Ivacaftor / Tezacaftor / Elexacaftor (6) – Kaftrio®

Cystic fibrosis (CF), combination treatment with ivacaftor, from 6 to ≤ 11 years (heterozygous for F508del and MF mutation)

Characteristics

Start date 15.02.2022 – Marketing authorisation: 07.01.2022
Resolution 04.08.2022
INN Ivacaftor/Tezacaftor/Elexacaftor
Brand name Kaftrio®
Pharm. company Vertex Pharmaceuticals (Germany) GmbH
G-BA Procedure ID D-773
ATC code R07AX32 Other respiratory system products (R07AX)
DDD 2 O
Therapeutic area Metabolic diseases Orphan (turnover limit)
Reason for procedure New therapeutic indication
Specialty Bundling

Studies and Results

  • Clinical trials
    • To assess the additional benefit of IVA/TEZ/ELX + IVA in children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele, the pharmaceutical manufacturer submitted a multicentre, randomised, double-blind, placebo-controlled Phase III trial, VX19-445-116 (hereinafter referred to as Study 116).

Children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele

  • An overall analysis of the study results shows that, for the endpoints of pulmonary exacerbations, LCI2.5, BMI and BMI z-score; in the CFQ-R domains, in the categories of morbidity (respiratory and gastrointestinal symptoms) and quality of life (social limitations); as well as for the endpoint of abdominal pain (PT), a statistically significant difference in favour of IVA/TEZ/ELX + IVA.
  • In summary, for children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele, there is an indication of considerable additional benefit from IVA/TEZ/ELX + IVA compared with the appropriate comparator therapy, BSC.
  • Overall, the certainty of the evidence for the observed additional benefit is classified as ‘indication’.
  • mortality
    • No deaths occurred in study 116.
  • Morbidity – Pulmonary exacerbations
    • For pulmonary exacerbations, there is a statistically significant difference in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • For serious pulmonary exacerbations, there was no statistically significant difference between IVA/TEZ/ELX + IVA + BSC and placebo + BSC.
  • Morbidity – Symptoms measured using the Cystic Fibrosis Questionnaire – Revised (CFQ-R)
    • For the respiratory system and gastrointestinal symptoms domains, the patient version showed a statistically significant difference in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • In addition, the parent/carer version also showed a statistically significant difference in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC, whilst for the gastrointestinal symptoms domain, no statistically significant difference was observed between the treatment groups.
  • 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 in Study 116 as the absolute change over 24 weeks of treatment. Here, a statistically significant difference was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • 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.
  • Quality of life – Health-related quality of life measured using the CFQ-R
    • For the ‘social limitations’ domain, the patient version showed a statistically significant difference in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • For the domains of physical well-being, emotional state, body image, eating disorders and treatment burden, the patient version shows no statistically significant difference between the treatment groups.
    • In addition, the parent/carer version also showed a statistically significant difference in the ‘body image’ domain in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
  • Side effects
    • For the endpoints SUEs and discontinuation due to AEs, no statistically significant differences were observed between the treatment groups in either case.
    • For the endpoint abdominal pain (PT), a statistically significant difference was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • In the category of side effects, there was no statistically significant difference between the treatment arms when viewed as a whole.
  • Overall assessment
    • No deaths occurred in Study 116.
    • In the morbidity category, there was a statistically significant difference in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC for the endpoints of pulmonary exacerbations, LCI2.5, BMI and BMI z-score, as well as the ‘Respiratory System’ and ‘Gastrointestinal Symptoms’ domains of the patient version of the CFQ-R, a statistically significant difference in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • Furthermore, a statistically significant difference in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • No statistically significant difference was observed between the treatment groups for the endpoints of serious pulmonary exacerbations or for the additional domain of gastrointestinal symptoms in the parent/carer version of the CFQ-R.
    • In the health-related quality of life category, a statistically significant difference was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • For the domains of physical well-being, emotional state, eating disorders and treatment burden, no statistically significant difference was observed between the treatment groups in either version of the CFQ-R, nor in the additional domains of the parent/carer version—vitality, school difficulties and subjective health assessment.
    • In the ‘side effects’ category, there was no statistically significant difference between the treatment arms when viewed as a whole.
    • In summary, for children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and carry a minimal-function mutation on the second allele, there is a considerable additional benefit from IVA/TEZ/ELX + IVA compared with the appropriate comparator therapy, BSC.

Courtesy translation only, please refer to the German original.

Associated procedures

Ivacaftor / Tezacaftor / Elexacaftor (17) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, combination therapy with ivacaftor, ≥ 2 years, non-Class I mutation (a gating mutation and no F508del mutation) 100 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (16) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, combination therapy with ivacaftor, ≥ 2 years, non-Class I mutation (no F508del mutation and no gating mutation) 375 64% Hint for major additional benefit Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (11) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, combination treatment with ivacaftor, from 2 to ≤ 5 years of age (heterozygous for F508del and MF mutation) 160 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (12) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, combination treatment with ivacaftor, 2 to ≤ 5 years (homozygous for F508del mutation) 250 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (13) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, F508del mutation, heterozygous and gating mutation, ≥ 2 to ≤ 5 years, combination with ivacaftor 13 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (14) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, F508del mutation, heterozygous and RF mutation, ≥ 2 to ≤ 5 years, combination with ivacaftor 20 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (15) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, F508del mutation, heterozygous and other or unknown mutation, ≥ 2 to ≤ 5 years, combination with ivacaftor 33 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (6) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor, from 6 to ≤ 11 years (heterozygous for F508del and MF mutation) 233 100% Indication of considerable additional benefit Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (7) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor, 6 to ≤ 11 years (homozygous for F508del mutation) 470 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (8) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis, F508del mutation, heterozygous and gating mutation, ≥ 6 to ≤ 11 years, combination with ivacaftor) 28 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (10) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), F508del mutation, heterozygous and other or unknown mutation, ≥ 6 to ≤ 11 years, combination with ivacaftor 56 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (9) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), F508del mutation, heterozygous and RF mutation, ≥ 6 to ≤ 11 years, combination with ivacaftor 21 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (5) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor in patients ≥ 12 years (heterozygous for F508del and others or unknown mutation). 310 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (4) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor in patients ≥ 12 years (heterozygous for F508del and RF mutation) 173 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (3) Kaftrio® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor in patients > 12 years (heterozygous for F508del and gating mutation (incl. R117H)). 133 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (1) Kaftrio® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor in patients ≥12 years (heterozygous for F508del and MF mutation) 1,000 100% Hint for major additional benefit Orphan (turnover limit)
Ivacaftor / Tezacaftor / Elexacaftor (2) Kaftrio® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor in patients ≥ 12 years (homozygous for F508del mutation) 2,400 100% Indication of major additional benefit Orphan (turnover limit)


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