Ivacaftor / Tezacaftor / Elexacaftor (12) – Kaftrio®

• Clinical trials
  • Study 111 included children aged 2 to ≤ 5 years with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene or heterozygous for the F508del mutation in the CFTR gene and who have a minimal-function mutation on the second allele.

Children aged 2 to ≤ 5 years with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene

• In combination with ivacaftor, there is a hint of a non-quantifiable additional benefit in children aged 2 to ≤ 5 years with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene.
• Due to the uncertainty regarding the extrapolation of the additional benefit to a younger population, there is a hint of a non-quantifiable additional benefit.
• mortality
  • No deaths occurred in Study 111.
• 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 111, there were 6 pulmonary exacerbations, as well as one hospitalisation due to a pulmonary exacerbation and one pulmonary exacerbation requiring treatment with intravenous antibiotics, among the total of 23 study participants.
• Morbidity – ratio of body weight to height, z-score
  • In Study 111, the change in the z-score for body weight for height over 24 weeks was, amongst other things, assessed 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.
  • This endpoint is considered a patient-relevant morbidity parameter, particularly in children and infants with characteristic, disease-related growth disorders.
  • The infants 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).
  • 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.
• Morbidity – sweat chloride concentration
  • Measuring chloride concentration in sweat is routinely used as part of the diagnostic process, as the values 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 changes in symptoms, this endpoint is not considered to be of immediate relevance to patients and is regarded as supplementary.
  • In Study 111, a significant reduction in sweat chloride concentration was observed at 24 weeks compared with baseline.
• quality of life
  • Endpoints relating to health-related quality of life were not investigated in Study 111.
• Side effects
  • In Study 111, adverse events (AEs) occurred in all 23 children.
  • No serious AEs or severe AEs (Grade 3 or 4) occurred, and no patients discontinued treatment with IVA/TEZ/ELX due to adverse events.
• Conclusion
  • Taken together, based on the results of study VX20-445-111 and the results of studies involving older individuals with the same mutation (aged 6 to ≤ 11 years: Study VX18-445-106; aged 12 years and over: VX18-445-109), IVA/TEZ/ELX 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.