Ivacaftor (8) – Kalydeco®

• Clinical trials
  • The VX12-770-111 trial (hereinafter referred to as Trial 111) is a two-part trial. Part 1 of the trial consists of a randomised, double-blind, Phase III crossover design, in which twice-daily treatment with 150 mg of ivacaftor was compared with placebo, in each case in addition to standard therapy for the treatment of cystic fibrosis, for a duration of 8 weeks.
  • The randomised, double-blind, controlled Phase III (RCT) Study 102 investigates the efficacy and safety of ivacaftor compared with placebo, in each case in addition to standard therapy for the treatment of cystic fibrosis, in patients aged 12 years and over who carry the G551D mutation in the CFTR gene.
  • RCT study 103 is also investigating efficacy and safety endpoints in children aged between 6 and 11 years with a G551D mutation following 48 months of treatment with ivacaftor versus placebo, in each case as an adjunct to standard therapy for cystic fibrosis.

Patients with cystic fibrosis aged 6 years and over who carry one of the following gating mutations (Class III) in the CFTR gene: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R

• Hint for a non-quantifiable additional benefit
• Overall, for ivacaftor in the treatment of cystic fibrosis in children aged 6 years and over in the present therapeutic indication with various gating mutations, there is an additional benefit compared with the appropriate comparator therapy; however, due to the limited evidence available, the extent of this benefit is non-quantifiable.
• With regard to the certainty of the finding (probability of additional benefit), there is, on the whole, a hint of additional benefit.
• mortality
  • No deaths occurred in Study 111.
• Morbidity – Pulmonary exacerbations and hospitalisation due to pulmonary exacerbations
  • For the endpoint of pulmonary exacerbations, operationalised on the basis of event rates (number of events per patient-year), there are no statistically significant differences between the treatment groups.
  • For the endpoint ‘hospitalisation due to pulmonary exacerbations’, no calculations regarding the statistical significance of the difference between the groups are available.
  • The endpoint ‘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.
• 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 as an absolute and relative change over 8 weeks of treatment. There is a statistically significant difference in favour of ivacaftor + BSC compared with placebo + BSC for both the absolute and relative change in the FEV1 value over 48 weeks.
  • There are differing views on the clinical relevance of FEV1 %. This does not affect the overall conclusion regarding the extent of the additional benefit.
• 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.
  • In the domains of vitality and subjective health assessment, there were statistically significant differences in favour of ivacaftor + BSC compared with placebo + BSC in patients aged 14 years and over. In this context, the 95% confidence interval for Hedges’ g lies entirely outside the irrelevance range, meaning that the effect is interpreted as clinically relevant.
  • For the remaining domains in the patient version, no statistically significant differences were observed between the treatment groups.
  • In the parent/carer version, a statistically significant difference between the treatment arms was observed only in the physical well-being domain. However, the 95% confidence interval of Hedges’ g does not lie entirely outside the irrelevance range, meaning that the clinical relevance of the effect cannot be assessed.
• Side effects
  • The data on SAE are not usable, as, amongst other things, events were recorded that could be attributed to both side effects and morbidity. Therefore, these cannot be assessed.
  • No data are available for estimating the effect size for the overall rate of AE events.
  • There were no discontinuations due to AEs during the 8-week treatment phase.
• Overall assessment
  • Taken together, ivacaftor demonstrates added benefit over the standard of care for the treatment of cystic fibrosis in children aged 6 years and over in the indicated therapeutic indication with various gating mutations, taking into account the results of Study 102 in patients aged 12 years and over with a G551Dmutation, as well as Study 111, which is presented here as supplementary information, Ivacaftor demonstrates additional benefit compared with the appropriate comparator therapy. Due to the limited available evidence, the extent of this additional benefit is non-quantifiable.
  • An overall review of the results of Study 111 reveals a statistically significant effect in favour of ivacaftor compared with the comparator arm for the endpoint BMI z-score; however, the extent of this effect cannot be conclusively assessed. In the category of health-related quality of life, the endpoints of vitality and subjective health assessment in patients aged 14 years and over each show statistically significant and clinically relevant advantages for ivacaftor compared with the control arm. No statistically significant differences were observed between the treatment groups in the other endpoints assessed in the categories of morbidity, quality of life, mortality and side effects.
  • As the 8-week study duration is too short to assess patient-relevant endpoints, the findings of the European Medicines Agency (EMA) are taken into account in this case to assess the long-term effects of ivacaftor. Accordingly, it can be assumed that the results of Study 111, as assessed here, are sufficiently comparable with those of Studies 102 and 103 at week 8 in patients with a G551D mutation. In the studies in question, an advantage was observed in the FEV1 endpoint following 48 weeks of ivacaftor treatment, as well as in the BMI and BMI z-score endpoints, the extent of which cannot be conclusively assessed. Furthermore, in Study 102, involving patients aged 12 years and over, an advantage for ivacaftor was observed in patient-relevant endpoints relating to morbidity and health-related quality of life. Against this background, and in view of the consistent use of appropriate comparator therapies in both studies, the identified additional benefit of ivacaftor in the treatment of patients aged 12 years and over with a G551D mutation is taken into account. However, due to the associated uncertainties and limitations of the available evidence, as well as the short study duration of Study 111, the extent of this added benefit is non-quantifiable.

Courtesy translation only, please refer to the German original.