Comment
contribute similarly to airflow limitation, but have a different role in exacerbations). By contrast with asthma, airway mucosa eosinophils obtained from patients during COPD exacerbations could respond to different chemotactic stimuli from interleukin 5 (eg, CCL5, also known as RANTES) and not express interleukin 5.12 Also, whereas benralizumab was shown to deplete both circulating and sputum eosinophils in people with asthma,8 its ability to deplete eosinophils in the airways and lung of COPD patients remains to be shown. Exacerbations of respiratory symptoms in asthma and COPD might be quite different. Exacerbations of asthma seem to be caused mainly by allergens and viral infections,1 whereas exacerbations of COPD can be caused by more complex mechanisms, including bacterial infections and extrapulmonary mechanisms.2 The large proportion of exacerbations treated with antibiotics in Brightling and colleagues’ COPD study,10 by contrast with Castro and colleagues’ asthma study9 in which only patients with steroid-treated exacerbations were included, suggests important differences in the characteristics of exacerbations examined in the two studies.9,10 For the same reason, the potentially increased risk of exacerbations in patients with COPD with low blood eosinophil counts who are treated with benralizumab should be carefully assessed. In view of the difficulties encountered in identification of the highly selected patients with asthma (with severe eosinophilia and at risk of exacerbations) as the target population sensitive to anti-interleukin 5 drugs, future studies should focus much more on selected patient populations for COPD. Both studies provided important information, suggesting that the simple count of circulating eosinophils might be sufficient to identify eosinophilic asthma or COPD. This message could be important for future clinical studies, in view of the invasiveness and complexity of bronchial biopsy specimens and sputum cytology.
Targeted therapies with new anti-interleukin 5 or anti-IL5Rα drugs seem very promising and safe for very selected patients with severe steroid-resistant asthma, and possibly some patients with COPD. Their role in less selected patients with asthma or COPD will need additional clinical trials comparing their efficacy and safety with those of existing anti-inflammatory therapies. Leonardo M Fabbri Section of Respiratory Diseases, University of Modena and Reggio Emilia, Department of Oncology, Haematology and Respiratory Diseases, Modena, 41124, Italy [email protected] I report grants and personal fees from AstraZeneca and GlaxoSmithKline, outside of the submitted work. 1 2
3
4 5
6
7 8
9
10
11
12
Global Initiative on Asthma (GINA). http://www.ginasthma.org (accessed Sept 20, 2014). Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. http://www.goldcopd.org (accessed Sept 20, 2014). Fabbri LM, Romagnoli M, Corbetta L et al, Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167: 418–24. Pavord ID. Eosinophilic phenotypes of airway disease. Ann Am Thorac Soc 2013; 10 (suppl): S143–49. Bafadhel M, Davies L, Calverley PM et al. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J 2014; 44: 789–91. Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994; 150: 1646–52. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respir Med 2013; 1: 639–52. Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy 2012; 42: 712–37. Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; published online Oct 9. http://dx.doi.org/10.1016/ S2213-2600(14)70201-2 Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med 2014; published online Sept 8. http://dx.doi.org/10.1016/S22132600(14)70187-0. Nair P. Anti-interleukin-5 monoclonal antibody to treat severe eosinophilic asthma. N Engl J Med 2014; published online Sept 8. DOI:10.1056/ NEJMe1408614. Zhu J, Qiu YS, Majumdar S, et al. Exacerbations of bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am J Respir Crit Care Med 2001; 164: 109–16.
Mutation-targeted personalised medicine for cystic fibrosis Modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) protein are a novel class of drugs under development that are aimed to correct the underlying basic defect of cystic fibrosis, as opposed to standard therapies that target the www.thelancet.com/respiratory Vol 2 November 2014
downstream effects of CFTR dysfunction to control symptoms. Ivacaftor, a CFTR potentiator, is the first disease modifying drug that has been approved for patients with cystic fibrosis with the Gly551Asp gating mutation
Published Online October 10, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70191-2 See Articles page 902
863
Comment
Laguna Design/Science Photo Library
(resulting in defective chloride-channel gating and little or no anion transport at the apical membrane of epithelial cells), and two trials1,2 have shown clinically relevant effects of treatment, as well as an acceptable safety profile. In The Lancet Respiratory Medicine, Edward F McKone and colleagues3 report the results of a phase 3, openlabel extension study of ivacaftor in 192 patients with cystic fibrosis who were 6 years or older with at least one Gly551Asp mutation, and had completed one of two 48-week, placebo-controlled trials (STRIVE and ENVISION) with the same study drug. Safety and efficacy data during an additional 96 weeks are presented, and show evidence of durable effects of treatment on lung function, weight, rate of respiratory exacerbations, and no new safety concerns. Safety was the primary endpoint of the study. Severe adverse events occurred in around 20% of patients and were similar to those described in previous studies. Nine patients had increases in transaminases 5 times or more than the upper limit of normal or reported as an adverse event resulting in dose interruption. Whether ivacaftor can change the natural history of cystic fibrosis remains to be established and there are key questions that still need addressing. First of all, the effects of ivacaftor in different organ systems should be further characterised with appropriate clinical endpoints. Ivacaftor has been shown to improve forced expiratory volume in 1 sec in patients with lung disease of different severity, however as a disease modifying treatment its administration should be ideally started from the time of diagnosis, during the first months of life, and probably continued lifelong. Identification of clinical outcome measures for early cystic fibrosis lung disease is therefore a research priority; chest CT to assess structural damage and lung clearance index with multiple breath washout to quantify ventilation inhomogeneity could provide information about the extent of lung disease at an early age when there are no clinical symptoms and spirometry is still normal. Indeed in a double-blind crossover study in patients with cystic fibrosis and at least one Gly551Asp mutation, ivacaftor led to improvements in lung clearance index,4 which could increasingly be used as an endpoint in clinical trials. The GOAL study,5 an assessment of a series of unexplored biomarkers, was done in a post-approval 864
setting in cystic fibrosis patients with the Gly551Asp mutation. The study showed further evidence of beneficial effects of CFTR modulation on pulmonary and gastrointestinal physiology in subsets of study participants. Of particular interest was the improvement in a fundamental defect underlying cystic fibrosis airways, mucociliary clearance, using γ scintigraphy, and increase in intestinal pH, measured by a wireless motility capsule, with sustained intestinal alkalinisation, which could be responsible for the rapid improvement in body-mass index consistently noted in patients given ivacaftor. Studies should further explore the effects of treatment on other extra pulmonary manifestations of cystic fibrosis, including cystic fibrosis-related diabetes and liver disease. To assess the effects of ivacaftor on liver disease, a crucial issue is the availability of reliable outcome measures of efficacy, a problem that is inherent to the focal distribution of hepatic lesions of cystic fibrosis-associated liver disease. Indeed no specific and sensitive diagnostic markers have been so far validated and standard liver function tests could be normal even in cases of advanced cirrhosis.6 Hepatobiliary scintigraphy might prove useful, as documented several years ago in studies assessing the efficacy of ursodeoxycholic acid treatment.7 Similarly important is the need to determine the harm–benefit balance of ivacaftor and other CFTR modulators. Their potential hepatotoxicity should be strictly monitored in patients on long-term treatment, keeping in mind that in patients with cystic fibrosis, druginduced liver injury can occur, however several other factors (antibiotic therapy, pulmonary exacerbation, malnutrition) can induce liver enzyme alterations. Although the subtype of liver injury described during treatment with ivacaftor in the study by McKone and colleagues seems to be hepatocellular rather than cholestatic, this should be further characterised on the basis of the pattern of serum liver enzymes. Contribution of an underlying liver disease to the risk of drug-induced liver injury has been shown for patients with a variety of chronic liver diseases who might require dose adjustment. To identify patients at risk of developing drug hepatotoxicity, detailed information should be obtained about the hepatic status of patients with cystic fibrosis who develop liver enzyme abnormalities during ivacaftor treatment and whether similar fluctuations had occurred in the past while not on treatment. www.thelancet.com/respiratory Vol 2 November 2014
Comment
Further developments in this field are expected to occur in the near future. Beneficial effects of ivacaftor have been documented in patients with cystic fibrosis with eight different gating mutations,8 and its indication has been approved for these mutations. Studies are underway on the efficacy and safety of ivacaftor in small children (2–5 years) with Gly551Asp mutation as well as in patients with other mutations that confer residual CFTR function at the apical membrane of epithelial cells. However, ivacaftor cannot work if there is no CFTR on the cell surface, and other drugs called correctors are used to bring mutant CFTR to the cell surface. Ivacaftor has been given in combination with the corrector lumacaftor to patients who are Phe508delhomozygous.9 This approach might not work as expected because potentiators make CFTR less stable, accelerating its removal from the cell membrane. There is also evidence that double or even triple combination therapy might be required to allow synergistic Phe508del-CFTR correction by other compounds at distinct conformational sites.10 Several novel CFTR modulators are in the drug development pipeline after being extensively assessed in vitro and patients with cystic fibrosis will be in demand for the many competing clinical trials. The study by McKone and colleagues3 confirms the potential of CFTR-specific therapies and supports efforts aimed to develop drugs for mutation-targeted personalised medicine that could ultimately affect 90% of patients with cystic fibrosis. However, personalised medicine for cystic fibrosis remains expensive, thus efforts should be made to make such potentially life-changing treatment affordable and available for patients with cystic fibrosis worldwide.11
Carla Colombo Cystic Fibrosis Center, University of Milan, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milan, Italy [email protected] CC has served on advisory boards for Novartis, Gilead, and Vertex, and has been a site principal investigator for trials sponsored by Novartis, Gilead, and Vertex. 1
2
3
4
5
6
7
8
9
10
11
Ramsey BW, Davies J, McElvaney NG, et al, VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–72. Davies JC, Wainwright CE, Canny GJ, et al, VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013; 187: 1219–25. McKone EF, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014; published online Oct 10. http://dx.doi. org/10.1016/S2213-2600(14)70218-8 Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551DCFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013; 1: 630–38. Rowe SM, Heltshe SL, Gonska T, et al; GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175–84. Debray D, Kelly D, Houwen R, Strandvik B, Colombo C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. Cyst Fibros 2011; 10: S29–36. Colombo C, Castellani MR, Balistreri WF, Seregni E, Assaisso ML, Giunta A. Scintigraphic documentation of an improvement in hepatobiliary excretory function after treatment with ursodeoxycholic acid in patients with cystic fibrosis and associated liver disease. Hepatology 1992; 15: 677–84. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a nonG551D gating mutation. Cyst Fibros 2014; published online Sept 26. DOI:10.1016/j.jcf.2014.09.005. Boyle MP, Bell SC, Konstan MW, et al; VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2014; 2: 527–38. Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls. Pharmacol Ther 2014; published online June 14. DOI:10.1016/j.pharmthera.2014.06.005. Balfour-Lynn IM. Personalized medicine in cystic fibrosis is unaffordable. Paediatr Respir Rev 2014; 15: 2–5.
Paradoxical response to bronchodilators in COPD: curious enigma or clinically important phenotype? The physiological hallmark of chronic obstructive pulmonary disease (COPD) is expiratory airflow limitation,1 which is partly reversible in some patients after bronchodilator therapy.2 Because COPD is such a heterogeneous disease, it is not surprising that bronchodilator response and reversibility are also highly variable over time and between patients3 and Global www.thelancet.com/respiratory Vol 2 November 2014
Initiative for Chronic Obstructive Lung Disease (GOLD) grades. Although there is an increasing understanding of the breadth and importance of COPD phenotypes, cause, mechanisms, and clinical implications of bronchodilator response, or lack thereof, still remain obscure. In The Lancet Respiratory Medicine, Surya Bhatt and colleagues4 describe the first systematic study of a
Published Online September 10, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70198-5 See Articles page 911
865
contribute similarly to airflow limitation, but have a different role in exacerbations). By contrast with asthma, airway mucosa eosinophils obtained from patients during COPD exacerbations could respond to different chemotactic stimuli from interleukin 5 (eg, CCL5, also known as RANTES) and not express interleukin 5.12 Also, whereas benralizumab was shown to deplete both circulating and sputum eosinophils in people with asthma,8 its ability to deplete eosinophils in the airways and lung of COPD patients remains to be shown. Exacerbations of respiratory symptoms in asthma and COPD might be quite different. Exacerbations of asthma seem to be caused mainly by allergens and viral infections,1 whereas exacerbations of COPD can be caused by more complex mechanisms, including bacterial infections and extrapulmonary mechanisms.2 The large proportion of exacerbations treated with antibiotics in Brightling and colleagues’ COPD study,10 by contrast with Castro and colleagues’ asthma study9 in which only patients with steroid-treated exacerbations were included, suggests important differences in the characteristics of exacerbations examined in the two studies.9,10 For the same reason, the potentially increased risk of exacerbations in patients with COPD with low blood eosinophil counts who are treated with benralizumab should be carefully assessed. In view of the difficulties encountered in identification of the highly selected patients with asthma (with severe eosinophilia and at risk of exacerbations) as the target population sensitive to anti-interleukin 5 drugs, future studies should focus much more on selected patient populations for COPD. Both studies provided important information, suggesting that the simple count of circulating eosinophils might be sufficient to identify eosinophilic asthma or COPD. This message could be important for future clinical studies, in view of the invasiveness and complexity of bronchial biopsy specimens and sputum cytology.
Targeted therapies with new anti-interleukin 5 or anti-IL5Rα drugs seem very promising and safe for very selected patients with severe steroid-resistant asthma, and possibly some patients with COPD. Their role in less selected patients with asthma or COPD will need additional clinical trials comparing their efficacy and safety with those of existing anti-inflammatory therapies. Leonardo M Fabbri Section of Respiratory Diseases, University of Modena and Reggio Emilia, Department of Oncology, Haematology and Respiratory Diseases, Modena, 41124, Italy [email protected] I report grants and personal fees from AstraZeneca and GlaxoSmithKline, outside of the submitted work. 1 2
3
4 5
6
7 8
9
10
11
12
Global Initiative on Asthma (GINA). http://www.ginasthma.org (accessed Sept 20, 2014). Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. http://www.goldcopd.org (accessed Sept 20, 2014). Fabbri LM, Romagnoli M, Corbetta L et al, Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167: 418–24. Pavord ID. Eosinophilic phenotypes of airway disease. Ann Am Thorac Soc 2013; 10 (suppl): S143–49. Bafadhel M, Davies L, Calverley PM et al. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J 2014; 44: 789–91. Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994; 150: 1646–52. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. Lancet Respir Med 2013; 1: 639–52. Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy 2012; 42: 712–37. Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med 2014; published online Oct 9. http://dx.doi.org/10.1016/ S2213-2600(14)70201-2 Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med 2014; published online Sept 8. http://dx.doi.org/10.1016/S22132600(14)70187-0. Nair P. Anti-interleukin-5 monoclonal antibody to treat severe eosinophilic asthma. N Engl J Med 2014; published online Sept 8. DOI:10.1056/ NEJMe1408614. Zhu J, Qiu YS, Majumdar S, et al. Exacerbations of bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am J Respir Crit Care Med 2001; 164: 109–16.
Mutation-targeted personalised medicine for cystic fibrosis Modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) protein are a novel class of drugs under development that are aimed to correct the underlying basic defect of cystic fibrosis, as opposed to standard therapies that target the www.thelancet.com/respiratory Vol 2 November 2014
downstream effects of CFTR dysfunction to control symptoms. Ivacaftor, a CFTR potentiator, is the first disease modifying drug that has been approved for patients with cystic fibrosis with the Gly551Asp gating mutation
Published Online October 10, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70191-2 See Articles page 902
863
Comment
Laguna Design/Science Photo Library
(resulting in defective chloride-channel gating and little or no anion transport at the apical membrane of epithelial cells), and two trials1,2 have shown clinically relevant effects of treatment, as well as an acceptable safety profile. In The Lancet Respiratory Medicine, Edward F McKone and colleagues3 report the results of a phase 3, openlabel extension study of ivacaftor in 192 patients with cystic fibrosis who were 6 years or older with at least one Gly551Asp mutation, and had completed one of two 48-week, placebo-controlled trials (STRIVE and ENVISION) with the same study drug. Safety and efficacy data during an additional 96 weeks are presented, and show evidence of durable effects of treatment on lung function, weight, rate of respiratory exacerbations, and no new safety concerns. Safety was the primary endpoint of the study. Severe adverse events occurred in around 20% of patients and were similar to those described in previous studies. Nine patients had increases in transaminases 5 times or more than the upper limit of normal or reported as an adverse event resulting in dose interruption. Whether ivacaftor can change the natural history of cystic fibrosis remains to be established and there are key questions that still need addressing. First of all, the effects of ivacaftor in different organ systems should be further characterised with appropriate clinical endpoints. Ivacaftor has been shown to improve forced expiratory volume in 1 sec in patients with lung disease of different severity, however as a disease modifying treatment its administration should be ideally started from the time of diagnosis, during the first months of life, and probably continued lifelong. Identification of clinical outcome measures for early cystic fibrosis lung disease is therefore a research priority; chest CT to assess structural damage and lung clearance index with multiple breath washout to quantify ventilation inhomogeneity could provide information about the extent of lung disease at an early age when there are no clinical symptoms and spirometry is still normal. Indeed in a double-blind crossover study in patients with cystic fibrosis and at least one Gly551Asp mutation, ivacaftor led to improvements in lung clearance index,4 which could increasingly be used as an endpoint in clinical trials. The GOAL study,5 an assessment of a series of unexplored biomarkers, was done in a post-approval 864
setting in cystic fibrosis patients with the Gly551Asp mutation. The study showed further evidence of beneficial effects of CFTR modulation on pulmonary and gastrointestinal physiology in subsets of study participants. Of particular interest was the improvement in a fundamental defect underlying cystic fibrosis airways, mucociliary clearance, using γ scintigraphy, and increase in intestinal pH, measured by a wireless motility capsule, with sustained intestinal alkalinisation, which could be responsible for the rapid improvement in body-mass index consistently noted in patients given ivacaftor. Studies should further explore the effects of treatment on other extra pulmonary manifestations of cystic fibrosis, including cystic fibrosis-related diabetes and liver disease. To assess the effects of ivacaftor on liver disease, a crucial issue is the availability of reliable outcome measures of efficacy, a problem that is inherent to the focal distribution of hepatic lesions of cystic fibrosis-associated liver disease. Indeed no specific and sensitive diagnostic markers have been so far validated and standard liver function tests could be normal even in cases of advanced cirrhosis.6 Hepatobiliary scintigraphy might prove useful, as documented several years ago in studies assessing the efficacy of ursodeoxycholic acid treatment.7 Similarly important is the need to determine the harm–benefit balance of ivacaftor and other CFTR modulators. Their potential hepatotoxicity should be strictly monitored in patients on long-term treatment, keeping in mind that in patients with cystic fibrosis, druginduced liver injury can occur, however several other factors (antibiotic therapy, pulmonary exacerbation, malnutrition) can induce liver enzyme alterations. Although the subtype of liver injury described during treatment with ivacaftor in the study by McKone and colleagues seems to be hepatocellular rather than cholestatic, this should be further characterised on the basis of the pattern of serum liver enzymes. Contribution of an underlying liver disease to the risk of drug-induced liver injury has been shown for patients with a variety of chronic liver diseases who might require dose adjustment. To identify patients at risk of developing drug hepatotoxicity, detailed information should be obtained about the hepatic status of patients with cystic fibrosis who develop liver enzyme abnormalities during ivacaftor treatment and whether similar fluctuations had occurred in the past while not on treatment. www.thelancet.com/respiratory Vol 2 November 2014
Comment
Further developments in this field are expected to occur in the near future. Beneficial effects of ivacaftor have been documented in patients with cystic fibrosis with eight different gating mutations,8 and its indication has been approved for these mutations. Studies are underway on the efficacy and safety of ivacaftor in small children (2–5 years) with Gly551Asp mutation as well as in patients with other mutations that confer residual CFTR function at the apical membrane of epithelial cells. However, ivacaftor cannot work if there is no CFTR on the cell surface, and other drugs called correctors are used to bring mutant CFTR to the cell surface. Ivacaftor has been given in combination with the corrector lumacaftor to patients who are Phe508delhomozygous.9 This approach might not work as expected because potentiators make CFTR less stable, accelerating its removal from the cell membrane. There is also evidence that double or even triple combination therapy might be required to allow synergistic Phe508del-CFTR correction by other compounds at distinct conformational sites.10 Several novel CFTR modulators are in the drug development pipeline after being extensively assessed in vitro and patients with cystic fibrosis will be in demand for the many competing clinical trials. The study by McKone and colleagues3 confirms the potential of CFTR-specific therapies and supports efforts aimed to develop drugs for mutation-targeted personalised medicine that could ultimately affect 90% of patients with cystic fibrosis. However, personalised medicine for cystic fibrosis remains expensive, thus efforts should be made to make such potentially life-changing treatment affordable and available for patients with cystic fibrosis worldwide.11
Carla Colombo Cystic Fibrosis Center, University of Milan, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milan, Italy [email protected] CC has served on advisory boards for Novartis, Gilead, and Vertex, and has been a site principal investigator for trials sponsored by Novartis, Gilead, and Vertex. 1
2
3
4
5
6
7
8
9
10
11
Ramsey BW, Davies J, McElvaney NG, et al, VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663–72. Davies JC, Wainwright CE, Canny GJ, et al, VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013; 187: 1219–25. McKone EF, Borowitz D, Drevinek P, et al. Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med 2014; published online Oct 10. http://dx.doi. org/10.1016/S2213-2600(14)70218-8 Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551DCFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013; 1: 630–38. Rowe SM, Heltshe SL, Gonska T, et al; GOAL Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175–84. Debray D, Kelly D, Houwen R, Strandvik B, Colombo C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. Cyst Fibros 2011; 10: S29–36. Colombo C, Castellani MR, Balistreri WF, Seregni E, Assaisso ML, Giunta A. Scintigraphic documentation of an improvement in hepatobiliary excretory function after treatment with ursodeoxycholic acid in patients with cystic fibrosis and associated liver disease. Hepatology 1992; 15: 677–84. De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G, Higgins M. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a nonG551D gating mutation. Cyst Fibros 2014; published online Sept 26. DOI:10.1016/j.jcf.2014.09.005. Boyle MP, Bell SC, Konstan MW, et al; VX09-809-102 study group. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2014; 2: 527–38. Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls. Pharmacol Ther 2014; published online June 14. DOI:10.1016/j.pharmthera.2014.06.005. Balfour-Lynn IM. Personalized medicine in cystic fibrosis is unaffordable. Paediatr Respir Rev 2014; 15: 2–5.
Paradoxical response to bronchodilators in COPD: curious enigma or clinically important phenotype? The physiological hallmark of chronic obstructive pulmonary disease (COPD) is expiratory airflow limitation,1 which is partly reversible in some patients after bronchodilator therapy.2 Because COPD is such a heterogeneous disease, it is not surprising that bronchodilator response and reversibility are also highly variable over time and between patients3 and Global www.thelancet.com/respiratory Vol 2 November 2014
Initiative for Chronic Obstructive Lung Disease (GOLD) grades. Although there is an increasing understanding of the breadth and importance of COPD phenotypes, cause, mechanisms, and clinical implications of bronchodilator response, or lack thereof, still remain obscure. In The Lancet Respiratory Medicine, Surya Bhatt and colleagues4 describe the first systematic study of a
Published Online September 10, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70198-5 See Articles page 911
865
