Ivacaftor (6) – Kalydeco®

• Clinical trials
  • The study on which the marketing authorisation is based, VX14-661-106 (hereinafter referred to as Study 106), is a multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase III trial.
  • Studies VX12-809-103 and VX12-809-104 (hereinafter referred to as Studies 103 and 104) are randomised, double-blind, placebo-controlled, parallel-group Phase III studies.

Patients aged 12 years and over with cystic fibrosis who are homozygous for the F508del mutation.

• mortality
  • No deaths occurred in any of the studies 106, 103 and 104.
• 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 studies 106, 103 and 104 as the absolute change over 24 weeks of treatment. In the adjusted indirect comparison, a statistically significant difference in FEV1% was observed in favour of IVA + TEZ/IVA compared with LUM/IVA.
  • There are differing views on the clinical relevance of FEV1%. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Sweat chloride concentration (mmol/l)
  • Measurement of chloride levels in sweat is routinely used as part of the diagnostic process, as these 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.
  • The endpoint of sweat chloride concentration was recorded only in Study 106. In Studies 103 and 104, this endpoint was not measured in either case; consequently, based on the available data, it was not possible to perform an adjusted indirect comparison with LUM/IVA using the bridge comparator placebo.
  • Pulmonary exacerbations, hospitalisation and intravenous antibiotic therapy due to pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are considered to be of relevance to patients.
  • For the endpoint of pulmonary exacerbations, the adjusted indirect comparison – operationalised as the annual event rate – showed no statistically significant difference between the treatment groups.
  • For the endpoint of hospitalisation due to pulmonary exacerbations, the adjusted indirect comparison, based on the annual event rate, showed a statistically significant disadvantage of IVA + TEZ/IVA compared with LUM/IVA.
  • However, the results of this adjusted indirect comparison are subject to major uncertainty for this endpoint. The bridge comparator for the adjusted indirect comparison of studies 106 (IVA + TEZ/IVA vs. placebo), 103 (LUM/IVA vs. placebo) and 104 (LUM/IVA vs. placebo) is placebo. The number of events per patient-year in the placebo arm of Study 106 (IVA + TEZ/IVA vs. placebo) is 0.28, which is significantly lower than in the two placebo arms of the studies with LUM/IVA (Study 103: 0.54; Study 104: 0.69). By contrast, the number of pulmonary exacerbations leading to hospitalisation in the respective active treatment arms across the three studies is of a comparable order of magnitude: Study 106 (IVA + TEZ/IVA vs. placebo): 0.23; Study 103 (LUM/IVA vs. placebo): 0.21; and Study 104 (LUM/IVA vs. placebo): 0.27 per patient-year.
  • Furthermore, there are significant imbalances between Study 106 and Studies 103/104 with regard to the baseline parameter ‘region’. In Study 106, the vast majority of patients were from Europe, whilst in Studies 103/104, the vast majority of patients were recruited in the USA. Particularly given that the conditions of hospitalisation depend on the structure of the respective healthcare system, the results cannot be interpreted validly.
  • Owing to these major uncertainties and the finding that no statistically significant difference was observed between the treatment groups in the overall rate for the endpoint ‘pulmonary exacerbations’, the statistically significant disadvantage of IVA + TEZ/IVA compared with LUM/IVA for the endpoint of hospitalisation due to pulmonary exacerbations does not, however, lead the G-BA to conclude that IVA + TEZ/IVA offers less benefit.
  • The endpoint of intravenous antibiotic therapy due to pulmonary exacerbations does not allow for any further conclusions (e.g. regarding severe exacerbations), as intravenous administration also depends on the spectrum of pathogens and does not correlate solely with the severity of the pulmonary exacerbation.
  • Symptoms measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
  • The endpoint ‘symptoms’ was assessed using the disease-specific CFQ-R (patient version) and covered the respiratory, weight and gastrointestinal domains. The CFQ-R is a questionnaire that measures patients’ subjective perceptions (known as ‘patient-reported outcomes’, PROs) or their assessment by parents/carers.
  • For the respiratory system domain, a statistically significant advantage of IVA + TEZ/IVA over LUM/IVA was observed in the indirect comparison for the patient version. However, the 95% confidence interval for Hedges’ g does not lie entirely outside the irrelevance range, meaning that the clinical relevance of the effect observed in the mean difference cannot be assessed.
  • For both the ‘weight problems’ domain and the gastrointestinal domain, no statistically significant difference between the treatment groups could be demonstrated.
  • Body Mass Index (BMI) and BMI z-score
  • BMI is used to assess body weight in relation to height. Body weight, or BMI, is of significance in this indication, as growth 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 with characteristic, disease-related growth disorders. Data adjusted for age and sex (z-scores) are preferred over absolute values.
  • The endpoint ‘absolute change in BMI z-score’ was assessed in studies 106, 103 and 104 for patients under 20 years of age. For the endpoint ‘absolute change in BMI z-score’, an adjusted indirect comparison in each case showed a statistically significant difference to the detriment of IVA + TEZ/IVA compared with LUM/IVA; however, the extent of this difference cannot be conclusively assessed.
• quality of life
  • Health-related quality of life measured using the CFQ-R

Courtesy translation only, please refer to the German original.