Ivacaftor (15) – Kalydeco®

Cystic fibrosis (CF), combination therapy with ivacaftor/tezacaftor/elexacaftor in patients ≥ 12 years (homozygous for F508del mutation)

Characteristics

Start date 01.09.2020 – Marketing authorisation: 21.08.2020
Resolution 18.02.2021
INN Ivacaftor
Brand name Kalydeco®
Pharm. company Vertex Pharmaceuticals (Ireland) Limited
G-BA Procedure ID D-587
ATC code R07AX02 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 0.15 g O
Therapeutic area Metabolic diseases Cystic fibrosis (CF) Orphan (turnover limit)
Reason for procedure New therapeutic indication – Orphan turnover exceeded
Specialty Bundling

Therapeutic indication of the resolution

Kalydeco tablets are indicated in a combination regimen with ivacaftor 75 mg/tezacaftor 50 mg/elexacaftor 100mg tablets for the treatment of adults and adolescents aged 12 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation in the CFTR gene.
Subpopulation Indication Comparator
Patients 12 years and older with cystic fibrosis who are homozygous for an F508del mutation in the CFTR gene. Lumacaftor/Ivacaftor or Tezacaftor/Ivacaftor in combination with Ivacaftor

Studies and Results

No. of studies
(best subpopulation) 		1 (VX18-445- 109)
Study design
(best subpopulation) 		H2H vs. ACT
Meta analysis
(best subpopulation) 		no

  • Clinical trials
    • Study 109 was a multicentre, randomised, double-blind, parallel-group, controlled Phase III trial.
    • A total of 178 children, adolescents and adults aged 12 years and over, who were homozygous for the F508del mutation in the CFTR gene, were randomised in a 1:1 ratio to the intervention arm (IVA/TEZ/ELX + IVA; N=88) or the control arm (TEZ/IVA + IVA; N=88).

Patients aged 12 years and over with cystic fibrosis who are homozygous and carry an F508del mutation in the CFTR gene

  • There is an indication of a major additional benefit.
  • Overall, the certainty of the evidence for the observed additional benefit is classified as ‘indication’.
  • mortality
    • No deaths occurred in study 109.
  • Morbidity – Pulmonary exacerbations and serious pulmonary exacerbations
    • Pulmonary exacerbations, particularly those leading to hospital admission, represent a clinically relevant endpoint and are to be regarded as patient-relevant.
    • Overall, a statistically significant advantage of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA was observed for both pulmonary exacerbations and serious pulmonary exacerbations.
  • Morbidity – 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 of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA.
    • For the gastrointestinal symptoms domain, the responder analysis (improvement of at least 15 points) showed no statistically significant difference between the treatment groups.
  • Morbidity – Body Mass Index (BMI) and BMI z-score
    • For the endpoint of absolute change in BMI and change in BMI z-score, a statistically significant difference in favour of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA; however, the extent of the clinical relevance of this finding 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.
  • Morbidity – Forced Expiratory Volume in One Second (FEV1 %)
    • In Study 109, a statistically significant difference in FEV1% was observed in favour of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA.
    • Opinions differ as to the clinical relevance of FEV1% for patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Morbidity – Sweat chloride concentration (mmol/l)
    • Study 109 found a statistically significant difference in sweat chloride concentration in favour of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA.
    • As the extent of the reduction in sweat chloride concentration is not directly associated with the extent of the change in symptoms, this endpoint is not considered to be of direct clinical relevance to patients and is therefore treated as a supplementary measure.
  • Health-related quality of life – measured using the CFQ-R
    • For the domains of physical well-being, vitality, role functioning, treatment burden and subjective health assessment, the responder analysis (improvement of at least 15 points) showed a statistically significant advantage of IVA/TEZ/ELX + IVA over TEZ/IVA + IVA.
    • For the domains of emotional state, social limitations, body image and eating disorders, the responder analysis (improvement of at least 15 points) showed no statistically significant difference between the treatment groups.
  • 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, there was no statistically significant difference between the treatment groups in either case.
    • In the ‘side effects’ category, there was no statistically significant difference between the treatment arms when viewed as a whole.
  • Overall assessment
    • In the morbidity category, a statistically significant difference in favour of IVA/ for the endpoints pulmonary exacerbations, serious pulmonary exacerbations, and the domains of the CFQ-R (respiratory system and weight problems) was found.TEZ/ELX + IVA compared with TEZ/IVA + IVA.
    • In the health-related quality of life category, a statistically significant difference in favour of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA was observed for the domains of the health-related quality of life category of the CFQ-R (physical well-being, vitality, role functioning, treatment burden and subjective health assessment) showed a statistically significant difference in favour of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA.
    • In the categories of mortality and side effects, there were no statistically significant differences overall between IVA/TEZ/ELX + IVA and TEZ/IVA + IVA.
    • In summary, for patients aged 12 years and over who are homozygous for the F508del mutation in the CFTR gene, an overall assessment of the results regarding mortality, morbidity, quality of life and side effects, there is a major additional benefit for IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA.

Courtesy translation only, please refer to the German original.

Associated procedures

Ivacaftor (27) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), F508del mutation, heterozygous and other or unknown mutation, ≥ 6 to ≤ 11 years, combination with ivacaftor / tezacaftor / elexacaftor 56 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (26) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), F508del mutation, heterozygous and RF mutation, ≥ 6 to ≤ 11 years, combination with ivacaftor / tezacaftor / elexacaftor 21 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (25) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), F508del mutation, heterozygous and gating mutation, ≥ 6 to ≤ 11 years, combination with ivacaftor / tezacaftor / elexacaftor). 28 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (24) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor/tezacaftor/elexacaftor, 6 to ≤ 11 years (homozygous for F508del mutation) 470 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (23) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor/tezacaftor/elexacaftor, 6 to ≤ 11 years (heterozygous for F508del and MF mutation) 230 100% Indication of considerable additional benefit Orphan (turnover limit)
Ivacaftor (22) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor/tezacaftor/elexacaftor in patients ≥ 12 years (heterozygous for F508del and others or unknown mutation) 310 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (21) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor/tezacaftor/elexacaftor in patients ≥ 12 years (heterozygous for F508del and RF mutation) 173 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (20) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), combination treatment with ivacaftor/tezacaftor/elexacaftor in patients ≥ 12 years (heterozygous for F508del and gating mutation (incl. R117H)) 133 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (19) Kalydeco® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), combination therapy with tezacaftor/ivacaftor in patients 6 to < 12 years (heterozygous for F508del and MF mutation) 50 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (18) Kalydeco® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), combination therapy with tezacaftor/ivacaftor in patients 6 to < 12 years (homozygous for F508del mutation) 470 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (17) Kalydeco® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), patients from 4 to < 6 months, R117H mutation 1 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (16) Kalydeco® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), patients from 4 to < 6 months, gating mutations 1 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (15) Kalydeco® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), combination therapy with ivacaftor/tezacaftor/elexacaftor in patients ≥ 12 years (homozygous for F508del mutation) 2,400 100% Indication of major additional benefit Orphan (turnover limit)
Ivacaftor (14) Kalydeco® Vertex Pharmaceuticals (Ireland) Limited Metabolic diseases Cystic fibrosis (CF), combination therapy with ivacaftor/tezacaftor/elexacaftor in patients ≥ 12 years (heterozygous for F508del and MF mutation) 1,000 100% Hint for major additional benefit Orphan (turnover limit)
Ivacaftor (13) Kalydeco® Vertex Pharmaceuticals Metabolic diseases Cystic fibrosis (CF), patients ≥ 6 months to < 18 years 26 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (12) Kalydeco® Vertex Pharmaceuticals Metabolic diseases Cystic fibrosis (CF), ≥ 6 to < 12 months 2 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (11) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), 12 ro < 24 months 5 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (10) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), patients ≥ 18 years with R117H mutation 35–44 100% Hint for minor additional benefit Orphan (turnover limit)
Ivacaftor (9) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), patients from 2 to 5 years 15 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (8) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), various gating mutations, ≥ 6 years 10–11 100% Hint for non-quantifiable additional benefit Orphan (turnover limit)
Ivacaftor (7) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), heterozygous for F508del, ≥ 12 years, combination with tezacaftor 200–300 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (6) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), homozygous for F508del, ≥ 12 years, combination with tezacaftor 2,400 100% additional benefit not proven Orphan (turnover limit)
Ivacaftor (5) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), G551D mutation, ≥ 6 years 210 86% Hint for considerable additional benefit Orphan (turnover limit)
Ivacaftor (4) Kalydeco® Vertex Pharmaceuticals (Germany) GmbH Metabolic diseases Cystic fibrosis (CF), ≥ 12 years, combination with tezacaftor n.d. discontinued Orphan
Ivacaftor (3) Kalydeco® Vertex Pharmaceuticals (Europe) Limited Metabolic diseases Cystic fibrosis (CF), R117H mutation, 2 to 5 years, > 18 years 0
59 		75% minor additional benefit Orphan repealed
Ivacaftor (2) Kalydeco® Vertex Pharmaceuticals Limited Metabolic diseases Cystic fibrosis (CF), various mutations, ≥ 6 years 0
10–11 		100% minor additional benefit Orphan repealed
Ivacaftor (1) Kalydeco® Vertex Pharmaceuticals GmbH Metabolic diseases Cystic fibrosis (CF), G551D mutation, ≥ 6 years 0
170 		84% considerable additional benefit Orphan repealed


<< List of all resolutions