Lumacaftor / Ivacaftor (1) – Orkambi®

• Clinical trials
  • To demonstrate the additional benefit of lumacaftor/ivacaftor, the pharmaceutical manufacturer has submitted the two double-blind, randomised trials VX12-809-103 and VX12-809-104 (hereinafter referred to as studies 103 and 104).

a) Patients aged 12 years and over who are homozygous for the F508del mutation in the CFTR gene

• For the treatment of cystic fibrosis (CF) in patients aged 12 years and over who are homozygous for the F508del mutation in the CFTR gene, there is an indication of considerable additional benefit for lumacaftor/ivacaftor compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of lumacaftor/ivacaftor as considerable, 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 the treatment of the disease.
• Having weighed up the aspects discussed, the certainty of the findings in this assessment is classified as an indication.
• mortality
  • No deaths occurred in the study. With regard to mortality, no conclusion regarding additional benefit can be drawn from the available results.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations, particularly those leading to hospital admission or intravenous antibiotic treatment, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
  • In both studies, the number of pulmonary exacerbations, the number of hospitalisations required due to exacerbations, and the number of courses of intravenous antibiotic therapy due to exacerbations were statistically significantly lower in the lumacaftor/ivacaftor group compared with the best-supportive-care (BSC) control group.
  • For the endpoint of pulmonary exacerbations, the hazard ratio (HR) was 0.60 [95% CI 0.47; 0.77]; p<0.001.
  • For the outcome of hospitalisation due to pulmonary exacerbations, the HR was 0.38 [95% CI 0.26; 0.56]; p<0.001.
  • For the endpoint of antibiotic treatment due to pulmonary exacerbations, a hazard ratio (HR) of 0.41 [95% CI 0.28; 0.61]; p<0.001 was observed.
  • These results regarding pulmonary exacerbations represent a significant improvement in treatment-related benefit.
• Morbidity – Body Mass Index (BMI)
  • The endpoint ‘body mass index (BMI)’ is regarded as an important parameter in efficacy studies on CF. Guidelines recommend that it be assessed.
  • In studies 103 and 104, a statistically significant advantage with regard to BMI was achieved in only one study (104).
  • The meta-analysis of the two studies revealed a statistically significant difference in the mean change in BMI of 0.3 kg/m² [95% CI 0.04; 0.47] in favour of lumacaftor/ivacaftor.
  • For the subgroup characteristic of region, there is proof of an effect modification, with the statistically significant advantage for lumacaftor/ivacaftor observed only in the North America patient population.
• Morbidity – Visual Analogue Scale of the European Quality of Life 5-Dimensions Questionnaire (EQ-5D-VAS)
  • The endpoint ‘Visual Analogue Scale of the European Quality of Life 5-Dimensions Questionnaire’ (EQ-5D-VAS) reflects general health status and is assigned to the endpoint category ‘morbidity’.
  • The meta-analytic summary of the results for the change in the EQ-5D-VAS was statistically significant.
  • As no information is available on the ‘Minimal Important Difference’ (MID) of the EQ-5D-VAS, Hedges’ g was calculated. With a Hedges’ g of 0.16 [95% CI 0.01; 0.30], the effect remained below the relevance threshold of 0.2 and cannot therefore be used to assess the additional benefit.
• Quality of life – Cystic Fibrosis Questionnaire-Revised
  • Quality of life was assessed using the validated, disease-specific quality-of-life instrument, the Cystic Fibrosis Questionnaire-Revised (CFQ-R), employing two versions (self-assessment and assessment by parents or carers).
  • In both studies, no statistically significant improvement was observed for the ‘respiratory system’ domain with lumacaftor/ivacaftor.
  • In the self-assessment, a statistically significant change in favour of lumacaftor/ivacaftor was observed only in the ‘role functioning’ domain. With a Hedges’ g of 0.17 [95% CI 0.01; 0.32], the effect is below the relevance threshold of 0.2.
  • In the assessment by parents or carers, changes in favour of lumacaftor/ivacaftor were statistically significant in the meta-analytic summary only for the ‘treatment burden’ domain; here too, the effect lies below the relevance threshold.
  • Overall, these results are considered to be clinically irrelevant. Consequently, no conclusion regarding additional benefit for the quality of life endpoint can be drawn on the basis of the available results.
• Side effects
  • The incidence of serious adverse events (SAEs) was statistically significantly lower in the lumacaftor/ivacaftor group.
  • As both infectious pulmonary exacerbations of CF and hospitalisations are classified as SAE, it is severe to distinguish the incidence of SAE from the efficacy of lumacaftor/ivacaftor treatment.
  • Consequently, no conclusion regarding additional benefit for the ‘side effects’ endpoint can be drawn from the available results.
• Overall assessment
  • The G-BA classifies the extent of the additional benefit of lumacaftor/ivacaftor as considerable, 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 the treatment of the disease.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a significant improvement in treatment-related benefit not previously achieved, as a reduction in patient-relevant symptoms (pulmonary exacerbations) and, consequently, a significant alleviation of the condition that is perceptible to patients is achieved.

Courtesy translation only, please refer to the German original.