- Email: [email protected]
Mutation-specific therapy in cystic fibrosis: the earlier, the better
Comment
Chronic sinopulmonary disease defines morbidity and prognosis in most individuals with cystic fibrosis.1 The disease-causing mutations in the CFTR gene lead to impaired transport of chloride and bicarbonate across apical epithelial membranes.2,3 Mucins that are concomitantly released into the glandular ducts are not properly hydrated and folded because of the perturbed ion, water, and pH homeostasis. This inappropriate hydration and folding causes mucus plugging and retention, which in the lower airways initiate a vicious cycle of colonisation with pathogens, inflammation, and irreversible tissue remodelling and dedifferentiation.1 Today’s treatment of cystic fibrosis is symptomatic, but new drugs have recently been developed that aim to correct the basic defect by improving the biosynthesis or activity of mutant CFTR.1,4 The opening of the CFTR ion channel usually requires ATP, but the potentiator ivacaftor (VX-770) promotes an ATP-independent opening of the channel.5 CFTR-mediated ion transport can thus be restored in CFTR mutants that are defective in ATP-dependent gating. Results from clinical studies of cystic fibrosis carriers of the most common gating mutation G551D-CFTR showed that treatment with ivacaftor can correct the basic defect in patients’ sweat glands.6 Results from trials of patients with abnormal forced expiratory volume in 1 s (FEV1) at baseline reported significant and persisting improvements of pulmonary function during treatment with ivacaftor.6 The annual decline of FEV1 is a robust measure for the individual’s long-term outcome and the quality of care provided by a cystic fibrosis centre. However, thanks to the continuous progress of treatment programmes, a normal FEV1 (higher than 80% predicted) has become common in children, adolescents, and young adults with cystic fibrosis. For this reason, measures more sensitive than FEV1 are needed, particularly for clinical studies of patients with cystic fibrosis with preserved spirometry. In The Lancet Respiratory Medicine, Jane Davies and colleagues7 report on the outcome of a multicentre, placebo-controlled, double-blind crossover study of ivacaftor treatment in 20 patients with cystic fibrosis, a G551D-CFTR mutation, a FEV1 higher than 90% www.thelancet.com/respiratory Vol 1 October 2013
predicted, and an abnormal lung clearance index (LCI) higher than 7·4.7 Patients received two cycles of 4-week treatment, one cycle with ivacaftor and another with placebo, separated by a 4-week washout period in between. One group of patients received ivacaftor first followed by placebo, the other group received placebo first followed by ivacaftor. The investigators chose LCI as the primary outcome measure for efficacy. Treatment with ivacaftor led to a significant mean reduction of LCI of 2·16 (95% CI 1·44–2·88), which is interpreted as an improvement of pulmonary function. Although the concept of the LCI has already been introduced into the scientific literature some decades ago, readers might not be familiar with its meaning or with the underlying multiple-breath washout technique, because until recently, no easy-to-use equipment was available for clinical practice.8 LCI is defined as the number of lung volume turnovers needed until the lungs are cleared from an inert tracer gas that has been inhaled before. An increased LCI (>7·0) indicates ventilation inhomogeneity,8 which is mainly caused by processes in the peripheral airways whereas changes in FEV1 mainly relate to processes in the large conducting airways. Inflammation, mucus plugging, and mucus retention are the major manifestations of cystic fibrosis lung disease that are in principle reversible and accessible to therapeutic intervention. Davies and colleagues7 deliberately selected patients with abnormal LCI but preserved spirometry.7 During treatment with ivacaftor, the mean LCI was significantly reduced compared with placebo, implying that a substantial part of ventilation inhomogeneity was not caused by irreversible lung damage, but by reversible blockage of small airways with mucous secretions that could be resolved by the correction of the basic defect. However, this conclusion might overinterpret the data. Indeed, multicentre feasibility among centres with no previous specific expertise in performing multiple-breath washout has not been reported yet with this equipment in an independent study. Data of repeatability of LCI within patients at the same visit differentiated by study centre would have clarified this issue. In other words, there is room for improvement
Simon Fraser/Science Photo Library
Mutation-specific therapy in cystic fibrosis: the earlier, the better
Published Online September 10, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70186-3 See Articles page 630
591
Comment
of study design for future investigations of the efficacy of CFTR modulators in mildly affected patients with cystic fibrosis. Assuming that the correction of the basic defect in cystic fibrosis airways will be most successful in patients with virtually no irreversibly fixed lung abnormalities, the cohort with normal FEV1 and normal LCI (<7·0) should also be investigated. To detect regional and focal changes with high sensitivity, the global outcome measures for efficacy such as FEV1 or LCI could potentially be substituted by emerging MRI technology that visualises lung morphology, ventilation, and perfusion with high temporal and spatial resolution.9
I have served on advisory boards for Vertex Pharmaceuticals Incorporated. 1 2 3
4 5
6
7
Burkhard Tümmler Clinical Research Group, Clinic for Paediatric Pneumology, Allergology and Neonatology, OE 6710, Hanover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research, Hannover, Germany [email protected]
8
9
O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009; 373: 1891–1904. Quinton PM. Role of epithelial HCO3 transport in mucin secretion: lessons from cystic fibrosis. Am J Physiol Cell Physiol 2010; 299: C1222–33. Pezzulo AA, Tang XX, Hoegger MJ, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 2012; 487: 109–13. Hoffman LR, Ramsey BW. Cystic fibrosis therapeutics: the road ahead. Chest 2013; 143: 207–13. Eckford PD, Li C, Ramjeesingh M, Bear CE. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem 2012; 287: 36639–49. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–72. Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013; published online Sept 10. http://dx.doi. org/10.1016/S2213-2600(13)70182-6. Robinson PD, Latzin P, Verbanck S, et al. Consensus statement for inert gas washout measurement using multiple- and single- breath tests. Eur Respir J 2013; 41: 507–22. Wielpütz MO, Eichinger M, Puderbach M. Magnetic resonance imaging of cystic fibrosis lung disease. J Thorac Imaging 2013; 28: 151–59.
Corrections Published Online September 3, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70188-7
Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delerium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; 1: 515–23—In this Article (published online Aug 21), the data in table 1 for patients with COPD as the main diagnosis at ICU admission were incorrect. The data should have been 1 (1%) for the haloperidol group and 2 (3%) for the placebo group. This correction has been made to the online version as of Sept 3, 2013. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respiratory Medicine 2013; 8: 639–52—In this Review (published online Aug 9), the search strategy and selection criteria panel was missing. This correction has been made to the online version as of Oct 7, 2013, and to the printed Review. Latronico N, Nisoli E, Eikermann M. Muscle weakness and nutrition in critical illness: matching nutrient supply and use. Lancet Respir Med 2013; 8: 589—In this Comment (published online Sept 10), reference 7 should be “Casaer MP, Langouche L, Coudyzer W, et al. Impact of early parenteral nutrition on muscle and adipose tissue compartments during critical illness. Crit Care Med 2013; published online July 15. DOI:10.1097/ CCM.0b013e31828cef02.” This correction has been made to the online version as of Oct 7, 2013, and to the printed Comment.
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www.thelancet.com/respiratory Vol 1 October 2013
Chronic sinopulmonary disease defines morbidity and prognosis in most individuals with cystic fibrosis.1 The disease-causing mutations in the CFTR gene lead to impaired transport of chloride and bicarbonate across apical epithelial membranes.2,3 Mucins that are concomitantly released into the glandular ducts are not properly hydrated and folded because of the perturbed ion, water, and pH homeostasis. This inappropriate hydration and folding causes mucus plugging and retention, which in the lower airways initiate a vicious cycle of colonisation with pathogens, inflammation, and irreversible tissue remodelling and dedifferentiation.1 Today’s treatment of cystic fibrosis is symptomatic, but new drugs have recently been developed that aim to correct the basic defect by improving the biosynthesis or activity of mutant CFTR.1,4 The opening of the CFTR ion channel usually requires ATP, but the potentiator ivacaftor (VX-770) promotes an ATP-independent opening of the channel.5 CFTR-mediated ion transport can thus be restored in CFTR mutants that are defective in ATP-dependent gating. Results from clinical studies of cystic fibrosis carriers of the most common gating mutation G551D-CFTR showed that treatment with ivacaftor can correct the basic defect in patients’ sweat glands.6 Results from trials of patients with abnormal forced expiratory volume in 1 s (FEV1) at baseline reported significant and persisting improvements of pulmonary function during treatment with ivacaftor.6 The annual decline of FEV1 is a robust measure for the individual’s long-term outcome and the quality of care provided by a cystic fibrosis centre. However, thanks to the continuous progress of treatment programmes, a normal FEV1 (higher than 80% predicted) has become common in children, adolescents, and young adults with cystic fibrosis. For this reason, measures more sensitive than FEV1 are needed, particularly for clinical studies of patients with cystic fibrosis with preserved spirometry. In The Lancet Respiratory Medicine, Jane Davies and colleagues7 report on the outcome of a multicentre, placebo-controlled, double-blind crossover study of ivacaftor treatment in 20 patients with cystic fibrosis, a G551D-CFTR mutation, a FEV1 higher than 90% www.thelancet.com/respiratory Vol 1 October 2013
predicted, and an abnormal lung clearance index (LCI) higher than 7·4.7 Patients received two cycles of 4-week treatment, one cycle with ivacaftor and another with placebo, separated by a 4-week washout period in between. One group of patients received ivacaftor first followed by placebo, the other group received placebo first followed by ivacaftor. The investigators chose LCI as the primary outcome measure for efficacy. Treatment with ivacaftor led to a significant mean reduction of LCI of 2·16 (95% CI 1·44–2·88), which is interpreted as an improvement of pulmonary function. Although the concept of the LCI has already been introduced into the scientific literature some decades ago, readers might not be familiar with its meaning or with the underlying multiple-breath washout technique, because until recently, no easy-to-use equipment was available for clinical practice.8 LCI is defined as the number of lung volume turnovers needed until the lungs are cleared from an inert tracer gas that has been inhaled before. An increased LCI (>7·0) indicates ventilation inhomogeneity,8 which is mainly caused by processes in the peripheral airways whereas changes in FEV1 mainly relate to processes in the large conducting airways. Inflammation, mucus plugging, and mucus retention are the major manifestations of cystic fibrosis lung disease that are in principle reversible and accessible to therapeutic intervention. Davies and colleagues7 deliberately selected patients with abnormal LCI but preserved spirometry.7 During treatment with ivacaftor, the mean LCI was significantly reduced compared with placebo, implying that a substantial part of ventilation inhomogeneity was not caused by irreversible lung damage, but by reversible blockage of small airways with mucous secretions that could be resolved by the correction of the basic defect. However, this conclusion might overinterpret the data. Indeed, multicentre feasibility among centres with no previous specific expertise in performing multiple-breath washout has not been reported yet with this equipment in an independent study. Data of repeatability of LCI within patients at the same visit differentiated by study centre would have clarified this issue. In other words, there is room for improvement
Simon Fraser/Science Photo Library
Mutation-specific therapy in cystic fibrosis: the earlier, the better
Published Online September 10, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70186-3 See Articles page 630
591
Comment
of study design for future investigations of the efficacy of CFTR modulators in mildly affected patients with cystic fibrosis. Assuming that the correction of the basic defect in cystic fibrosis airways will be most successful in patients with virtually no irreversibly fixed lung abnormalities, the cohort with normal FEV1 and normal LCI (<7·0) should also be investigated. To detect regional and focal changes with high sensitivity, the global outcome measures for efficacy such as FEV1 or LCI could potentially be substituted by emerging MRI technology that visualises lung morphology, ventilation, and perfusion with high temporal and spatial resolution.9
I have served on advisory boards for Vertex Pharmaceuticals Incorporated. 1 2 3
4 5
6
7
Burkhard Tümmler Clinical Research Group, Clinic for Paediatric Pneumology, Allergology and Neonatology, OE 6710, Hanover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; and Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research, Hannover, Germany [email protected]
8
9
O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009; 373: 1891–1904. Quinton PM. Role of epithelial HCO3 transport in mucin secretion: lessons from cystic fibrosis. Am J Physiol Cell Physiol 2010; 299: C1222–33. Pezzulo AA, Tang XX, Hoegger MJ, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 2012; 487: 109–13. Hoffman LR, Ramsey BW. Cystic fibrosis therapeutics: the road ahead. Chest 2013; 143: 207–13. Eckford PD, Li C, Ramjeesingh M, Bear CE. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem 2012; 287: 36639–49. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–72. Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013; published online Sept 10. http://dx.doi. org/10.1016/S2213-2600(13)70182-6. Robinson PD, Latzin P, Verbanck S, et al. Consensus statement for inert gas washout measurement using multiple- and single- breath tests. Eur Respir J 2013; 41: 507–22. Wielpütz MO, Eichinger M, Puderbach M. Magnetic resonance imaging of cystic fibrosis lung disease. J Thorac Imaging 2013; 28: 151–59.
Corrections Published Online September 3, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70188-7
Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delerium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; 1: 515–23—In this Article (published online Aug 21), the data in table 1 for patients with COPD as the main diagnosis at ICU admission were incorrect. The data should have been 1 (1%) for the haloperidol group and 2 (3%) for the placebo group. This correction has been made to the online version as of Sept 3, 2013. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respiratory Medicine 2013; 8: 639–52—In this Review (published online Aug 9), the search strategy and selection criteria panel was missing. This correction has been made to the online version as of Oct 7, 2013, and to the printed Review. Latronico N, Nisoli E, Eikermann M. Muscle weakness and nutrition in critical illness: matching nutrient supply and use. Lancet Respir Med 2013; 8: 589—In this Comment (published online Sept 10), reference 7 should be “Casaer MP, Langouche L, Coudyzer W, et al. Impact of early parenteral nutrition on muscle and adipose tissue compartments during critical illness. Crit Care Med 2013; published online July 15. DOI:10.1097/ CCM.0b013e31828cef02.” This correction has been made to the online version as of Oct 7, 2013, and to the printed Comment.
592
www.thelancet.com/respiratory Vol 1 October 2013