Ivacaftor (16) – Kalydeco®

Infants with cystic fibrosis aged between 4 and < 6 months who have one of the following gating mutations (Class III) in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R

• Hint for 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 Study 124, there were no deaths among infants aged 4 to < 6 months receiving treatment with ivacaftor.
• 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. In Study 124, two different definitions of pulmonary exacerbations were used.
  • Even when both definitions are taken into account, the incidence of pulmonary exacerbations in this age group remains very minor. The same applies to hospitalisations due to pulmonary exacerbations.
  • Body weight-for-height z-scores In study 124, the change in the body weight-for-height z-score over 24 weeks was recorded as an endpoint. The weight-for-height ratio is significant for this indication, as developmental disorders and impaired nutrient absorption are among the typical signs of cystic fibrosis.
  • The infants included in the study already had a weight-for-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). At the end of the study, no changes in the weight-for-height ratio were observed compared with baseline. However, it cannot be conclusively assessed to what extent the patients’ increasing age and development influenced the result.
  • Sweat chloride concentration Measuring chloride levels in sweat is standard practice 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 124, a significant reduction in sweat chloride levels was observed at 24 weeks compared with baseline.
• Health-related quality of life
  • Endpoints in the health-related quality of life category were not investigated in Study 124.
• Side effects
  • Adverse events occurred in all infants; one patient (16.7%) experienced a serious adverse event. No patient discontinued treatment with ivacaftor due to adverse events.
• Conclusion
  • Overall, the G-BA concludes that the additional benefit of ivacaftor observed in children and adolescents aged 6 and 12 years, respectively, is transferable to infants aged 4 to 6 months with cystic fibrosis who have the following gating mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R, particularly given the comparable clinical presentation, the progressive course of the disease and the limitations on 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.