Lumacaftor / Ivacaftor (5) – Orkambi®

• Clinical trials
  • For the assessment of the additional benefit of lumacaftor/ivacaftor (LUMA/IVA) for the treatment of children aged 1 to <2 years with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, the pharmaceutical manufacturer presents the single-arm, open-label Phase IIIstudy VX16-809-122 Part B (hereinafter ‘122’) over 24 weeks.
  • Furthermore, due to a lack of comparative data, the pharmaceutical manufacturer refers to the results of the studies on lumacaftor/ivacaftor in older people with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene: study VX16-809-121 in children aged 2 to 5 years, Study VX14-809-109 in children aged 6 to <12 years, and studies VX12-809-103 and VX12-809-104 in patients aged 12 years and over.

Children with cystic fibrosis aged 1 to <2 years who are homozygous for the F508del mutation in the CFTR gene

• For children with cystic fibrosis aged 1 to <2 years who are homozygous for the F508del mutation in the CFTR gene, 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
  • No deaths occurred in Study 122.
• 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 122, there were 9 pulmonary exacerbations and 3 hospitalisations due to pulmonary exacerbations among the total of 46 study participants.
• Morbidity – Body mass index (BMI), z-score
  • In Study 122, the change in the z-score for body weight-for-height over 24 weeks was, amongst other things, assessed as an endpoint.
  • The body weight-to-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.
• 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 change in symptoms, this endpoint is not considered to be of immediate relevance to patients and is regarded as supplementary.
  • In Study 122, 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 122.
• Side effects
  • In Study 122, adverse events (AEs) occurred in almost all children (44 out of 46).
  • Two (4.3%) patients experienced severe AEs (Grade 3 or 4) and five (10.9%) experienced serious AEs.
  • Treatment with IVA/LUMA was discontinued in one toddler due to adverse events.
• Conclusion
  • Overall, the G-BA concludes that the additional benefit of LUMA/IVA can be extrapolated from older patients to children aged 1 to <2 years with cystic fibrosis, who are homozygous for the F508del mutation in the CFTR gene, is assumed.
  • Taken together, based on the results of study VX16-809-122 and the results of studies involving older individuals with the same mutation (2 to 5 years: study VX16-809-121; 6 to <12 years: study VX14-809-109; 12 years and over: VX12-809-103 and VX12-809-104), an additional benefit over 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.