Ivacaftor (14) – Kalydeco®

• Clinical trials
  • To assess the additional benefit of IVA/TEZ/ELX + IVA in patients aged 12 years and over with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and who also have a minimally functional mutation on the second allele, the pharmaceutical manufacturer submitted a multicentre, randomised, double-blind, placebo-controlled Phase III trial, VX17-445-102 (hereinafter referred to as Study 102).

Patients aged 12 years and over with cystic fibrosis who are heterozygous and carry an F508del mutation in the CFTR gene as well as a minimal-function mutation on the second allele

• There is a hint of a major additional benefit.
• In summary, for patients with cystic fibrosis aged 12 years and over who are heterozygous for the F508del mutation in the CFTR gene and carry an MF mutation, there is a hint of major additional benefit from IVA/TEZ/ELX + IVA compared with the appropriate comparator therapy, BSC.
• Based on Study 102, at most, there are hints to determine the additional benefit for all endpoints presented.
• mortality
  • No deaths occurred in Study 102.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
  • For pulmonary exacerbations, there is a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
• Morbidity – Hospitalisation due to pulmonary exacerbations
  • For hospitalisation due to pulmonary exacerbations, there is a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
• Morbidity – Symptoms measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
  • The endpoint ‘symptoms’ was assessed using the disease-specific CFQ-R (patient version) and comprised the respiratory, weight-related and gastrointestinal domains.
  • For the respiratory system and weight-related problems domains, the responder analysis (improvement of at least 15 points) showed a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
  • For the gastrointestinal symptoms domain, the responder analysis (improvement of at least 15 points) showed no statistically significant difference between the treatment groups.
• Morbidity – Body Mass Index (BMI) and BMI z-score
  • For the endpoint of absolute change in BMI and change in BMI z-score, Study 102 showed a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC; however, the extent of the clinical relevance of this finding cannot be conclusively assessed, as the patients included in both treatment groups already had a BMI within the normal range at the start of the studies.
• Morbidity – Forced Expiratory Volume in One Second (FEV1)
  • Forced expiratory volume in one second (FEV1), expressed as a percentage of the standardised normal value (FEV1 %), was measured in Study 102 as the absolute change over 24 weeks of treatment. Here, a statistically significant advantage was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
  • Opinions differ regarding the clinical relevance of FEV1%. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – sweat chloride concentration (mmol/l)
  • As the extent of the reduction in sweat chloride concentration is not directly associated with the extent of the change in symptoms, this endpoint is not considered to be of direct relevance to patients and is regarded as supplementary.
  • There is a statistically significant difference in favour of ivacaftor + ivacaftor/tezacaftor/elexacaftor + BSC compared with placebo + BSC for the absolute change in sweat chloride concentration.
• Quality of life – Health-related quality of life measured using the CFQ-R
  • Quality of life was assessed using the validated, disease-specific quality-of-life instrument CFQ-R, employing the patient version, and covered the domains of physical well-being, emotional state, vitality, social limitations, role functioning, body image, eating disorders, treatment burden and subjective health assessment.
  • For all domains within the health-related quality of life category of the CFQ-R (physical well-being, emotional state, vitality, social limitations, role functioning, body image, eating disorders, treatment burden and subjective health assessment), the responder analysis (improvement of at least 15 points) revealed statistically significant advantages in each case for ivacaftor + ivacaftor/tezacaftor/elexacaftor + BSC compared with placebo + BSC.
• Side effects
  • No data are available for estimating the effect size regarding the overall rate of adverse events (AEs).
  • For the endpoints of SUEs and discontinuation due to AEs, no statistically significant differences were observed between the treatment groups.
  • In the category of side effects, there is no statistically significant difference between the treatment arms when viewed as a whole.
• Overall assessment
  • No deaths occurred in Study 102.
  • In the morbidity category, for the endpoints of pulmonary exacerbations, hospitalisation due to pulmonary exacerbations and in the respiratory system and weight problems domains of the CFQ-R, a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC. For the gastrointestinal symptoms domain of the CFQ-R, no statistically significant difference was observed between the treatment groups. A summary of the morbidity results revealed a difference relevant to the benefit assessment in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
  • In the quality of life category, statistically significant differences in favour of Ivacaftor + Ivacaftor/Tezacaftor were observed in all domains of the CFQ-R (physical well-being, emotional state, vitality, social restrictions, role functioning, body image, eating disorders, treatment burden and subjective health assessment), statistically significant advantages were observed in each case for ivacaftor + ivacaftor/tezacaftor/elexacaftor + BSC compared with placebo + BSC. When the results on health-related quality of life were considered as a whole, a difference relevant to the benefit assessment was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
  • In the categories of mortality and side effects, there were no statistically significant differences between the treatment groups when considered as a whole.
  • In summary, for patients with cystic fibrosis aged 12 years and over who are heterozygous for the F508del mutation in the CFTR gene and carry an MF mutation, there is a major additional benefit from IVA/TEZ/ELX + IVA compared with the appropriate comparator therapy, BSC.

Courtesy translation only, please refer to the German original.