Tezacaftor / Ivacaftor (1) – Symkevi®

• Clinical trials
  • To assess the additional benefit of TEZ/IVA in patients aged 12 years and over with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene, the pharmaceutical manufacturer submitted the Phase III multicentre, randomised, double-blind, placebo-controlled parallel-group study VX14-661-106 (hereinafter referred to as Study 106), which formed the basis for marketing authorisation. multicentre, randomised, double-blind, placebo-controlled, parallel-group Phase III trial VX14-661-106 (hereinafter referred to as Study 106).
  • To assess the additional benefit of TEZ/IVA in patients aged 12 years and over with cystic fibrosis who are heterozygous for the F508del mutation in the CFTR gene and who carry, on the second allele, a mutation with residual CFTR function (RF mutation) on the second allele, the pharmaceutical manufacturer submitted the Phase III, multicentre, randomised, double-blind, placebo-controlled crossover study VX14-661-108 (hereinafter ‘Study 108’) was submitted by the pharmaceutical company.

a) Patients aged 12 years and over with cystic fibrosis who are homozygous for the F508del mutation.

• mortality
  • No deaths occurred in Study 106.
• 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 as the absolute change over 24 weeks of treatment.
  • The absolute change in FEV1% at week 24 in Study 106 was, on average, +3.60% in the TEZ/IVA arm and –1.47% in the control arm.
  • In Study 106, a statistically significant difference in FEV1% was observed in favour of TEZ/IVA compared with placebo (MWD [95% CI]: 4.79 [3.58; 6.00]; p < 0.0001).
  • There are differing views on the clinical relevance of FEV1% to 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
  • Quality of life was assessed using the validated, disease-specific quality-of-life instrument CFQ-R, employing the patient version.
  • For the patient version, the following were assessed for the physical well-being domain (MWD [95% CI]: 3.85 [1.88; 5.82]; p=0.0001), vitality (MWD [95% CI]: 2.30 [0.10; 4.49]; p = 0.0401), subjective health assessment (MWD [95% CI]: 3.20 [1.15; 5.24]; p=0.0022), treatment burden (MWD [95% CI]: 3.37 [1.65; 5.10]; p = 0.0001), as well as for the domain of social limitations (MWD [95% CI]: 1.52 [0.03; 3.01]; p=0.0452).
  • However, the 95% confidence interval for Hedges’ g in each case does not lie entirely outside the irrelevance range of –0.2 to 0.2, meaning that it cannot be concluded that the effects observed in the mean differences are clinically relevant.
  • No statistically significant difference was found between the treatment groups for the domains of emotional state, body image, eating disorders and role functioning.
• Side effects
  • In Study 106, no statistically significant difference was observed between TEZ/IVA and the control arm for the endpoints of serious adverse events (SAE) and severe adverse events (AE ≥ Grade 3).
  • No statistically significant difference was demonstrated between TEZ/IVA and placebo for the endpoint of discontinuation due to AEs.
  • Overall, there were no statistically significant differences between the treatment arms in the category of side effects.
• Overall assessment / Conclusion
  • For the benefit assessment of TEZ/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, the randomised, double-blind, placebo-controlled Phase III trial 106 was presented.
  • No deaths occurred in Study 106.
  • The endpoints in the morbidity category included the percentage of forced expiratory volume in one second (FEV1 %), symptoms as measured by the CFQ-R, pulmonary exacerbations, hospitalisation and intravenous antibiotic therapy due to pulmonary exacerbations, as well as BMI and BMI z-score.
  • Study 106 revealed a statistically significant difference in favour of TEZ/IVA compared with the control group for the endpoint of pulmonary exacerbations within the morbidity category.
  • In the respiratory system domain of the CFQ-R, a statistically significant and clinically relevant advantage of TEZ/IVA compared with the control group was demonstrated.
  • No statistically significant differences were found between the treatment arms for the endpoints of hospitalisation due to pulmonary exacerbations, BMI and BMI z-score.
  • In the health-related quality of life category, the study 106 assessed the endpoints CFQ-R and SF-12.
  • For the CFQ-R endpoint, statistically significant differences in favour of TEZ/IVA compared with placebo were observed for the domains of physical well-being, vitality, subjective health assessment, treatment burden and social limitations, with the clinical relevance of these statistically significant improvements being impossible to assess in each case.
  • For the SF-12 endpoint, a statistically significant advantage of TEZ/IVA over placebo was observed in the PCS domain, although the clinical relevance of this statistically significant improvement cannot be assessed.
  • No statistically significant difference was found between the treatment arms in the MCS domain.
  • In the category of side effects, no statistically significant difference was found between the TEZ/IVA and placebo treatment arms.
  • Overall, there is a considerable additional benefit.
• Overall assessment / Conclusion
  • For the benefit assessment of TEZ/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, the randomised, double-blind, placebo-controlled Phase III trial 106 was presented.
  • No deaths occurred in Study 106.
  • The endpoints in the morbidity category included the percentage of forced expiratory volume in one second (FEV1 %), symptoms as measured by the CFQ-R, pulmonary exacerbations, hospitalisation and intravenous antibiotic therapy due to pulmonary exacerbations, as well as BMI and BMI z-score.
  • Study 106 revealed a statistically significant difference in favour of TEZ/IVA compared with the control group for the endpoint of pulmonary exacerbations within the morbidity category.
  • In the respiratory system domain of the CFQ-R, a statistically significant and clinically relevant advantage of TEZ/IVA compared with the control group was demonstrated.
  • No statistically significant differences were found between the treatment arms for the endpoints of hospitalisation due to pulmonary exacerbations, BMI and BMI z-score.
  • In the health-related quality of life category, the study 106 assessed the endpoints CFQ-R and SF-12.
  • For the CFQ-R endpoint, statistically significant differences in favour of TEZ/IVA compared with placebo were observed for the domains of physical well-being, vitality, subjective health assessment, treatment burden and social limitations, with the clinical relevance of these statistically significant improvements being impossible to assess in each case.
  • For the SF-12 endpoint, a statistically significant advantage of TEZ/IVA over placebo was observed in the PCS domain; however, the clinical relevance of this statistically significant improvement cannot be assessed.

b) Patients aged 12 years and over with cystic fibrosis who are heterozygous for the F508del mutation and carry one of the following mutations in the CFTR gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G and 3849+10kbC→T.

• mortality
  • There were no deaths in Study 108.
• 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 as the absolute change over 4 and 8 weeks of treatment.
  • The absolute change in FEV1% at weeks 4 and 8 in Study 108 was, on average, +6.4% in the TEZ/IVA arm and –0.3% in the control arm.
  • In Study 108, a statistically significant difference in FEV1% was observed in favour of TEZ/IVA compared with placebo (MWD [95% CI]: 6.7 [5.5; 7.8]; p < 0.0001).
  • 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
  • Quality of life was assessed using the validated, disease-specific quality-of-life instrument CFQ-R, employing the patient version.
  • For the patient version of the CFQ-R, statistically significant and clinically relevant differences in favour of TEZ/IVA compared with placebo were observed for the domains of physical well-being (MWD [95% CI]: 6.8 [4.0; 9.5]; p < 0.0001; Hedges’ g [95% CI]: 0.5 [0.3; 0.7]), vitality (MWD [95% CI]: 7.9 [5.2; 10.5]; p < 0.0001; Hedges’ g [95% CI]: 0.6 [0.3; 0.8]) and subjective health assessment (MWD [95% CI]: 8.9 [6.7; 11.2]; p < 0.0001; Hedges’ g [95% CI]: 0.7 [0.5; 1.0]).
  • For the domains of emotional state (MWD [95% CI]: 2.5 [0.8; 4.2]; p = 0.0036), body image (MWD [95% CI]: 2.2 [0.5; 3.9]; p = 0.0123), and treatment burden (MWD [95% CI]: 2.9 [0.9; 4.9]; p=0.0056), role functioning (MWD [95% CI]: 3.1 [0.8; 5.5]; p=0.0086) and social limitations (MWD [95% CI]: 2.8 [1.0; 4.6]; p=0.0021), statistically significant differences were observed in favour of TEZ/IVA compared with placebo.
  • However, the 95% confidence interval for Hedges’ g in each case does not lie entirely outside the irrelevance range of –0.2 to 0.2; consequently, it cannot be concluded that the effects observed in the mean differences are clinically relevant.
  • No statistically significant difference was found between the treatment groups in the eating disorders domain.
• Side effects
  • In Study 108, no statistically significant difference was observed between TEZ/IVA and the control arm for the endpoints of serious adverse events (SAE) and severe adverse events (AE ≥ Grade 3).
  • No statistically significant difference was demonstrated between TEZ/IVA and placebo for the endpoint of discontinuation due to AEs.
  • A statistically significant difference in favour of TEZ/IVA compared with the control group was observed only for the endpoint ‘respiratory, thoracic and mediastinal disorders’ (SOC) (RR [95% CI]: 0.8 [0.6; 0.997]; p=0.0471).
  • In the category of side effects, there were no statistically significant differences between the treatment arms when viewed as a whole.
• Overall assessment / Conclusion
  • For the benefit assessment of TEZ/IVA for the treatment of cystic fibrosis (CF) in patients aged 12 years and over who are heterozygous for the F508del mutation in the CFTR gene and carry an RF mutation in the CFTR gene, the multicentre, randomised, double-blind, placebo-controlled, crossover, Phase III trial 108 was presented.
  • No deaths occurred in Study 108.
  • The morbidity endpoints included the forced expiratory volume in one second (FEV1 %), symptoms as measured by the CFQ-R, pulmonary exacerbations, hospitalisation and intravenous antibiotic therapy due to pulmonary exacerbations, as well as BMI and BMI z-score.
  • For the endpoint ‘symptoms’ as measured by the CFQ-R, a statistically significant and clinically relevant difference in favour of TEZ/IVA compared with the control group was observed in the respiratory system domain.
  • For the ‘weight problems’ domain, a statistically significant difference was observed in favour of TEZ/IVA compared with placebo; for the gastrointestinal domain, however, a statistically significant difference was observed to the detriment of TEZ/IVA compared with placebo; the clinical relevance of the observed changes remains unclear, however.
  • For the endpoints of pulmonary exacerbations, hospitalisation due to pulmonary exacerbations, as well as BMI and BMI z-score, no statistically significant differences were observed between TEZ/IVA and placebo.
  • In the health-related quality of life category, the study 108 assessed the CFQ-R and SF-12 endpoints.
  • For the CFQ-R domains: physical well-being, vitality and subjective health assessment, a statistically significant and clinically relevant difference in favour of TEZ/IVA compared with placebo was found in each case.
  • For the CFQ-R domains of emotional state, body image, treatment burden, role functioning and social limitations, statistically significant differences were observed in favour of TEZ/IVA compared with placebo; however, the clinical relevance of these statistically significant improvements could not be assessed in each case.
  • For the SF-12 endpoint, a statistically significant advantage of TEZ/IVA over placebo was observed in the PCS domain, which is also clinically relevant.
  • For the MCS domain, a statistically significant advantage of TEZ/IVA over placebo was also demonstrated, although its clinical relevance cannot be assessed.
  • In the category of side effects, no statistically significant advantages or disadvantages were observed for treatment with TEZ/IVA compared with placebo.
  • Given the chronic nature of cystic fibrosis and the need for long-term treatment of patients, the 8-week treatment duration of the presented RCT is considered unsuitable for assessing the sustainability of the effects.
  • It remains unclear whether the statistically significant advantages of TEZ/IVA over placebo demonstrated in the categories of morbidity (symptoms as measured by the CFQ-R) and quality of life (CFQ-R, SF-12) represent long-term effects.
  • Consequently, given the short study duration, the extent of the demonstrated advantages can be classified as no more than minor.

Courtesy translation only, please refer to the German original.