- Email: [email protected]
Remarkable progress toward new treatments for cystic fibrosis
2014 Research Highlights
exacerbation (3·01 exacerbations per year compared with 2·51 exacerbations per year without human rhinovirus infection). Human rhinovirus infection load fell and sputum bacterial load rose between day 7 and day 14, indicating a pattern of viral infection preceding rise in bacterial load and symptoms, similar to observed time patterns and clinical evolution in experimental studies of the virus. These observations should prompt studies that assess preventative strategies to minimise risk of viral upper respiratory infection and its consequences in COPD. The advent of once daily longacting bronchodilator combination inhalers and evidence to support their benefit in symptom control, along with concerns about the adverse effects of inhaled corticosteroids, has led to growing concern that inhaled corticosteroids are overprescribed and might not be efficacious in many individuals. The WISDOM study,6 a 12-month, doubleblind, step down study of inhaled corticosteroids in 2485 patients with an exacerbation in the preceding year and moderate-severe COPD, showed that in patients receiving tiotropium, salmeterol, and fluticasone propionate, withdrawal of inhaled corticosteroids in the first 12 study weeks was not inferior to continuation during 12 months, for time to first exacerbation. It could be argued whether the HR cut-off of 1·20 truly indicated no effect, considering that a 20% reduction in exacerbation rate on inhaled corticosteroids has been a common positive outcome of previous randomised controlled trials. Importantly, a significant decrease in trough FEV1 at 18 weeks, and at 52 weeks was noted in the inhaled corticosteroids withdrawal group compared with the continuation group. Whether there was a specific subgroup with more substantial loss of lung function, and their particular characteristics, has yet to be clarified. This information would be essential to assist clinicians in identification of those patients in whom withdrawal of
inhaled corticosteroids could constitute a risk for poorer lung function. Finally, no quick overview of COPD in 2014 would be complete without mention of physical activity and its relation to exacerbations, quality of life, hospital admissions, and mortality. A systematic review7 and an observational, real world study8 reinforce growing evidence and the crucial importance of maintenance of physical activity in patients with COPD. We need randomised controlled trials to clarify the best approaches to initiate and sustain physical activity in patients whose disease naturally diminishes their capacity and enthusiasm for it. Christine Jenkins Respiratory Discipline, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Thoracic Medicine, Concord Hospital, Hospital Road, Concord NSW 2137, Australia; and Head, Respiratory Trials, The George Institute for Global Health, NSW, Australia [email protected] CJ reports personal fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, and Novartis outside of the submitted work. 1 2
3
4
5 6
7
8
Faner R, Tal-Singer R, Riley JH, et al. Lessons from ECLIPSE: a review of COPD biomarkers. Thorax 2014; 69: 666–72. Vestbo J, Agusti A, Wouters EF, et al. Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. Am J Respir Crit Care Med 2014; 189: 1022–30. Sanchez-Salcedo P, Divo M, Casanova C, et al. Disease progression in young patients with COPD: rethinking the Fletcher and Peto model. Eur Respir J 2014; 44: 324–31. de Torres JP, Casanova C, Marín JM, et al. Prognostic evaluation of COPD patients: GOLD 2011 versus BODE and the COPD comorbidity index COTE. Thorax 2014; 69: 799–804. George SN, Garcha DS, Mackay AJ, et al. Human rhinovirus infection during naturally occurring COPD exacerbations. Eur Respir J 2014; 44: 87–96. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014; 371: 1285–94. Gimeno-Santos E, Frei A, Steurer-Stey C, et al. Determinants and outcomes of physical activity in patients with COPD: a systematic review. Thorax 2014; 69: 731–39. Esteban C, Arostegui I, Aburto M, et al. Influence of changes in physical activity on frequency of hospitalization in chronic obstructive pulmonary disease. Respirology 2014; 19: 330–38.
Remarkable progress toward new treatments for cystic fibrosis Published Online November 19, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70272-3
962
Cystic fibrosis is a life-shortening, autosomal recessive disorder, which affects more than 70 000 individuals worldwide, and is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is an epithelial anion channel that regulates the salt and water balance in many organs, including the lung, pancreas, and
gastrointestinal tract.1 In the past two decades, remarkable progress has been made towards understanding the pathophysiology of cystic fibrosis and how to use this knowledge to develop therapeutic approaches. In 2014, this progress has continued in both animal models and clinical trials, bringing hope to individuals with cystic fibrosis. www.thelancet.com/respiratory Vol 2 December 2014
New animal models of cystic fibrosis are enabling scientists to see the earliest changes caused by CFTR dysfunction. Two important studies2,3 in animal models of cystic fibrosis could change our understanding of the pathophysiology of this disease. Hoegger and colleagues2 used x-ray CT to assess mucociliary transport of radiodense microdisks in transgenic piglets expressing CFTR mutations compared with control piglets. Cholinergic stimulation, which elicits mucus secretion, impeded mucociliary transport in piglets expressing the CFTR mutation while accelerating clearance in noncystic fibrosis piglet airways. The mucociliary transport defect was localised to the submucosal gland; secreted mucus strands remained tethered in piglets expressing the CFTR mutation, rather than stretching and detaching, as seen in the control piglets. Unlike cultured cystic fibrosis airway epithelia, the newborn animal model did not show a reduced periciliary liquid level in cystic fibrosis compared with non-cystic fibrosis piglets. Thus, CFTR-expressing submucosal glands could be a primary therapeutic target for the treatment of cystic fibrosis. Keiser and colleagues3 assessed innate airway immunity in a CFTR knockout ferret model of cystic fibrosis, in which the animals develop submucosal glands postnatally. Although CFTR knockout ferrets had normal mucociliary clearance at birth, at 7 days of age their mucociliary clearance was impaired, and they were unable to eradicate postnatal infection with Pseudomonas spp. Bronchoalveolar lavage fluid from CFTR knockout ferrets had diminished antimicrobial activity and deregulated expression of inflammatory cytokines, including interleukin 1β, interleukin 8, and tumour necrosis factor α.3 These changes suggest early synergistic defects in the host defence of the cystic fibrosis airway. Investigators worldwide are focusing on the earliest structural and physiological changes in the cystic fibrosis lung in vivo. An Australian study4 showed the appearance of bronchiectasis in the first year of life using chest CT. However, widespread application of repeated CT scans in children has been restricted by concerns regarding cumulative radiation doses.5 One promising alternate approach is use of MRI, as reported by Wielputz and colleagues.6 Early changes in both lung structure and perfusion were recorded in 50 children aged 0–6 years with cystic fibrosis.4 Similar to chest CT, MRI detected lung structural changes beginning in infancy. By 6 years of age, 93% of children with cystic fibrosis had bronchial www.thelancet.com/respiratory Vol 2 December 2014
Jacopin/Bsip/Science Photo Library
2014 Research Highlights
wall thickening, bronchiectasis, or both. MRI also showed perfusion deficits at this early age. MRI scores acutely worsened during pulmonary exacerbations and improved within the month after antibiotic therapy. Morgan and colleagues7 made another breakthrough with in-vivo x-ray imaging to quantify changes in the depth of airway surface liquid in mice. Depth of airway surface liquid and distance from airway surface to underlying cartilage were increased in normal mice after treatment with inhaled hypertonic saline. These results show successful transition of non-invasive measurements from ex vivo to in vivo. Both of these imaging techniques could afford the opportunity to investigate initial cystic fibrosis airway pathogenesis and the effect of therapeutics therein. An important milestone in the treatment of cystic fibrosis was the approval of an oral drug, ivacaftor, in 2012 for patients with at least one Gly551Asp mutation.8 In the past year, further insights into the mechanisms of actions of this CFTR potentiator were reported by Rowe and colleagues.9 The significant clinical effect of ivacaftor on lung function, body-mass index, and rate of admissions to hospital when prescribed to patients with at least one copy of Gly551Asp was verified. Additionally, ivacaftor affected airway microbiology, by reducing the prevalence of positive respiratory cultures of Pseudomonas aeruginosa and raising Prevotella spp abundance, which suggests that ivacaftor shifts microbial diversity. Two other encouraging findings were improved mucociliary clearance and alkalinisation of duodenal pH towards normal values.9 The alkalinisation finding emphasises the role of CFTR as a bicarbonate transporter. 963
2014 Research Highlights
Substantial effort by the cystic fibrosis research community has been directed at development of therapies to correct CFTR function in homozygous Phe508del patients. In-vitro studies10 have shown that combination therapy is necessary, including a corrector (lumacaftor) to increase trafficking of the Phe508 protein to the cell surface and a potentiator to enhance chloride transport. The report from a phase 2 dose-escalation study by Boyle and colleagues11 of lumacaftor (a corrector) and ivacaftor (a potentiator) is the first to show that this drug combination might be effective in homozygous Phe508del patients. This trial tested sequential cohorts of participants receiving increasing doses of lumacaftor monotherapy followed by addition of ivacaftor. Although lumacaftor monotherapy resulted in a dose dependent decrease in the forced expiratory volume in 1 sec (FEV1), the addition of ivacaftor resulted in a significant increase in FEV1 (treatment difference vs placebo for absolute change in percent predicted FEV1 of 7·7 [95% Cl 2·7– 12·6]) at the highest dose, lumacaftor 400 mg with ivacaftor 250 mg, both taken every 12 h. The encouraging results in the homozygous Phe508del population led to the undertaking of two large phase 3 trials. These phase 3 trials of lumacaftor and ivacaftor combination therapy—TRAFFIC (NCT01807923) and TRANSPORT (NCT01807949)—were completed in 2014 and the results presented at the North American Cystic Fibrosis Conference in Atlanta, GA, USA, in October 2014. In both dose groups tested (lumacaftor 600 mg once daily and lumacaftor 400 mg every 12 h, both combined with ivacaftor 250 mg every 12 h) a treatment difference compared with placebo in absolute change in percent predicted FEV1 ranging from 2·6 to 4·0 percentage points was recorded. From animal models to clinical trials, the abundance of publications about cystic fibrosis in 2014 provides additional optimism. Indeed, an analysis of a cystic
fibrosis registry reported in August, 2014, that median survival increased by 1·8% per year from 2000 to 2010.12 Patients born in 2010 are now projected to survive to 39 years; these patients could survive to 56 years if the rate of mortality continues to decrease at the rate observed from 2000 to 2010.12 Laurie C Eldredge, *Bonnie W Ramsey Department of Pediatrics, Seattle Children’s Research Institute, University of Washington, Seattle, WA 98121, USA (BWR); and Department of Pediatrics, Division of Pulmonary and Sleep Medicine, University of Washington, Seattle, WA, USA (LCE) [email protected] We declare no competing interests. 1 2
3
4
5
6
7
8 9
10
11
12
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352: 1992–2001. Hoegger MJ, Fischer AJ, McMenimen JD, et al. Cystic fibrosis. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 2014; 345: 818–22. Keiser NW, Birket SE, Evans IA, et al. Defective innate immunity and hyperinflammation in newborn CFTR-knockout ferret lungs. Am J Respir Cell Mol Biol 2014; published online Oct 15. DOI:10.1165/rcmb.2014-0250OC. Mott LS, Park J, Murray CP, et al. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012; 67: 509–16. Kuo W, Ciet P, Tiddens HA, Zhang W, Guillerman RP, van Straten M. Monitoring cystic fibrosis lung disease by computed tomography. Radiation risk in perspective. Am J Respir Crit Care Med 2014; 189: 1328–36. Wielpütz MO, Puderbach M, Kopp-Schneider A, et al. Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease. Am J Respir Crit Care Med 2014; 189: 956–65. Morgan KS, Donnelley M, Farrow N, et al. In vivo X-ray imaging reveals improved airway surface hydration after a therapy designed for cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 469–72. 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. Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551Dmediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175–84. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Correction of the F508delCFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci 2011; 108: 18843–48. Boyle MP, Bell SC, Konstan MW, et al. 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. MacKenzie T, Gifford AH, Sabadosa KA, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry. Ann Intern Med 2014; 161: 233–41.
A new era of drug therapy for idiopathic pulmonary fibrosis Published Online November 19, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70257-7
964
In 2014, for the first time in idiopathic pulmonary fibrosis, two drugs were shown to slow decline of lung function in randomised placebo-controlled trials. The effects of nintedanib in the INPULSIS studies1 and pirfenidone in ASCEND2 were very similar. Both reduced the decline in forced vital capacity in patients with
idiopathic pulmonary fibrosis at 52 weeks by about half compared with placebo (table). Neither drug had a demonstrable effect on patient reported outcomes, such as breathlessness or quality of life scores, which perhaps is not surprising because of the insensitivity of the instruments used and the need for thousands www.thelancet.com/respiratory Vol 2 December 2014
exacerbation (3·01 exacerbations per year compared with 2·51 exacerbations per year without human rhinovirus infection). Human rhinovirus infection load fell and sputum bacterial load rose between day 7 and day 14, indicating a pattern of viral infection preceding rise in bacterial load and symptoms, similar to observed time patterns and clinical evolution in experimental studies of the virus. These observations should prompt studies that assess preventative strategies to minimise risk of viral upper respiratory infection and its consequences in COPD. The advent of once daily longacting bronchodilator combination inhalers and evidence to support their benefit in symptom control, along with concerns about the adverse effects of inhaled corticosteroids, has led to growing concern that inhaled corticosteroids are overprescribed and might not be efficacious in many individuals. The WISDOM study,6 a 12-month, doubleblind, step down study of inhaled corticosteroids in 2485 patients with an exacerbation in the preceding year and moderate-severe COPD, showed that in patients receiving tiotropium, salmeterol, and fluticasone propionate, withdrawal of inhaled corticosteroids in the first 12 study weeks was not inferior to continuation during 12 months, for time to first exacerbation. It could be argued whether the HR cut-off of 1·20 truly indicated no effect, considering that a 20% reduction in exacerbation rate on inhaled corticosteroids has been a common positive outcome of previous randomised controlled trials. Importantly, a significant decrease in trough FEV1 at 18 weeks, and at 52 weeks was noted in the inhaled corticosteroids withdrawal group compared with the continuation group. Whether there was a specific subgroup with more substantial loss of lung function, and their particular characteristics, has yet to be clarified. This information would be essential to assist clinicians in identification of those patients in whom withdrawal of
inhaled corticosteroids could constitute a risk for poorer lung function. Finally, no quick overview of COPD in 2014 would be complete without mention of physical activity and its relation to exacerbations, quality of life, hospital admissions, and mortality. A systematic review7 and an observational, real world study8 reinforce growing evidence and the crucial importance of maintenance of physical activity in patients with COPD. We need randomised controlled trials to clarify the best approaches to initiate and sustain physical activity in patients whose disease naturally diminishes their capacity and enthusiasm for it. Christine Jenkins Respiratory Discipline, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Department of Thoracic Medicine, Concord Hospital, Hospital Road, Concord NSW 2137, Australia; and Head, Respiratory Trials, The George Institute for Global Health, NSW, Australia [email protected] CJ reports personal fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, and Novartis outside of the submitted work. 1 2
3
4
5 6
7
8
Faner R, Tal-Singer R, Riley JH, et al. Lessons from ECLIPSE: a review of COPD biomarkers. Thorax 2014; 69: 666–72. Vestbo J, Agusti A, Wouters EF, et al. Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. Am J Respir Crit Care Med 2014; 189: 1022–30. Sanchez-Salcedo P, Divo M, Casanova C, et al. Disease progression in young patients with COPD: rethinking the Fletcher and Peto model. Eur Respir J 2014; 44: 324–31. de Torres JP, Casanova C, Marín JM, et al. Prognostic evaluation of COPD patients: GOLD 2011 versus BODE and the COPD comorbidity index COTE. Thorax 2014; 69: 799–804. George SN, Garcha DS, Mackay AJ, et al. Human rhinovirus infection during naturally occurring COPD exacerbations. Eur Respir J 2014; 44: 87–96. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014; 371: 1285–94. Gimeno-Santos E, Frei A, Steurer-Stey C, et al. Determinants and outcomes of physical activity in patients with COPD: a systematic review. Thorax 2014; 69: 731–39. Esteban C, Arostegui I, Aburto M, et al. Influence of changes in physical activity on frequency of hospitalization in chronic obstructive pulmonary disease. Respirology 2014; 19: 330–38.
Remarkable progress toward new treatments for cystic fibrosis Published Online November 19, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70272-3
962
Cystic fibrosis is a life-shortening, autosomal recessive disorder, which affects more than 70 000 individuals worldwide, and is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is an epithelial anion channel that regulates the salt and water balance in many organs, including the lung, pancreas, and
gastrointestinal tract.1 In the past two decades, remarkable progress has been made towards understanding the pathophysiology of cystic fibrosis and how to use this knowledge to develop therapeutic approaches. In 2014, this progress has continued in both animal models and clinical trials, bringing hope to individuals with cystic fibrosis. www.thelancet.com/respiratory Vol 2 December 2014
New animal models of cystic fibrosis are enabling scientists to see the earliest changes caused by CFTR dysfunction. Two important studies2,3 in animal models of cystic fibrosis could change our understanding of the pathophysiology of this disease. Hoegger and colleagues2 used x-ray CT to assess mucociliary transport of radiodense microdisks in transgenic piglets expressing CFTR mutations compared with control piglets. Cholinergic stimulation, which elicits mucus secretion, impeded mucociliary transport in piglets expressing the CFTR mutation while accelerating clearance in noncystic fibrosis piglet airways. The mucociliary transport defect was localised to the submucosal gland; secreted mucus strands remained tethered in piglets expressing the CFTR mutation, rather than stretching and detaching, as seen in the control piglets. Unlike cultured cystic fibrosis airway epithelia, the newborn animal model did not show a reduced periciliary liquid level in cystic fibrosis compared with non-cystic fibrosis piglets. Thus, CFTR-expressing submucosal glands could be a primary therapeutic target for the treatment of cystic fibrosis. Keiser and colleagues3 assessed innate airway immunity in a CFTR knockout ferret model of cystic fibrosis, in which the animals develop submucosal glands postnatally. Although CFTR knockout ferrets had normal mucociliary clearance at birth, at 7 days of age their mucociliary clearance was impaired, and they were unable to eradicate postnatal infection with Pseudomonas spp. Bronchoalveolar lavage fluid from CFTR knockout ferrets had diminished antimicrobial activity and deregulated expression of inflammatory cytokines, including interleukin 1β, interleukin 8, and tumour necrosis factor α.3 These changes suggest early synergistic defects in the host defence of the cystic fibrosis airway. Investigators worldwide are focusing on the earliest structural and physiological changes in the cystic fibrosis lung in vivo. An Australian study4 showed the appearance of bronchiectasis in the first year of life using chest CT. However, widespread application of repeated CT scans in children has been restricted by concerns regarding cumulative radiation doses.5 One promising alternate approach is use of MRI, as reported by Wielputz and colleagues.6 Early changes in both lung structure and perfusion were recorded in 50 children aged 0–6 years with cystic fibrosis.4 Similar to chest CT, MRI detected lung structural changes beginning in infancy. By 6 years of age, 93% of children with cystic fibrosis had bronchial www.thelancet.com/respiratory Vol 2 December 2014
Jacopin/Bsip/Science Photo Library
2014 Research Highlights
wall thickening, bronchiectasis, or both. MRI also showed perfusion deficits at this early age. MRI scores acutely worsened during pulmonary exacerbations and improved within the month after antibiotic therapy. Morgan and colleagues7 made another breakthrough with in-vivo x-ray imaging to quantify changes in the depth of airway surface liquid in mice. Depth of airway surface liquid and distance from airway surface to underlying cartilage were increased in normal mice after treatment with inhaled hypertonic saline. These results show successful transition of non-invasive measurements from ex vivo to in vivo. Both of these imaging techniques could afford the opportunity to investigate initial cystic fibrosis airway pathogenesis and the effect of therapeutics therein. An important milestone in the treatment of cystic fibrosis was the approval of an oral drug, ivacaftor, in 2012 for patients with at least one Gly551Asp mutation.8 In the past year, further insights into the mechanisms of actions of this CFTR potentiator were reported by Rowe and colleagues.9 The significant clinical effect of ivacaftor on lung function, body-mass index, and rate of admissions to hospital when prescribed to patients with at least one copy of Gly551Asp was verified. Additionally, ivacaftor affected airway microbiology, by reducing the prevalence of positive respiratory cultures of Pseudomonas aeruginosa and raising Prevotella spp abundance, which suggests that ivacaftor shifts microbial diversity. Two other encouraging findings were improved mucociliary clearance and alkalinisation of duodenal pH towards normal values.9 The alkalinisation finding emphasises the role of CFTR as a bicarbonate transporter. 963
2014 Research Highlights
Substantial effort by the cystic fibrosis research community has been directed at development of therapies to correct CFTR function in homozygous Phe508del patients. In-vitro studies10 have shown that combination therapy is necessary, including a corrector (lumacaftor) to increase trafficking of the Phe508 protein to the cell surface and a potentiator to enhance chloride transport. The report from a phase 2 dose-escalation study by Boyle and colleagues11 of lumacaftor (a corrector) and ivacaftor (a potentiator) is the first to show that this drug combination might be effective in homozygous Phe508del patients. This trial tested sequential cohorts of participants receiving increasing doses of lumacaftor monotherapy followed by addition of ivacaftor. Although lumacaftor monotherapy resulted in a dose dependent decrease in the forced expiratory volume in 1 sec (FEV1), the addition of ivacaftor resulted in a significant increase in FEV1 (treatment difference vs placebo for absolute change in percent predicted FEV1 of 7·7 [95% Cl 2·7– 12·6]) at the highest dose, lumacaftor 400 mg with ivacaftor 250 mg, both taken every 12 h. The encouraging results in the homozygous Phe508del population led to the undertaking of two large phase 3 trials. These phase 3 trials of lumacaftor and ivacaftor combination therapy—TRAFFIC (NCT01807923) and TRANSPORT (NCT01807949)—were completed in 2014 and the results presented at the North American Cystic Fibrosis Conference in Atlanta, GA, USA, in October 2014. In both dose groups tested (lumacaftor 600 mg once daily and lumacaftor 400 mg every 12 h, both combined with ivacaftor 250 mg every 12 h) a treatment difference compared with placebo in absolute change in percent predicted FEV1 ranging from 2·6 to 4·0 percentage points was recorded. From animal models to clinical trials, the abundance of publications about cystic fibrosis in 2014 provides additional optimism. Indeed, an analysis of a cystic
fibrosis registry reported in August, 2014, that median survival increased by 1·8% per year from 2000 to 2010.12 Patients born in 2010 are now projected to survive to 39 years; these patients could survive to 56 years if the rate of mortality continues to decrease at the rate observed from 2000 to 2010.12 Laurie C Eldredge, *Bonnie W Ramsey Department of Pediatrics, Seattle Children’s Research Institute, University of Washington, Seattle, WA 98121, USA (BWR); and Department of Pediatrics, Division of Pulmonary and Sleep Medicine, University of Washington, Seattle, WA, USA (LCE) [email protected] We declare no competing interests. 1 2
3
4
5
6
7
8 9
10
11
12
Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352: 1992–2001. Hoegger MJ, Fischer AJ, McMenimen JD, et al. Cystic fibrosis. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 2014; 345: 818–22. Keiser NW, Birket SE, Evans IA, et al. Defective innate immunity and hyperinflammation in newborn CFTR-knockout ferret lungs. Am J Respir Cell Mol Biol 2014; published online Oct 15. DOI:10.1165/rcmb.2014-0250OC. Mott LS, Park J, Murray CP, et al. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012; 67: 509–16. Kuo W, Ciet P, Tiddens HA, Zhang W, Guillerman RP, van Straten M. Monitoring cystic fibrosis lung disease by computed tomography. Radiation risk in perspective. Am J Respir Crit Care Med 2014; 189: 1328–36. Wielpütz MO, Puderbach M, Kopp-Schneider A, et al. Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease. Am J Respir Crit Care Med 2014; 189: 956–65. Morgan KS, Donnelley M, Farrow N, et al. In vivo X-ray imaging reveals improved airway surface hydration after a therapy designed for cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 469–72. 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. Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551Dmediated cystic fibrosis. Am J Respir Crit Care Med 2014; 190: 175–84. Van Goor F, Hadida S, Grootenhuis PDJ, et al. Correction of the F508delCFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci 2011; 108: 18843–48. Boyle MP, Bell SC, Konstan MW, et al. 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. MacKenzie T, Gifford AH, Sabadosa KA, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry. Ann Intern Med 2014; 161: 233–41.
A new era of drug therapy for idiopathic pulmonary fibrosis Published Online November 19, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70257-7
964
In 2014, for the first time in idiopathic pulmonary fibrosis, two drugs were shown to slow decline of lung function in randomised placebo-controlled trials. The effects of nintedanib in the INPULSIS studies1 and pirfenidone in ASCEND2 were very similar. Both reduced the decline in forced vital capacity in patients with
idiopathic pulmonary fibrosis at 52 weeks by about half compared with placebo (table). Neither drug had a demonstrable effect on patient reported outcomes, such as breathlessness or quality of life scores, which perhaps is not surprising because of the insensitivity of the instruments used and the need for thousands www.thelancet.com/respiratory Vol 2 December 2014