who carry one of the above-mentioned gating mutations (Class III) in the CFTR gene, the pharmaceutical manufacturer has submitted a single-arm trial (VX11-770-108, hereinafter 108) and its expansion trial (VX11-770-109, hereinafter referred to as 109).
  • Study 108, involving children aged 2 to 5 years with cystic fibrosis, is a single-arm, open-label Phase III trial.
  • The effects of ivacaftor treatment in patients aged 6 years and over with various non-G551D gating mutations were investigated in an 8-week randomised, placebo-controlled crossover study (111).

Children with cystic fibrosis aged between 2 and 5 years who have one of the following gating mutations (Class III) in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R

• For the treatment of children with cystic fibrosis aged 2 to 5 years who have one of the following gating mutations (Class III) in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R, there is a hint of a non-quantifiable additional benefit.
• Due to the uncertainty surrounding the transfer of the additional benefit to a younger population, there is a hint of a non-quantifiable additional benefit.
• mortality
  • In studies 108 and 109 involving children aged 2 to 5 years, no deaths occurred during treatment with ivacaftor.
• 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 studies 108 and 109, two different definitions of pulmonary exacerbations were used. Even when both definitions are taken into account, the incidence of pulmonary exacerbations and the resulting hospital admissions in this age group remains minor.
  • The endpoint of intravenous antibiotic therapy due to pulmonary exacerbations does not allow for any further conclusions (e.g. regarding severe exacerbations), as intravenous administration also depends on the spectrum of pathogens and does not correlate solely with the severity of the pulmonary exacerbation.
• Morbidity – Forced expiratory volume in one second (FEV₁ %)
  • The endpoint forced expiratory volume in one second (FEV₁ %) was recorded in studies 108 and 109 for too few patients to provide interpretable results.
  • Furthermore, measuring this in children up to 5 years of age is severe in terms of implementation and is therefore subject to uncertainty.
  • There are differing views on the clinical relevance of FEV₁ %. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Body Mass Index (BMI) z-score
  • In studies 108 and 109, both BMI and the BMI z-score were assessed as endpoints.
  • BMI is used to assess body weight in relation to height. Body weight, or BMI, is significant in this indication, as developmental disorders and impaired nutrient absorption are among the typical signs of cystic fibrosis.
  • This endpoint is considered a patient-relevant morbidity parameter, particularly in children with characteristic, disease-related growth disorders.
  • At the end of the study, both studies (108 and 109) showed an improvement in the BMI z-score with ivacaftor compared with baseline.
  • 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 – Sweat chloride levels
  • Measurement of chloride levels in sweat is routinely used as part of the diagnostic process, as these levels reflect the functionality of the CFTR protein, which is the pathophysiological cause of the disease.
  • As the extent of a reduction in sweat chloride concentration is not directly associated with the extent of change in symptoms, this endpoint is not considered to be of immediate relevance to patients and is regarded as supplementary.
  • In Study 108, a significant reduction in sweat chloride levels was observed at 24 weeks compared with baseline. After a further 84 weeks (Study 109), the levels showed little difference from those at week 24 in Study 108.
• Health-related quality of life
  • Endpoints in the health-related quality of life category were not investigated in studies 108 and 109.
• Side effects
  • Adverse events occurred in 33 patients in each of the two studies (97.1% in Study 108; 100% in Study 109); serious adverse events were experienced by 6 patients (17.6%) in Study 108 and 11 (33%) in Study 109.
  • In total, one patient in each study (2.9% in study 108; 3% in study 109) discontinued treatment with ivacaftor due to adverse events.
• Conclusion
  • On balance, the G-BA concludes that the additional benefit of ivacaftor in children and adolescents aged 6 to 11 years and 12 to 18 years, respectively, is transferable to children aged 2 to 5 years with cystic fibrosis who have the following gating mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R, particularly in light of the comparable clinical presentation, the progressive course of the disease and the limitations in conducting clinical trials in this age group.
  • However, the additional benefit is non-quantifiable, as the current scientific evidence does not permit this at this stage.

Courtesy translation only, please refer to the German original.