Ivacaftor (13) – Kalydeco®

• Clinical trials
  • For the benefit assessment of ivacaftor in children aged 6 years and over but under 18 years with cystic fibrosis who carry an R117H mutation in the CFTR gene, the pharmaceutical manufacturer presents the randomised, controlled trial VX11-770-110 (hereinafter ‘Study 110’), in which ivacaftor plus best standard care (BSC) was compared with placebo plus BSC over a treatment period of 24 weeks.
  • Study 122 is an ongoing observational study in which available data from the US Cystic Fibrosis Foundation registry were collected on patients aged between 2 years and < 18 years with an R117H mutation.

a) Patients aged 6 months to < 6 years with cystic fibrosis who carry an R117H mutation in the CFTR gene

• For patients aged 6 months to < 6 years with cystic fibrosis who carry an R117H mutation in the CFTR gene, there is a hint of a non-quantifiable additional benefit.
• Due to the uncertainty surrounding the transferability of the additional benefit to a younger population, a hint of additional benefit is derived overall.
• In particular, given the comparable clinical presentation, the progressive course of the disease and the limitations in conducting clinical trials, the G-BA concludes that the transferability of the additional benefit from adults (resolution of 20 February 2020) to children aged 6 months to < 6 years with cystic fibrosis and an R117H mutation in this age group is assumed, taking into account the safety data for children with gating mutations.
• However, the additional benefit is non-quantifiable, as the current scientific evidence does not permit this at this stage.
• Morbidity – Body Mass Index (BMI) and BMI z-score
  • Study 122 assessed, amongst other things, the change in the BMI z-score from the start of treatment at > 0 to 12 months, > 12 to 24 months and > 24 to 36 months thereafter.
  • Although only a descriptive analysis was carried out in the study, there does not appear to be any relevant change here. However, it cannot be conclusively assessed to what extent the patients’ increasing age and development influence the result.
• Overall assessment
  • In its overall assessment, the G-BA concludes that the transferability of the additional benefit of ivacaftor from patients aged 18 years and over to children aged 6 months to < 6 years with cystic fibrosis and an R117H mutation in the CFTR gene, is assumed, 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, whilst taking into account the safety data for children with gating mutations.

b) Patients aged 6 years or over but under 18 years with cystic fibrosis who have an R117H mutation in the CFTR gene

• For patients aged 6 years or older but under 18 years with cystic fibrosis who carry an R117H mutation in the CFTR gene, there is a hint of a non-quantifiable additional benefit.
• Given the limitations of the available evidence and the uncertainties regarding patient-relevant effects in this age group, a hint of added benefit is derived overall.
• mortality
  • No deaths occurred in study 110.
• Morbidity – Pulmonary exacerbations and hospitalisation 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.
  • In Study 110, no pulmonary exacerbations occurred in the relevant patient population and, consequently, no hospitalisations due to pulmonary exacerbations occurred during the course of the study.
• 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 as the absolute and relative change over 24 weeks of treatment.
  • There was a statistically significant difference in favour of placebo + BSC compared with ivacaftor + BSC for both the absolute and relative change in the FEV1 value over 24 weeks.
  • However, as lung damage in the age group of the present patient population has generally not yet manifested to such an extent that it can be adequately reflected by FEV1, the interpretability of the result remains unclear.
• Morbidity – Symptoms measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
  • In Study 110, the endpoint ‘symptoms’ was assessed using the disease-specific CFQ-R (patient version) and comprised the domains of respiratory system, gastrointestinal symptoms and weight problems (the ‘weight problems’ domain is not intended for children aged 6 to < 12 years).
  • For the respiratory system and gastrointestinal symptoms domains of the CFQ-R, no statistically significant difference was observed between ivacaftor + BSC and placebo + BSC.
• Morbidity – Body Mass Index (BMI) and BMI z-score
  • BMI is used to assess body weight in relation to height.
  • In Study 110, there was no statistically significant difference in the BMI z-score between ivacaftor + BSC and placebo + BSC.
• Morbidity – Sweat chloride concentration (mmol/l)
  • The endpoint of sweat chloride concentration was assessed in Study 110 as the absolute change at week 24.
  • There is a statistically significant difference in the absolute change in sweat chloride concentration in favour of ivacaftor + BSC compared with placebo + BSC.
• 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 the patient version.
  • No statistically significant differences were observed between the treatment groups in these domains of health-related quality of life as measured by the CFQ-R.
• Side effects
  • For the endpoint of discontinuation due to AEs and serious adverse events (SAEs), no statistically significant difference was observed between the treatment groups.
  • In the category of side effects, there was no statistically significant difference between the treatment arms when viewed as a whole.
• Overall assessment
  • For the benefit assessment of ivacaftor for the treatment of cystic fibrosis in patients aged 6 to < 18 years who carry the R117H mutation in the CFTR gene, the pivotal, multicentre, randomised, double-blind, placebo-controlled Phase III trial 110 was presented.
  • No deaths occurred in Study 110.
  • No statistically significant differences were observed between the treatment arms for the endpoints of pulmonary exacerbations, hospitalisation due to pulmonary exacerbations, the BMI z-score, or in the symptom domains assessed using the patient-reported version of the CFQ-R.
  • Nor were there any statistically significant differences between the treatment groups, when viewed as a whole, in the category of health-related quality of life across the relevant domains of the CFQ-R or in the category of side effects; consequently, neither an advantage nor a disadvantage of ivacaftor compared with standard of care (BSC) can be inferred.
  • Taken together, based on the results of Study 110 and taking into account the results for patients aged 18 and over, ivacaftor for the treatment of cystic fibrosis in patients aged 6 to < 18 years with an R117H mutation in the CFTR gene Ivacaftor 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.