Ivacaftor / Tezacaftor / Elexacaftor (16) – Kaftrio®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the results of study VX21-445-124. The trial is a randomised, double-blind, placebo-controlled Phase 3 trial comparing ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + best standard care (BSC) against placebo + BSC.

a) Adults with cystic fibrosis who have at least one non-Class I mutation in the CFTR gene, which is neither an F508del mutation nor a gating mutation.

• Hint of a major additional benefit.
• Uncertainties arise regarding the operationalisation of the endpoint ‘severe adverse events’. Furthermore, the generalisability of the results to patients without the mutations investigated in the study is limited. The certainty of the evidence is therefore classified as ‘a hint’.
• mortality
  • In the VX21-445-124 study, only one death occurred in the intervention arm. For the endpoint of overall survival, there is therefore no statistically significant difference between the treatment groups.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations were defined as the simultaneous occurrence of at least four specific symptoms or clinical signs requiring new or altered antibiotic therapy. The analysis was based on the proportion of patients affected and the annual event rate, in order to reflect both the occurrence and frequency of events over the course of the study.
  • For the endpoint of pulmonary exacerbations, a statistically significant advantage was observed in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Morbidity – Severe pulmonary exacerbations
  • Hospitalisation due to pulmonary exacerbations was used as a measure of severe pulmonary exacerbations. The proportion of patients with at least one event was analysed. Exacerbations requiring intravenous antibiotic therapy are included in this endpoint and were not considered separately.
  • For the endpoint of severe pulmonary exacerbations, a statistically significant advantage was observed in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Morbidity – Symptoms (CFQ-R) – Respiratory system
  • For the respiratory system domain of the CFQ-R, a statistically significant advantage was observed in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Morbidity – Symptoms (CFQ-R) – Gastrointestinal symptoms and weight-related issues
  • For the gastrointestinal symptoms and weight-related problems domain of the CFQ-R, no statistically significant difference was observed between the treatment groups in either case.
• Health-related quality of life – Physical well-being, subjective health assessment
  • For the domains ‘physical well-being’ and ‘subjective health assessment’ (domain assessed only in patients aged 14 years and over) of the CFQ-R, a statistically significant advantage was observed in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC. However, for both domains, there are effect modifications due to the characteristics of age and FEV₁. For patients aged ≥ 18 years or with an FEV₁ < 70 %, statistically significant advantages were observed in the relevant domains in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC. For patients < 18 years of age or with an FEV₁ ≥ 70%, however, no statistically significant difference was observed between the treatment arms.
• Health-related quality of life – vitality, role functioning
  • For the domains of vitality and role functioning (both domains were assessed only in patients aged 14 years and over) of the CFQ-R, a statistically significant advantage was observed in each case in favour of ivacaftor/tezacaftor/Elexacaftor in combination with Ivacaftor + BSC compared with placebo + BSC.
• Health-related quality of life – social limitations
  • For the social limitations domain of the CFQ-R, there was a statistically significant advantage in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC. However, there was an effect modification by the characteristic of gender. For female patients, there is a statistically significant advantage in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC; for male patients, however, this is not the case.
• Health-related quality of life – emotional state, body image, eating disorders, treatment burden
  • For the domains of emotional state, body image, eating disorders and treatment burden on the CFQ-R, a statistically significant advantage was observed in each case in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC. However, the 95 % confidence interval for the standardised mean difference is not entirely outside the irrelevance range in each case, so it cannot be concluded that the difference is clinically relevant.
• Side effects – SUEs, severe AEs and discontinuation due to AEs
  • For the endpoints SUEs, severe AEs and discontinuation due to AEs, there was no statistically significant difference between the treatment groups in any case.
• Side effects – specific AEs
  • For the endpoint ‘rash (AEs)’ in the category of non-serious/mild side effects, there is a statistically significant difference to the disadvantage of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Overall assessment
  • Overall, there are therefore clear advantages for the adult patient population in both the morbidity and health-related quality of life endpoint categories. Overall, for adults with cystic fibrosis who have at least one non-Class I mutation in the CFTR gene – which is neither an F508del mutation nor a gating mutation – there is a major additional benefit from ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared with the appropriate comparator therapy, best standard care (BSC).

b) Children and adolescents aged ≥ 6 to < 18 years with cystic fibrosis who have at least one non-Class I mutation in the CFTR gene, which is neither an F508del mutation nor a gating mutation.

• Hint of considerable additional benefit.
• Uncertainties arise regarding the operationalisation of the endpoint ‘severe adverse events’. Furthermore, the generalisability of the results to patients without the mutations investigated in the study is limited. The certainty of the evidence is therefore classified as ‘a hint’.
• Overall, this therefore provides there is a hint of considerable additional benefit from ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared with the appropriate comparator therapy, best standard care (BSC).
• mortality
  • In the VX21-445-124 study, only one death occurred in the intervention arm. There is therefore no statistically significant difference between the treatment groups for the endpoint of overall survival.
• Morbidity – Pulmonary exacerbations
  • Pulmonary exacerbations were defined as the simultaneous occurrence of at least four specific symptoms or clinical signs requiring new or altered antibiotic therapy. The analysis was based on the proportion of patients affected and the annual event rate, in order to reflect both the occurrence and frequency of events over the course of the study.
  • For the endpoint of pulmonary exacerbations, a statistically significant advantage was observed in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Morbidity – Severe pulmonary exacerbations
  • Hospitalisation due to pulmonary exacerbations was used as a measure of severe pulmonary exacerbations. The proportion of patients with at least one event was analysed. Exacerbations requiring intravenous antibiotic therapy are included in this endpoint and were not considered separately.
  • For the endpoint of severe pulmonary exacerbations, there was a statistically significant advantage in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Morbidity – Symptoms (CFQ-R) – Respiratory system
  • For the respiratory system domain of the CFQ-R, a statistically significant advantage was observed in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Health-related quality of life – Vitality, Role Function
  • For the vitality and role functioning domains (both domains were assessed only in patients aged 14 years and over) of the CFQ-R, a statistically significant advantage was observed in favour of ivacaftor/tezacaftor/Elexacaftor in combination with Ivacaftor + BSC compared with placebo + BSC.
  • The domains of vitality and role functioning were assessed exclusively for patients aged 14 to 17 years. It remains unclear whether these effects are also applicable to younger age groups, as the corresponding domains of the CFQ-R were not designed for children under 14 years of age.
• Health-related quality of life – social limitations
  • For the ‘social limitations’ domain of the CFQ-R, there is a statistically significant advantage in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC. However, there is an effect modification by the characteristic of gender. A statistically significant advantage was observed in favour of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC in female patients, but not in male patients.
• Side effects – SUEs, severe AEs and discontinuation due to AEs
  • For the endpoints SUEs, severe AEs and discontinuation due to AEs, there was no statistically significant difference between the treatment groups in any case.
• Side effects – specific adverse events
  • For the endpoint ‘rash (ADEs)’ in the category of non-serious/mild side effects, there was a statistically significant difference to the disadvantage of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor + BSC compared with placebo + BSC.
• Overall assessment
  • Overall, there are clear advantages for the patient population of children and adolescents aged ≥ 6 to < 18 years in both the morbidity endpoint category and that of health-related quality of life. When interpreting the results for children and adolescents aged ≥ 6 to < 18 years, it should be borne in mind that patients in this age group have a minor symptom burden compared to adults due to the typically less advanced stage of the disease. There is therefore uncertainty as to whether children and adolescents aged ≥ 6 to < 18 years will benefit from the treatment to the same extent as adult patients in the short term. Long-term data are also not available.
  • Overall, for children and adolescents aged ≥ 6 to < 18 years with cystic fibrosis who have at least one non-Class I mutation in the CFTR gene, which is neither an F508del mutation nor a gating mutation, a considerable additional benefit from ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared with the appropriate comparator therapy, best standard care (BSC).

c) Children aged ≥ 2 to < 6 years with cystic fibrosis who have at least one non-Class I mutation in the CFTR gene, which is neither an F508del mutation nor a gating mutation.

• Hint for a non-quantifiable additional benefit.
• Due to the uncertainty surrounding the extrapolation of the additional benefit to a younger patient population, only a hint of the additional benefit can be established with certainty.
• Overall, based on the extrapolation of the results of the VX21-445-124 study in children and adolescents aged 6 to 17-year-old children and adolescents, there is evidence for children aged ≥ 2 to < 6 years with cystic fibrosis who have at least one non-Class I mutation in the CFTR gene that is neither an F508del mutation nor a gating mutation, there is a hint of a non-quantifiable additional benefit of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared with the appropriate comparator therapy, best standard care (BSC).
• Although no direct comparative study data are available for children aged ≥ 2 to < 6 years, the extrapolation of the results is based on the following aspects.
• Firstly, cystic fibrosis is an inherited multisystem disorder in which mutations in the CFTR gene cause dysfunction of the chloride channels in exocrine glands. The pathophysiological mechanisms (disruption of the chloride channel) are therefore identical for the patient population relevant here—children aged ≥ 2 to < 6 years—to those in older patients.
• Cystic fibrosis is a progressive condition, although younger children, such as the patient group under consideration here, exhibit fewer symptoms; however, this does not fundamentally limit the significance of patient-relevant endpoints. However, this means that the impact on the course of the disease in terms of patient-relevant endpoints can only be measured to a limited extent.
• The appropriate comparator therapy (BSC) defined by the G-BA applies to all children, adolescents and adults with cystic fibrosis who have at least one non-Class I mutation in the CFTR gene, which is neither an F508del mutation nor a gating mutation. In this respect, this provides a key criterion for the transfer of evidence within the framework of early benefit assessment.
• Furthermore, the criteria to be applied for the recognition of evidence based on a low level of evidence take into account the specific characteristics and limitations in the conduct of paediatric clinical trials.
• It is also evident from the assessment report of the European Medicines Agency (EMA) that extrapolating the results from older patients to children aged ≥ 2 to < 6 years is considered appropriate. The marketing authorisation is based on comparable pharmacokinetic profiles and the shared pathophysiological mechanism of the disease (CFTR dysfunction).
• Overall, therefore, given the identical genetic cause and comparable pathophysiology of the condition, it is assumed that the positive effects of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor from the VX21-445-124 in children and adolescents aged 6 to 17 years are also transferable to children aged ≥ 2 to < 6 years.

Courtesy translation only, please refer to the German original.