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)
ICD-10 codes (AIS) E84.0Cystic fibrosis with pulmonary manifestations, E84.1Cystic fibrosis with intestinal manifestations, E84.80, E84.87, E84.88, E84.9Cystic fibrosis, unspecified
Alpha-ID codes (AIS) I129376Neonatal hepatobiliary disease in cystic fibrosis, I130516Cystic fibrosis with other multiple manifestations, I18531Cystic fibrosis, I2487Cystic fibrosis with pulmonary manifestation, I2488Cystic fibrosis with intestinal manifestation, I32495Cystic fibrosis with manifestations in the lungs and digestive tract
ORPHAcodes (AIS) 586Neonatal hepatobiliary disease in cystic fibrosis, 586Cystic fibrosis with other multiple manifestations, 586Cystic fibrosis, 586Cystic fibrosis with pulmonary manifestation, 586Cystic fibrosis with intestinal manifestation, 586Cystic fibrosis with manifestations in the lungs and digestive tract
DDD 2 O
Therapeutic area Metabolic diseases Cystic fibrosis (CF) Orphan (turnover limit)
Reason for procedure New therapeutic indication
Specialty Bundling

Therapeutic indication of the resolution

Kaftrio is indicated in a combination regimen with ivacaftor for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

Subpopulation Indication Comparator
A) Children aged 6 to 11 years with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and carry a mutation with minimal function on the second allele. minimal function on the second allele Best Supportive Care (BSC)

Studies and Results

No. of studies
(best subpopulation) 		1 (VX19-445-116)
Study design
(best subpopulation) 		H2H vs. ACT
Meta analysis
(best subpopulation) 		no

  • 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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