Ivacaftor / Tezacaftor / Elexacaftor (2) – Kaftrio®
Cystic fibrosis (CF), combination treatment with ivacaftor 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/Tezacaftor/Elexacaftor |
| Brand name | Kaftrio® |
| Pharm. company | Vertex Pharmaceuticals (Ireland) Limited |
| G-BA Procedure ID | D-585 |
| 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 | 0.15 g O |
| Therapeutic area | Metabolic diseases Cystic fibrosis (CF) Orphan (turnover limit) |
| Reason for procedure | Initial assessment – Orphan turnover exceeded |
| Specialty | Bundling |
| Therapeutic indication of the resolution |
|---|
|
Kaftrio is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (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 comparator arm (TEZ/IVA + IVA; N=88), stratified by FEV1 (< 70% / ≥ 70%), age (< 18 / ≥ 18 years) and use of a CFTR modulator (yes / no).
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 identified 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.
- The endpoint ‘pulmonary exacerbations’ was monitored as a safety endpoint using the Preferred Term (PT) ‘infectious pulmonary exacerbation of cystic fibrosis’.
- The endpoint ‘severe pulmonary exacerbations’ was also assessed as a safety endpoint, defined as a severe adverse event (SAE), using the PT ‘infectious pulmonary exacerbation of cystic fibrosis’.
- 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)
- The endpoint ‘symptoms’ was assessed using the disease-specific CFQ-R (patient version) and comprised the respiratory, weight-related and gastrointestinal domains.
- For the respiratory and weight-related 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
- BMI is used to assess body weight in relation to height.
- 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 difference 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 study.
- 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.
- Health-related quality of life – measured using the CFQ-R
- Quality of life was assessed using the validated, disease-specific quality-of-life instrument CFQ-R, employing the patient version, and covered the domains of physical well-being, emotional state, vitality, social limitations, role functioning, body image, eating disorders, treatment burden and subjective health assessment.
- 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
- For the benefit assessment of ivacaftor in combination with ivacaftor/tezacaftor/elexacaftor for the treatment of cystic fibrosis (CF, cystic fibrosis) in patients aged 12 years and over who are homozygous for the F508del mutation in the CFTR gene, Study 109, which directly compared IVA/TEZ/ELX + IVA with TEZ/IVA + IVA, was used.
- No deaths occurred in Study 109. 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.
- For the ‘gastrointestinal symptoms’ domain of the CFQ-R, there was no statistically significant difference 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 compared with TEZ/IVA + IVA.
- In the ‘health-related quality of life’ category, a statistically significant difference was observed in the domains of the CFQ-R’s ‘health-related quality of life’ category (physical well-being, vitality, role functioning, treatment burden and subjective health assessment), a statistically significant difference was observed in favour of IVA/TEZ/ELX + IVA compared with TEZ/IVA + IVA.
- For the domains of emotional state, social restrictions, body image and eating disorders of the CFQ-R, there was no statistically significant difference between the treatment groups. 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 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
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