Ivacaftor (2) – Kalydeco®

• Clinical trials
  • To address the question regarding the extent of the additional benefit, the results of study VX12-770-111 (hereinafter referred to as Study 111) are available; this is the main study on which the marketing authorisation is based. This is a Phase III study, which was a multicentre, double-blind, randomised, placebo-controlled trial with a crossover design, which investigated the efficacy and tolerability of treatment with 150 mg of ivacaftor twice daily compared with placebo over two 8-week treatment phases each, followed by an extended open-label treatment phase lasting a further 16 weeks.

Patients with gating mutations (Class III) in the CFTR gene, specifically those with the following gating mutations: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R

• In summary, the extent of the additional benefit of ivacaftor is assessed as follows: for patients with the following gating mutations (Class III) in the CFTR gene – G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R, there is a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of ivacaftor as minor, based on 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 treating 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, in particular, an improvement in health-related quality of life 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. On the basis of the information in the dossier, it can be concluded for both endpoints that no causal relationship or influence/change in mortality due to the change in the respective surrogate has been demonstrated.
  • Taken together, no conclusion can be drawn regarding the extent of the additional benefit in terms of mortality based on the available results.
• Morbidity – FEV1% and BMI
  • The endpoints FEV1% and BMI are regarded as important parameters in efficacy studies on CF. Guidelines therefore recommend that the relevant influencing factors be assessed.
  • In Study 111, statistically significant advantages were achieved for both FEV1% and BMI.
  • It should be noted that, due to the studies’ inclusion and exclusion criteria, patients with mild or moderate, but not severe, lung disease were included (FEV1(%) ≥ 40 at baseline). Consequently, the effect of ivacaftor is limited to this population.
  • 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.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission or the administration of intravenous antibiotics, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
  • In Study 111, the incidence of events (treatment days), duration, number of hospitalisations and number of patients requiring intravenous antibiotics were recorded. However, no significant difference was observed between the treatment groups for any of the operationalisation approaches mentioned.
  • The data from the open-label extension phase of Study 111, submitted during the commenting procedure, can only be assessed to a limited extent due to the lack of a control group; they do not allow for a valid assessment of a possible effect of the treatment on the rate of pulmonary exacerbations.
• quality of life
  • Quality of life was assessed using a validated, disease-specific quality-of-life instrument [Cystic Fibrosis Questionnaire-Revised (CFQ-R)], employing two versions (paediatric and adult).
  • In the study, a statistically significant improvement was observed in the ‘respiratory system’ domain with ivacaftor. The confidence interval for the difference exceeds the minimum clinically meaningful difference of 4 specified by the pharmaceutical manufacturer; however, the applicability of this value to the study population in question cannot be conclusively assessed.
  • The G-BA concludes that the results regarding quality of life should be regarded as an improvement in treatment-related benefit.
• Side effects
  • Overall, the adverse reaction profile in this study was comparable to that in the studies involving patients with the G551D gating mutation.
  • No significant differences were observed between the groups; this also applies to the data from the open-label extension phase of Study 111 submitted during the commenting procedure.

Courtesy translation only, please refer to the German original.