Tezacaftor / Ivacaftor (2) – Symkevi®
Cystic fibrosis (CF), combination treatment with ivacaftor in patients ≥ 12 years (homozygous for F508del)
Characteristics
| Start date | 01.07.2020 – Marketing authorisation: 31.10.2018 |
|---|---|
| Resolution | 17.12.2020 |
| INN | Tezacaftor/Ivacaftor |
| Brand name | Symkevi® |
| Pharm. company | Vertex Pharmaceuticals |
| G-BA Procedure ID | D-552 |
| ATC code | R07AX31 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 | 1 U O |
| Therapeutic area | Metabolic diseases Cystic fibrosis (CF) Orphan (turnover limit) |
| Reason for procedure |
Reassessment: Orphan turnover exceeded
Original resolution: Tezacaftor / Ivacaftor (1) (16.05.2019) |
| Specialty | Bundling |
| Therapeutic indication of the resolution |
|---|
|
Symkevi is indicated in a combination regimen with ivacaftor 150 mg tablets for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation. |
| Subpopulation | Indication | Comparator |
|---|---|---|
| Patients 12 years and older with cystic fibrosis who are homozygous for the F508del mutation | Lumacaftor/Ivacaftor |
Studies and Results
|
No. of studies
(best subpopulation) |
3 (VX14-661-106, VX14-661-103, VX14-661-104) |
|---|---|
|
Study design
(best subpopulation) |
H2H vs. non-ACT + ITC (Bucher) |
|
Meta analysis
(best subpopulation) |
yes |
- Clinical trials
- The study on which the marketing authorisation is based, VX14-661-106 (hereinafter referred to as Study 106), is a multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase III trial.
- Studies VX12-809-103 and VX12-809-104 (hereinafter referred to as Studies 103 and 104) are randomised, double-blind, placebo-controlled, parallel-group Phase III studies.
Patients aged 12 years and over with cystic fibrosis who are homozygous for the F508del mutation.
- mortality
- No deaths occurred in any of the studies 106, 103 and 104.
- 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 studies 106, 103 and 104 as the absolute change over 24 weeks of treatment.
- In the adjusted indirect comparison, a statistically significant difference in FEV1% was observed in favour of TEZ/IVA + IVA compared with LUM/IVA.
- Opinions differ regarding the clinical relevance of FEV1%. 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
- Quality of life was assessed using the validated, disease-specific quality-of-life instrument CFQ-R, employing the patient version.
- For the patient version, a statistically significant difference in favour of TEZ/IVA + IVA compared with LUM/IVA was observed in the adjusted indirect comparison for the ‘treatment burden’ domain. However, the 95% confidence interval for Hedges’ g does not lie entirely outside the irrelevance range, meaning that the clinical relevance of the observed effect cannot be assessed.
- For the domains of physical well-being, emotional state, vitality, social limitations, role functioning, body image, eating disorders and subjective health assessment, no statistically significant difference was found between the treatment groups in the adjusted indirect comparison.
- Side effects
- For the endpoint SUEs, the pharmaceutical manufacturer submitted analyses excluding the Preferred Term (PT) ‘infectious pulmonary exacerbations’, which is attributable to the underlying condition of cystic fibrosis. As a result of the analyses of SUEs submitted by the pharmaceutical manufacturer, the majority of events that can be attributed to the underlying condition are not included in the analyses.
- The effect estimate for the indirect comparison of the endpoints SUEs and therapy discontinuations due to AEs is not sufficiently reliable. It is therefore not proven that TEZ/IVA + IVA causes greater or minor harm compared with LUM/IVA in either case.
- With regard to specific adverse events, a statistically significant advantage of TEZ/IVA + IVA over LUM/IVA was observed for the endpoint ‘rash’ (PT) in the adjusted indirect comparison.
- In the category of side effects, there are no clinically relevant differences overall between TEZ/IVA + IVA and LUM/IVA.
- Overall assessment / Conclusion
- For the benefit assessment of TEZ/IVA + IVA for the treatment of cystic fibrosis (CF) in patients aged 12 years and over who are homozygous for the F508del mutation in the CFTR gene, an indirect comparison between TEZ/IVA + IVA and lumacaftor/ivacaftor (LUM/IVA) was used.
- No deaths occurred in any of the studies 106, 103 and 104.
- In the morbidity category, the adjusted indirect comparison for the endpoint of pulmonary exacerbations showed no statistically significant difference between the treatment groups.
- For the endpoint of hospitalisation due to pulmonary exacerbations, the adjusted indirect comparison showed a statistically significant disadvantage of TEZ/IVA + IVA compared with LUM/IVA.
- However, due to existing uncertainties regarding possible regional differences in hospitalisation rates and the fact that no statistically significant difference was found between the treatment groups in the overall rate for the endpoint of pulmonary exacerbations, the observed disadvantage of TEZ/IVA + IVA compared with LUM/IVA for the endpoint ‘hospitalisation due to pulmonary exacerbations’ does not, however, lead the G-BA to conclude that TEZ/IVA + IVA offers less benefit in its assessment.
- For the respiratory system domain of the CFQ-R, a statistically significant advantage of TEZ/IVA + IVA over LUM/IVA was found in the patient version in the indirect comparison, although the clinical relevance cannot be assessed.
- For both the ‘weight problems’ domain and the ‘gastrointestinal’ domain of the CFQ-R, no statistically significant difference could be demonstrated between the treatment groups.
- For the endpoint ‘absolute change in BMI z-score’, a statistically significant difference to the detriment of TEZ/IVA + IVA compared with LUM/IVA was demonstrated in the adjusted indirect comparison; however, the extent of this difference cannot be conclusively assessed.
- A comprehensive review of the morbidity results reveals no difference between TEZ/IVA + IVA and LUM/IVA that is relevant for the benefit assessment.
- In the categories of quality of life and side effects, there are no clinically relevant differences overall between TEZ/IVA + IVA and LUM/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 no additional benefit for TEZ/IVA + IVA compared with LUM/IVA.
- Overall assessment / Conclusion
- For the benefit assessment of TEZ/IVA + IVA for the treatment of cystic fibrosis (CF) in patients aged 12 years and over who are homozygous for the F508del mutation in the CFTR gene, an indirect comparison was carried out between TEZ/IVA + IVA and lumacaftor/ivacaftor (LUM/IVA).
- No deaths occurred in any of the studies 106, 103 and 104.
- In the morbidity category, the adjusted indirect comparison for the endpoint of pulmonary exacerbations showed no statistically significant difference between the treatment groups.
- For the endpoint of hospitalisation due to pulmonary exacerbations, the adjusted indirect comparison showed a statistically significant disadvantage of TEZ/IVA + IVA compared with LUM/IVA.
- However, due to existing uncertainties regarding possible regional differences in hospitalisation rates and the fact that no statistically significant difference was found between the treatment groups in the overall rate for the endpoint of pulmonary exacerbations, the observed disadvantage of TEZ/IVA + IVA compared with LUM/IVA for the endpoint of hospitalisation due to pulmonary exacerbations does not, however, lead the G-BA’s assessment to conclude that TEZ/IVA + IVA offers less benefit.
Courtesy translation only, please refer to the German original.
Associated procedures
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