Lumacaftor / Ivacaftor (4) – Orkambi®

• Clinical trials
  • To assess the additional benefit of LUM/IVA in children with cystic fibrosis aged between 2 and 5 years who are homozygous for the F508del mutation in the CFTR gene, the study VX16-809-121 (hereinafter referred to as Study 121) is used. Study 121 is a randomised, double-blind, two-part study in which, in Part 1, LUM/IVA + BSC was compared with placebo + BSC.

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

• Hint for 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 is derived overall.
• mortality
  • No deaths occurred in Study 121.
• 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.
  • For the endpoints of pulmonary exacerbations and hospitalisation due to pulmonary exacerbations, no statistically significant difference was observed between the treatment groups in Study 121.
• Morbidity – Body Mass Index (BMI) and BMI z-score
  • BMI is used to assess body weight in relation to height. Body weight, or BMI, is significant in this indication, as growth failure and impaired nutrient absorption are among the typical signs of cystic fibrosis. This endpoint is considered a patient-relevant endpoint, particularly in children with characteristic, disease-related growth disorders. Data adjusted for age and sex (z-scores) are preferred over absolute values.
  • In Study 121, a statistically significant advantage was observed for the BMI z-score in favour of LUM/IVA + BSC compared with placebo + BSC; however, the extent of this advantage cannot be conclusively assessed.
• Morbidity – Sweat chloride concentration (mmol/l)
  • 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 underlies the pathophysiology 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.
• quality of life
  • Endpoints relating to health-related quality of life were not assessed in Study 121.
• Side effects
  • No events occurred in Study 121 for the endpoint of discontinuation due to adverse events. Consequently, there is no difference between the treatment groups.
  • For the endpoint ‘SUEs’, there was no statistically significant difference 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 re-benefit assessment following the expiry of the LUM/IVA authorisation for the treatment of children with cystic fibrosis aged 2 to 5 years who are homozygous for the F508del mutation in the CFTR gene, the randomised, double-blind, placebo-controlled Phase III study 121 was used. This study provides data on mortality, morbidity and side effects.
  • No deaths occurred in Study 121.
  • For the endpoints of pulmonary exacerbations, hospitalisation due to pulmonary exacerbations, LCI2.5 and the additional endpoint MRI score, there were no statistically significant differences between the treatment arms.
  • For the endpoint BMI z-score, there was a statistically significant advantage in favour of LUM/IVA + BSC compared with placebo + BSC; however, the extent of this advantage cannot be conclusively assessed. For the additional endpoint of sweat chloride concentration, a statistically significant advantage of LUM/IVA + BSC over placebo + BSC was observed.
  • Endpoints relating to health-related quality of life were not assessed in Study 121.
  • In the category of side effects, there is no statistically significant difference between the treatment arms when viewed as a whole.
  • Cystic fibrosis is a progressive condition, i.e. its severity increases with age, meaning that younger patients with cystic fibrosis – such as the children under consideration here – still exhibit relatively few symptoms. Consequently, the impact on the course of the disease in terms of patient-relevant endpoints can only be measured to a limited extent. For instance, the symptom burden and improvement in symptoms in the LUM/IVA arm are more pronounced in patients aged 12 years and over compared with children aged 2 to 5 years.
  • In view of the advantage in BMI and BMI z-score observed in children aged 2 to 5 years and in children and adolescents aged 12 years and over, as well as the benefits of LUM/IVA in older patients aged ≥ 6 to < 12 years and ≥ 12 years for the aforementioned endpoints, and given that there is an identical underlying genetic cause of the condition and a comparable pathophysiology, the severity of symptoms only increases with age, and given the consistent appropriate comparator therapies across the three populations, the identified additional benefit in the populations aged ≥ 6 to < 12 years (resolution of 2 August 2018) and those aged ≥ 12 years (resolution of 2 June 2016) is taken into account in the overall assessment. However, due to the associated uncertainties and the limitations of the available evidence, the extent of this added benefit is non-quantifiable.
• Conclusion
  • Taken together, the findings for LUM/IVA in the treatment of cystic fibrosis in children aged 2 to 5 years who are homozygous for the F508del mutation in the CFTR gene, based on the results of study 121, and, taking into account the results of study VX14-809-109 in children aged ≥ 6 to < 12 years, as well as the results of studies VX12-809-103 and VX12-809-104 in children and adolescents aged 12 years and over, 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.