Ivacaftor / Tezacaftor / Elexacaftor (1) – Kaftrio®

Cystic fibrosis (CF), combination treatment with ivacaftor in patients ≥12 years (heterozygous for F508del and MF mutation)

Characteristics

Start date 01.09.2020 – Marketing authorisation: 21.08.2020
Resolution 18.02.2021
INN Ivacaftor/Tezacaftor/Elexacaftor
Brand name Kaftrio®
Pharm. company Vertex Pharmaceuticals (Ireland) Limited
G-BA Procedure ID D-584
ATC code R07AX32 Other respiratory system products (R07AX)
DDD 0.15 g O
Therapeutic area Metabolic diseases Orphan (turnover limit)
Reason for procedure Initial assessment – Orphan turnover exceeded
Specialty Bundling

Studies and Results

  • Clinical trials
    • To assess the additional benefit of IVA/TEZ/ELX + IVA in patients aged 12 years and over with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and who also have a minimally functional mutation on the second allele, the pharmaceutical manufacturer submitted a multicentre, randomised, double-blind, placebo-controlled Phase III trial, VX17-445-102 (hereinafter referred to as Study 102).

Patients aged 12 years and over with cystic fibrosis who are heterozygous and carry an F508del mutation in the CFTR gene as well as a minimal-function mutation on the second allele

  • There is a hint of a major additional benefit.
  • In summary, for patients with cystic fibrosis aged 12 years and over who are heterozygous for the F508del mutation in the CFTR gene and carry an MF mutation, there is a hint of major additional benefit from IVA/TEZ/ELX + IVA compared with the appropriate comparator therapy, BSC.
  • Based on Study 102, at most, there are hints to determine the additional benefit for all endpoints presented.
  • mortality
    • No deaths occurred in Study 102.
  • morbidity
    • Pulmonary exacerbations
    • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
    • For pulmonary exacerbations, there is a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • Hospitalisation due to pulmonary exacerbations
    • A statistically significant advantage was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC for hospitalisation due to pulmonary exacerbations.
    • Symptoms measured using the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
    • For the respiratory system and weight problems domains, the responder analysis (improvement of at least 15 points) showed a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • For the gastrointestinal symptoms domain, the responder analysis (improvement of at least 15 points) showed no statistically significant difference between the treatment groups.
    • Body Mass Index (BMI) and BMI z-score
    • For the endpoint of absolute change in BMI and change in BMI z-score, Study 102 showed a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC; however, the clinical relevance of this extent cannot be conclusively assessed, as the patients included in both treatment groups already had a BMI within the normal range at the start of the studies.
    • Forced one-second volume (FEV1)
    • Here, a statistically significant advantage was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • Sweat chloride concentration (mmol/l)
    • There is a statistically significant difference in the absolute change in sweat chloride concentration in favour of ivacaftor + ivacaftor/tezacaftor/elexacaftor + BSC compared with placebo + BSC.
  • Health-related quality of life
    • Health-related quality of life as measured by the CFQ-R
    • For all domains within the health-related quality of life category of the CFQ-R (physical well-being, emotional state, vitality, social limitations, role functioning, body image, eating disorders, treatment burden and subjective health assessment), the responder analysis (improvement of at least 15 points) revealed statistically significant advantages in each case for ivacaftor + ivacaftor/tezacaftor/elexacaftor + BSC compared with placebo + BSC.
  • Side effects
    • No data are available for estimating the effect size regarding the overall rate of adverse events (AEs).
    • For the endpoints of SUEs and discontinuation due to AEs, no statistically significant differences were observed between the treatment groups.
    • In the category of side effects, there is no statistically significant difference between the treatment arms when viewed as a whole.
  • Overall assessment
    • In the morbidity category, a statistically significant difference was observed for the endpoints of pulmonary exacerbations, hospitalisation due to pulmonary exacerbations and in the respiratory system and weight problems domains of the CFQ-R, a statistically significant advantage in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • For the ‘gastrointestinal symptoms’ domain of the CFQ-R, no statistically significant difference was observed between the treatment groups.
    • A summary of the morbidity results revealed a difference relevant to the benefit assessment in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • In the quality of life category, statistically significant differences in favour of Ivacaftor + Ivacaftor/Tezacaftor were observed in all domains of the CFQ-R (physical well-being, emotional state, vitality, social restrictions, role functioning, body image, eating disorders, treatment burden and subjective health assessment) statistically significant advantages in favour of ivacaftor + ivacaftor/tezacaftor/elexacaftor + BSC compared with placebo + BSC.
    • When the results on health-related quality of life were considered as a whole, a difference relevant to the benefit assessment was observed in favour of IVA/TEZ/ELX + IVA + BSC compared with placebo + BSC.
    • In the categories of mortality and side effects, there were no statistically significant differences between the treatment groups when considered as a whole.
    • In summary, for patients with cystic fibrosis aged 12 years and over who are heterozygous for the F508del mutation in the CFTR gene and carry an MF mutation, there is a major 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)


<< List of all resolutions