Ivacaftor / Tezacaftor / Elexacaftor (11) – 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 heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele

• In combination with ivacaftor, there is evidence of non-quantifiable added benefit in children aged 2 to ≤ 5 years with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele, there is a hint of a non-quantifiable additional benefit.
• Due to the uncertainty regarding the transfer 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 – none of which led to hospitalisation – among the total of 52 study participants.
  • Body mass index (BMI), z-score
  • In Study 111, the change in the z-score for 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.
  • 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.
  • Sweat chloride concentration
  • Measuring chloride concentration in sweat is standard practice as part of the diagnostic process, as the values reflect the functionality of the CFTR protein, which is the pathophysiological cause of the disease.
  • 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 almost all children (51 out of 52) and serious AEs occurred in one patient.
  • No severe AEs (Grade 3 or 4) occurred.
  • Treatment with IVA/TEZ/ELX was discontinued in one child due to adverse events.
• Conclusion
  • Overall, the G-BA concludes that the additional benefit of IVA/TEZ/ELX from adult patients to children aged 2 to ≤ 5 years with cystic fibrosis, who are heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele, particularly given the comparable clinical presentation, the progressive course of the disease and the limitations in conducting clinical trials in this age group, is assumed.
  • Taken together, this results in a recommendation for IVA/TEZ/ELX for the treatment of cystic fibrosis in children aged 2 to ≤ 5 years who are heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele, based on the results of study VX20-445-111 and the results of studies involving older individuals with the same mutation (6 to ≤ 11 years: study VX19-445-116; from 12 years of age: VX17-445-102), an additional benefit compared with the appropriate comparator therapy, the extent of which is non-quantifiable due to the limited evidence available.

Courtesy translation only, please refer to the German original.