Correspondence
A new chapter in therapy for cystic fibrosis
Published Online June 25, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00234-9 If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
e20
In the New England Journal of Medicine, Wainwright and colleagues1 reported the results of two phase 3 studies to assess the effects of a combination of lumacaftor and ivacaftor for the treatment of cystic fibrosis; specifically, in patients homozygous for the most common mutation in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein, Phe508del. Although cystic fibrosis is a single-gene disease, wherein mutations in CFTR cause abnormalities in protein function and thus chloride-channel activity in the lungs and other secretory organs, more than 1000 mutations in CFTR have been identified, and the task of finding therapies appropriate for each mutation might seem too difficult a task (although not all of these mutations cause disease). However, recognition of the class effect of specific mutations at different points in the gene, ably described by Boyle and De Boeck in a Review in The Lancet Respiratory Medicine,2 has also allowed the design of classes of drugs that have specific effects on different mutation classes. The lumacaftor–ivacaftor combination 1 is based on that approach and the results of these trials bring hope of mutation-specific therapy to more patients with cystic fibrosis. Ivacaftor was licensed in Europe and the USA for the treatment of cystic fibrosis in patients with the Gly551Asp (class 3) mutation, in whom dysfunctional CFTR is present in the cell membrane.3 Ivacaftor is a CFTR potentiator, which ensures that the CFTR functions appropriately and stays open to allow chloride flux.2 Oral ivacaftor given twice per day was associated with improvements in lung function and other outcomes in a clinical trial,3 but this treatment is only suitable for the 5% of patients with cystic fibrosis who have the Gly551Asp mutation. The
effectiveness of the lumacaftor– ivacaftor combination1 brings hope of therapy to more patients with cystic fibrosis—more than 50% of people with cystic fibrosis in the UK are homozygous for the Phe508del mutation.4 Although evidence of a significant effect of the lumacaftor–ivacaftor combination is exciting, some caveats must be considered. First, compared with the results from the ivacaftor study in patients with the Gly551Asp mutation,3 the changes in lung function from baseline in the lumacaftor–ivacaftor trials1 are not so impressive—ie, from 2·6 to 4·0 percentage points in predicted forced expiratory volume in 1 s—although, encouragingly, the combination therapy did seem to be associated with a reduction in pulmonary exacerbations. Second, 17 (4·6%) of 369 patients who received the higher dose of lumacaftor treatment discontinued because of adverse events, compared to six (1·6%) of 370 patients who received placebo, a difference not seen in the ivacaftor monotherapy trial, in which only one (1%) of 83 patients receiving ivacaftor discontinued because of an adverse event, compared with four (5%) of 78 patients who received placebo.3 Does the combination of lumacaftor and ivacaftor represent the future for patients with Phe508del homozygous cystic fibrosis? Wainwright and colleagues’ results 1 suggest that drug–drug interactions between ivacaftor and lumacaftor could cause problems for some patients and an optimum dose regimen might not have yet been identified. Furthermore, alternative drugs to lumacaftor (the corrector agent in the combination that ensures the abnormal protein reaches the membrane) might be identified that work better in combination with ivacaftor. The publication of these trial results have brought excitement and hope for the future, but this reaction should be tempered by concerns regarding
the future funding of cystic fibrosis care. Health systems, including the UK National Health Service, have been burdened by the high cost of ivacaftor, which has so far benefited only a small proportion of patients. Negotiations should be pursued to ensure that a realistic price is set internationally for the lumacaftor–ivacaftor combination, especially because so many patients with cystic fibrosis are potentially eligible for the treatment and because the weaker effect seen with the combination compared with ivacaftor monotherapy should result in a lower price. Following the hard work put in by drug developers and trial collaborators, cystic fibrosis physicians worldwide should work together to define a threshold of clinical change that makes such expensive mutation-specific therapies cost-effective. I was a subinvestigator on the lumacaftor and ivacaftor trials.
Diana Bilton [email protected] Department of Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK 1
2
3
4
Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; published online May 17. DOI:10.1056/NEJMoa1409547. Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 2013; 1: 158–63. 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. UK Cystic Fibrosis Registry. Annual data report 2013. July 2014. http://www.cysticfibrosis.org. uk/media/598466/annual-data-report-2013jul14.pdf (accessed June 22, 2015).
COPD management: need for more consensus I would like to applaud Christopher Cooper and Igor Barjaktarevic 1 for their new algorithm for the management of chronic obstructive pulmonary disease (COPD). They fill the gap left by the Global Initiative www.thelancet.com/respiratory Vol 3 July 2015
Correspondence
for Chronic Obstructive Lung Disease (GOLD) 2011 pharmacotherapy recommendations for stable COPD, which abandoned the usual stepwise approach to treatment. All subsequent GOLD updates, including the most recent one from 2015, are confusing, difficult to use, and do not give clear guidance on pharmacological management. Since most primary care doctors in practice rely only on the tables and figures of the GOLD At-A-Glance Desk Reference as opposed to the 117 pages of the full GOLD document they will miss the problem—that most patients in C and D stages are non-exacerbators2 yet the first-choice recommendation for exacerbation prophylaxis is inhaled corticosteroids. This issue might explain the widespread overuse of these drugs even without clear indication. Adding the algorithm from Cooper and Barjaktarevic to the multidimensional GOLD assessment would overcome the most important weakness of the current GOLD document and enable its use in routine practice, in both primary and secondary care. However, several features of the algorithm deserve further considerations. First, Clinical Stage 0 might not be necessary because smoking cessation and environmental or occupational hygiene strategies are needed for everyone affected, irrespective of the unpredictable subsequent development of COPD. Second, Clinical Stage 1 COPD with intermittent breathlessness or wheezing is a fairly unusual presentation because such patients usually cope even without treatment for their symptoms.3 If patients in Clinical Stage 1 COPD are seeking medical care at all they need further diagnostic procedures to exclude New York Heart Association stage 1 or 2 heart failure or asthma. Both disorders need treatment other than shortacting bronchodilators. Furthermore, patients with true www.thelancet.com/respiratory Vol 3 July 2015
Clinical Stage 1 COPD already reduce their physical activity 4 because they have exertional dyspnoea. If compared with shortacting bronchodilators, as recommended by Cooper and Barjaktarevic, these patients could benefit more from a longacting bronchodilator, which would be better for the prevention of dynamic hyperinflation, the most common cause of shortness of breath on exertion in patients with COPD.5 Currently available shortacting muscarinic antagonists are not rapid-acting and as a monotherapy would not be preferred treatment for shortness of breath on exertion in most patients. Third, the authors use of the term of uncontrolled COPD (in parallel with asthma) might be misleading— COPD patients never achieve asthmalike disease control, with respect to the persistent airflow limitation, which is an integral part of the COPD definition. Certainly, COPD is a treatable disease, but available treatments can only relieve, not abolish, symptoms. Fourth, although the role of inhaled corticosteroids in fixed combinations for the treatment of COPD is controversial,6 these drugs probably should not be restricted exclusively to use in patients diagnosed with the poorly defined asthma-COPD overlap syndrome, as Cooper and Barjaktarevic seem to suggest. Finally, I believe that the most important strength of Cooper and Barjaktarevic’s Comment 1 is its introduction of highly relevant and clinically readily available phenotyping for severe COPD, thus differentiating between general and phenotypic treatment for patients with very severe disease. This approach is similar to that used in the Global Initiative for Asthma 2014 asthma treatment algorithm. This phenotyping will also encourage a proactive search for comorbidities in patients with severely symptomatic COPD.
I declare no competing interests.
Peter Kardos [email protected] Group Practice and Centre for Allergy, Respiratory, and Sleep Medicine, Maingau Red Cross Hospital, 60318 Frankfurt, Germany 1
2
3
4
5
6
Cooper CB, Barjaktarevic I. A new algorithm for the management of COPD. Lancet Respir Med 2015; 3: 266–68. Agusti A, Hurd S, Jones P, et al. FAQs about the GOLD 2011 assessment proposal of COPD: a comparative analysis of four different cohorts. Eur Respir J 2013; 42: 1391–401. Buffels J, Degryse J, Heyrman J, Decramer M. Office spirometry significantly improves early detection of COPD in general practice: the DIDASCO Study. Chest 2004; 125: 1394–99. Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with COPD. Eur Respir J 2009; 33: 262–72. O’Donnell DE, Laveneziana P. Dyspnea and activity limitation in COPD: mechanical factors. COPD 2007; 4: 225–36. Celli BR, Decramer M, Wedzicha JA, Wilson KC, Agusti A, Criner GJ et al. An official American Thoracic Society/European Respiratory Society statement: research questions in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 191: e4–e27.
For links to GOLD recommendations see http:// www.goldcopd.org/Guidelines/ guidelines-resources.html For more on the Global Initiative for Asthma 2014 see http://www.ginasthma.org/ local/uploads/files/GINA_ Report_2015.pdf
We question the potential effect of the new algorithm proposed by Christopher Cooper and Igor Barjaktarevic1 for the management of patients with chronic obstructive pulmonary disease (COPD). In the algorithm, clinical phenotyping is only suggested in patients with “uncontrolled disease”.1 However, patients with mild airflow limitation and bronchial hyperresponsiveness might respond well to inhaled corticosteroids. Eosinophil count has been shown to be a promising biomarker for response to inhaled corticosteroids.2 Additionally, patients with low-severity airflow limitation, but substantial static hyperinflation and exercise-induced dyspnoea, might benefit from optimum bronchodilator therapy.3 Therefore, early clinical phenotyping seems necessary to provide appropriate pharmacological therapy, even in patients with intermittent symptoms of dyspnoea. The choice of longacting beta agonist or longacting muscarinic antagonist seems interchangeable in Cooper and Barjaktarevic’s algorithm.1 Initiation of monotherapy e21
A new chapter in therapy for cystic fibrosis
Published Online June 25, 2015 http://dx.doi.org/10.1016/ S2213-2600(15)00234-9 If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
e20
In the New England Journal of Medicine, Wainwright and colleagues1 reported the results of two phase 3 studies to assess the effects of a combination of lumacaftor and ivacaftor for the treatment of cystic fibrosis; specifically, in patients homozygous for the most common mutation in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein, Phe508del. Although cystic fibrosis is a single-gene disease, wherein mutations in CFTR cause abnormalities in protein function and thus chloride-channel activity in the lungs and other secretory organs, more than 1000 mutations in CFTR have been identified, and the task of finding therapies appropriate for each mutation might seem too difficult a task (although not all of these mutations cause disease). However, recognition of the class effect of specific mutations at different points in the gene, ably described by Boyle and De Boeck in a Review in The Lancet Respiratory Medicine,2 has also allowed the design of classes of drugs that have specific effects on different mutation classes. The lumacaftor–ivacaftor combination 1 is based on that approach and the results of these trials bring hope of mutation-specific therapy to more patients with cystic fibrosis. Ivacaftor was licensed in Europe and the USA for the treatment of cystic fibrosis in patients with the Gly551Asp (class 3) mutation, in whom dysfunctional CFTR is present in the cell membrane.3 Ivacaftor is a CFTR potentiator, which ensures that the CFTR functions appropriately and stays open to allow chloride flux.2 Oral ivacaftor given twice per day was associated with improvements in lung function and other outcomes in a clinical trial,3 but this treatment is only suitable for the 5% of patients with cystic fibrosis who have the Gly551Asp mutation. The
effectiveness of the lumacaftor– ivacaftor combination1 brings hope of therapy to more patients with cystic fibrosis—more than 50% of people with cystic fibrosis in the UK are homozygous for the Phe508del mutation.4 Although evidence of a significant effect of the lumacaftor–ivacaftor combination is exciting, some caveats must be considered. First, compared with the results from the ivacaftor study in patients with the Gly551Asp mutation,3 the changes in lung function from baseline in the lumacaftor–ivacaftor trials1 are not so impressive—ie, from 2·6 to 4·0 percentage points in predicted forced expiratory volume in 1 s—although, encouragingly, the combination therapy did seem to be associated with a reduction in pulmonary exacerbations. Second, 17 (4·6%) of 369 patients who received the higher dose of lumacaftor treatment discontinued because of adverse events, compared to six (1·6%) of 370 patients who received placebo, a difference not seen in the ivacaftor monotherapy trial, in which only one (1%) of 83 patients receiving ivacaftor discontinued because of an adverse event, compared with four (5%) of 78 patients who received placebo.3 Does the combination of lumacaftor and ivacaftor represent the future for patients with Phe508del homozygous cystic fibrosis? Wainwright and colleagues’ results 1 suggest that drug–drug interactions between ivacaftor and lumacaftor could cause problems for some patients and an optimum dose regimen might not have yet been identified. Furthermore, alternative drugs to lumacaftor (the corrector agent in the combination that ensures the abnormal protein reaches the membrane) might be identified that work better in combination with ivacaftor. The publication of these trial results have brought excitement and hope for the future, but this reaction should be tempered by concerns regarding
the future funding of cystic fibrosis care. Health systems, including the UK National Health Service, have been burdened by the high cost of ivacaftor, which has so far benefited only a small proportion of patients. Negotiations should be pursued to ensure that a realistic price is set internationally for the lumacaftor–ivacaftor combination, especially because so many patients with cystic fibrosis are potentially eligible for the treatment and because the weaker effect seen with the combination compared with ivacaftor monotherapy should result in a lower price. Following the hard work put in by drug developers and trial collaborators, cystic fibrosis physicians worldwide should work together to define a threshold of clinical change that makes such expensive mutation-specific therapies cost-effective. I was a subinvestigator on the lumacaftor and ivacaftor trials.
Diana Bilton [email protected] Department of Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP, UK 1
2
3
4
Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor–ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; published online May 17. DOI:10.1056/NEJMoa1409547. Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 2013; 1: 158–63. 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. UK Cystic Fibrosis Registry. Annual data report 2013. July 2014. http://www.cysticfibrosis.org. uk/media/598466/annual-data-report-2013jul14.pdf (accessed June 22, 2015).
COPD management: need for more consensus I would like to applaud Christopher Cooper and Igor Barjaktarevic 1 for their new algorithm for the management of chronic obstructive pulmonary disease (COPD). They fill the gap left by the Global Initiative www.thelancet.com/respiratory Vol 3 July 2015
Correspondence
for Chronic Obstructive Lung Disease (GOLD) 2011 pharmacotherapy recommendations for stable COPD, which abandoned the usual stepwise approach to treatment. All subsequent GOLD updates, including the most recent one from 2015, are confusing, difficult to use, and do not give clear guidance on pharmacological management. Since most primary care doctors in practice rely only on the tables and figures of the GOLD At-A-Glance Desk Reference as opposed to the 117 pages of the full GOLD document they will miss the problem—that most patients in C and D stages are non-exacerbators2 yet the first-choice recommendation for exacerbation prophylaxis is inhaled corticosteroids. This issue might explain the widespread overuse of these drugs even without clear indication. Adding the algorithm from Cooper and Barjaktarevic to the multidimensional GOLD assessment would overcome the most important weakness of the current GOLD document and enable its use in routine practice, in both primary and secondary care. However, several features of the algorithm deserve further considerations. First, Clinical Stage 0 might not be necessary because smoking cessation and environmental or occupational hygiene strategies are needed for everyone affected, irrespective of the unpredictable subsequent development of COPD. Second, Clinical Stage 1 COPD with intermittent breathlessness or wheezing is a fairly unusual presentation because such patients usually cope even without treatment for their symptoms.3 If patients in Clinical Stage 1 COPD are seeking medical care at all they need further diagnostic procedures to exclude New York Heart Association stage 1 or 2 heart failure or asthma. Both disorders need treatment other than shortacting bronchodilators. Furthermore, patients with true www.thelancet.com/respiratory Vol 3 July 2015
Clinical Stage 1 COPD already reduce their physical activity 4 because they have exertional dyspnoea. If compared with shortacting bronchodilators, as recommended by Cooper and Barjaktarevic, these patients could benefit more from a longacting bronchodilator, which would be better for the prevention of dynamic hyperinflation, the most common cause of shortness of breath on exertion in patients with COPD.5 Currently available shortacting muscarinic antagonists are not rapid-acting and as a monotherapy would not be preferred treatment for shortness of breath on exertion in most patients. Third, the authors use of the term of uncontrolled COPD (in parallel with asthma) might be misleading— COPD patients never achieve asthmalike disease control, with respect to the persistent airflow limitation, which is an integral part of the COPD definition. Certainly, COPD is a treatable disease, but available treatments can only relieve, not abolish, symptoms. Fourth, although the role of inhaled corticosteroids in fixed combinations for the treatment of COPD is controversial,6 these drugs probably should not be restricted exclusively to use in patients diagnosed with the poorly defined asthma-COPD overlap syndrome, as Cooper and Barjaktarevic seem to suggest. Finally, I believe that the most important strength of Cooper and Barjaktarevic’s Comment 1 is its introduction of highly relevant and clinically readily available phenotyping for severe COPD, thus differentiating between general and phenotypic treatment for patients with very severe disease. This approach is similar to that used in the Global Initiative for Asthma 2014 asthma treatment algorithm. This phenotyping will also encourage a proactive search for comorbidities in patients with severely symptomatic COPD.
I declare no competing interests.
Peter Kardos [email protected] Group Practice and Centre for Allergy, Respiratory, and Sleep Medicine, Maingau Red Cross Hospital, 60318 Frankfurt, Germany 1
2
3
4
5
6
Cooper CB, Barjaktarevic I. A new algorithm for the management of COPD. Lancet Respir Med 2015; 3: 266–68. Agusti A, Hurd S, Jones P, et al. FAQs about the GOLD 2011 assessment proposal of COPD: a comparative analysis of four different cohorts. Eur Respir J 2013; 42: 1391–401. Buffels J, Degryse J, Heyrman J, Decramer M. Office spirometry significantly improves early detection of COPD in general practice: the DIDASCO Study. Chest 2004; 125: 1394–99. Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with COPD. Eur Respir J 2009; 33: 262–72. O’Donnell DE, Laveneziana P. Dyspnea and activity limitation in COPD: mechanical factors. COPD 2007; 4: 225–36. Celli BR, Decramer M, Wedzicha JA, Wilson KC, Agusti A, Criner GJ et al. An official American Thoracic Society/European Respiratory Society statement: research questions in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 191: e4–e27.
For links to GOLD recommendations see http:// www.goldcopd.org/Guidelines/ guidelines-resources.html For more on the Global Initiative for Asthma 2014 see http://www.ginasthma.org/ local/uploads/files/GINA_ Report_2015.pdf
We question the potential effect of the new algorithm proposed by Christopher Cooper and Igor Barjaktarevic1 for the management of patients with chronic obstructive pulmonary disease (COPD). In the algorithm, clinical phenotyping is only suggested in patients with “uncontrolled disease”.1 However, patients with mild airflow limitation and bronchial hyperresponsiveness might respond well to inhaled corticosteroids. Eosinophil count has been shown to be a promising biomarker for response to inhaled corticosteroids.2 Additionally, patients with low-severity airflow limitation, but substantial static hyperinflation and exercise-induced dyspnoea, might benefit from optimum bronchodilator therapy.3 Therefore, early clinical phenotyping seems necessary to provide appropriate pharmacological therapy, even in patients with intermittent symptoms of dyspnoea. The choice of longacting beta agonist or longacting muscarinic antagonist seems interchangeable in Cooper and Barjaktarevic’s algorithm.1 Initiation of monotherapy e21
