Ivacaftor (1) – Kalydeco®

• Clinical trials
  • The results of registration trials 102 and 103 are available to address the question regarding the extent of the additional benefit.
  • These are two-arm, controlled, randomised, double-blind, parallel-group Phase III trials involving patients aged 6 years and over with cystic fibrosis (CF) and a G551D mutation in the CFTR gene.
  • In Study 102, ivacaftor was tested in 83 patients aged 12 years and over, administered orally twice daily, compared with 78 patients receiving placebo over 24 and 48 weeks respectively.
  • Study 103 enrolled patients aged between 6 and 11 years; 26 patients receiving twice-daily doses of ivacaftor were evaluated against 26 patients receiving placebo over a period of 24 and 48 weeks, respectively.

Children (aged 6 to 11 years) with cystic fibrosis (CF) and a G551D mutation in the CFTR gene

• The G-BA classifies the extent of the additional benefit of ivacaftor as ‘minor’ on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a previously unachieved moderate improvement in treatment-related benefit, as a reduction in non-serious symptoms of the disease (the ‘morbidity’ endpoint) is achieved.
• mortality
  • No deaths were observed in the study.
  • The forced expiratory volume in one second (FEV1%) and the body mass index (BMI) are cited by the pharmaceutical manufacturer as surrogates for mortality; however, a causal link between either of these endpoints and overall survival remains unestablished.
  • Prospective long-term studies on this are still lacking.
• morbidity
  • FEV1% and BMI are regarded as important parameters in efficacy studies on CF.
  • Guidelines therefore recommend that these factors be assessed accordingly.
  • For children, the study observed 103 significant changes in these endpoints at both time points—24 and 48 weeks after the start of the study.
  • There are differing views on the clinical relevance of FEV1% for patients.
  • This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Due to the minor event rate in Study 103, an analysis of pulmonary exacerbations could only be carried out in Study 102.
  • Consequently, there are no (sufficient) results on pulmonary exacerbations for children aged between 6 and 11 years to allow this endpoint to be used to determine the extent of the additional benefit in this patient group.
• quality of life
  • Quality of life was assessed using a disease-specific quality-of-life instrument [Cystic Fibrosis Questionnaire-Revised (CFQ-R)], employing two versions (paediatric and adult).
  • The CFQ-R is a questionnaire that measures patients’ subjective perceptions [‘patient-reported outcome (PRO)’].
  • In the studies, only one domain (‘respiratory system’) was defined a priori as a secondary endpoint.
  • With regard to this domain, Study 103 showed a statistically significant result for the children when parents/carers were surveyed at the 24-week mark.
  • Although the other results in this study showed general, overall improvements with ivacaftor, the differences were not statistically significant.
• Side effects
  • No relevant differences were observed in adverse events, severe adverse events or adverse events leading to discontinuation of the study.

Adolescents (aged 12 years and over) and adults with cystic fibrosis (CF) and a G551D mutation in the CFTR gene

• The G-BA classifies the extent of the additional benefit of ivacaftor, based on the criteria in Section 5(7) of the AM-NutzenV and taking into account the severity of the disease and the therapeutic objective in treating the disease, as considerable for the patient group comprising adolescents (aged 12 and over) and adults as considerable.
• In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this constitutes a significant improvement in treatment-related benefit not previously achieved, in particular a noticeable alleviation of the disease and a relevant reduction in serious side effects.
• mortality
  • No deaths were observed in the study.
  • The forced expiratory volume in one second (FEV1%) and the body mass index (BMI) are cited by the pharmaceutical manufacturer as surrogates for mortality; however, a causal link between either of these endpoints and overall survival remains unestablished.
  • Prospective long-term studies on this subject are still lacking.
• morbidity
  • FEV1% and BMI are regarded as important parameters in efficacy studies on CF.
  • Guidelines therefore recommend that these factors be assessed accordingly.
  • In Study 102, statistically significant advantages were achieved with ivacaftor compared with placebo treatment in terms of FEV1% and BMI at both week 24 and week 48.
  • There are differing views on the clinical relevance of FEV1% for patients.
  • The overall conclusion regarding the extent of the additional benefit remains unaffected by this.
  • Pulmonary exacerbations, particularly those leading to hospital admission or intravenous antibiotic administration, are to be regarded as clinically relevant.
  • Study 102 showed statistically significant results in the following assessments: the number of pulmonary exacerbations and the event-free interval for pulmonary exacerbations in general, as well as the event-free interval for pulmonary exacerbations leading to intravenous antibiotic therapy, at weeks 24 and 48; and the event-free interval for pulmonary exacerbations leading to hospital admission at week 48.
  • Consequently, the G-BA concludes that the results regarding pulmonary exacerbations should be regarded as a significant improvement in treatment-related benefit.
• quality of life
  • Quality of life was assessed both using a validated, disease-specific quality-of-life instrument [Cystic Fibrosis Questionnaire-Revised (CFQ-R)]—using two versions (paediatric and adult)—and a generic questionnaire (EQ-5D).
  • The CFQ-R is a questionnaire that measures patients’ subjective perceptions [‘patient-reported outcome (PRO)’].
  • In the studies, only one domain (‘respiratory system’) was defined a priori as a secondary endpoint.
  • In the study involving patients aged 12 years and over (Study 102), a statistically significant improvement was observed consistently with ivacaftor.
  • However, no baseline data were provided in this study, which limits a precise assessment of the effect.
  • With regard to the assessments using the generic EQ-5D questionnaire, statistically significant advantages were also observed with ivacaftor treatment at both assessment time points.
  • Consequently, the G-BA concludes that the results on quality of life should be regarded as an improvement in treatment-related benefit.
• Side effects
  • Severe adverse events occurred less frequently with ivacaftor after 48 weeks.
  • This effect is attributable to the fact that, in the study, pulmonary exacerbations were recorded under the heading ‘side effect’.
  • These are taken into account in the present assessment under the morbidity endpoint ‘pulmonary exacerbations’.
• Overall assessment
  • Consequently, the G-BA concludes that the findings regarding pulmonary exacerbations should be regarded as a significant improvement in treatment-related benefit.
  • Consequently, the G-BA concludes that the findings on quality of life should be regarded as an improvement in treatment-related benefit.

Courtesy translation only, please refer to the German original.