Comment
Magnus P Ekström
5
Department of Clinical Sciences, Division of Respiratory Medicine and Allergology, Lund University, Lund, Sweden, and Department of Medicine, Blekinge Hospital, Karlskrona, Sweden [email protected]
6
I declare that I have no conflicts of interest. 1
2 3
4
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095–128. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine 2006; 3: e442. López-Campos JL, Ruiz-Ramos M, Soriano JB. Mortality trends in chronic obstructive pulmonary disease in Europe, 1994–2010: a joinpoint regression analysis. Lancet Respir Med 2013; Dec 6. http://dx.doi. org/10.1016/S2213-2600(13)70232-7. Moriyama I, Loy R, Robb-Smith A. History of the statistical classification of diseases and causes of death. Hyattsville, MD, USA: National Center for Health Statistics. 2011.
7 8
9
10
WHO. Manual of the International Statistical Classification of Diseases and Health Related Problems. 10th revision. Geneva, Switzerland: World Health Organization; 1992. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012; 380: 37–43. Jensen HH, Godtfredsen NS, Lange P, Vestbo J. Potential misclassification of causes of death from COPD. Eur Respir J 2006; 28: 781–85. Rothman KJ, Greenland S, Poole C, Lash TL. Rothman KJ, Greenland S, Lash TL, eds. Modern epidemiology. Philadelphia: Lippincott Williams and Wilkins, 2008: 5–31. Mladovsky P, Allin S, Masseria C, Hernández-Quevedo C, McDaid D, Mossialos E. Health in the European Union: trends and analysis. Observatory studies series, no 19. Copenhagen, Denmark: World Health Organization, European Observatory on Health Systems and Policies, 2009. Pirie K, Peto R, Reeves GK, Green J, Beral V. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 2013; 381: 133–41.
Astier/BSIP/Science Photo Library
New treatments for COPD: many miles still to go
Published Online December 5, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70242-X See Articles page 63
6
Primary and secondary preventive measures are of enormous importance for management of chronic obstructive pulmonary disease (COPD), but the residual disability associated with established COPD has led to much research on new ways to treat this intractable condition. At present, treatment focuses on decreasing airway smooth-muscle tone by bronchodilator drugs and modulating pulmonary inflammation with inhaled corticosteroids or the phosphodiesterase type 4 inhibitor roflumilast. Both approaches can improve lung function, as shown in recent trials of combined treatment,1,2 whereas evidence of a reduction of mortality3 and cardiac events4 is less consistent. However, at best, these drugs decrease the effect of COPD on health status, exercise capacity, and exacerbation frequency leaving the patients feeling better but not completely well. Modulating inflammation more effectively has been a particular target for COPD research. Data suggest that inhaled corticosteroids combined with longacting β-agonists or use of a phosphodiesterase type 4 inhibitor can decrease inflammatory cell infiltration in patients with COPD.5 Several other drugs that modulate anti-inflammatory pathways have been investigated and inhibition of the p38 mitogen-activated kinase (MAPK) is particularly promising according to evidence from in vitro studies. This pathway involves phosphorylation of several proteins involved in the generation of inflammatory cytokines. MAPK is a good
target because it is involved in multiple inflammatory pathways and might have a role in modulation of systemic inflammation, which occurs in some patients with COPD.6 Data from a 6-week study7 of a p38 MAPK inhibitor for treatment of patients defined as having moderate disease by spirometry reported an increase in forced expiratory volume in 1 s (FEV1) of 86–92 mL in the treated group. However, these data should be treated with caution, not least because of the modest size of the change but also because patients with less severe disease show a greater capacity to respond spirometrically to treatment interventions.8 A more robust test of the benefits of this type of antiinflammatory drug would involve more patients with more severe disease studied for longer, together with relevant symptomatic endpoints. In the Lancet Respiratory Medicine Henrik Watz and colleagues9 report the results of such a trial. They tested three doses (2·5 mg, 7·5 mg, and 15 mg twice daily) of the oral p38 MAPK antagonist losmapimod compared with placebo. They assessed the effects of the drug on patients with COPD (mean FEV1 postbronchodilator roughly 45% of that predicted) and measured lung function, health status by St George’s Respiratory Questionnaire (SGRQ), and exacerbations. The primary outcome was the difference in 6 min walking distance, which the investigators reasoned would be an integrated measure of the effect of COPD on patients and the response to treatment. www.thelancet.com/respiratory Vol 2 January 2014
Comment
The difference in 6 min walking distance between the placebo group and treatment groups was not significant for any of the doses: –6·7 m (95% CI –18·2 to 4·9) for losmapimod 2·5 mg, –4·7 m (–16·1 to 6·8) for losmapimod 7·5 mg, and –3·4 m (–15·1 to 8·2) for losmapimod 15 mg. Nor was the change in FEV1 at week 24 significantly different between groups, although small but significant differences in lung function were present at week 12 for the 15 mg dose. The drug was well tolerated, although rather more patients taking losmapimod complained of pruritus than did those taking placebo. Health status was somewhat better and fewer people had exacerbations in the losmapimod groups but these differences were a far from statistically significant, perhaps because only 20% of participants reported frequent exacerbations before study entry. With hindsight, the choice of walking distance as the primary outcome measure was unfortunate. Exercise capacity of patients with COPD is affected by many variables, especially disordered static and dynamic lung mechanics, cardiac function, peripheral muscle strength, and previous levels of daily activity. It is unlikely that any drug that does not directly affect one of these processes would change an integrated measurement like walking distance. Similar disappointing data about the effect of another antiinflammatory phosphodiesterase type 4 inhibitor— roflumilast—on exercise capacity have been published.10 In contrast to losmapimod, roflumilast reduces exacerbations in patients prone to these events11 and such an effect may be true of this class of drug as well. So, what does this well done but negative trial tell us about new drugs for COPD? First, any anti-inflammatory drug is unlikely to have a major effect on outcomes like exercise performance or breathlessness unless it modifies resting lung function at least as much as a bronchodilator. Second, choosing the correct endpoint is crucial when planning proof-of-concept and dose-ranging trials, which were combined in this case. Third, changes in anti-inflammatory markers such as fibrinogen—which was assessed by Watz and coworkers and was decreased in the treatment groups— do not translate readily into a clinically measureable
www.thelancet.com/respiratory Vol 2 January 2014
improvement detectable by present methods of assessment. Finally, exacerbations remain the most tractable outcome for anti-inflammatory treatment. Investigation of drugs that decrease less severe events— eg, combined bronchodilators—might give a better proof of concept trial to determine the clinical effect rather than studying endpoints that are easier to measure but less likely to be modified by treatment. We are still exploring the best options for COPD research but we need the courage not to abandon potentially valuable treatments because we took the wrong path. Only if we show this courage will we reach our goal of better patient care. Peter M A Calverley Clinical Science Centre, University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, UK [email protected] I have advised on the design and conduct of clinical trials done by GlaxoSmithKline and received honoraria for this work and for speaking at meetings supported by GlaxoSmithKline. I have also worked in a similar capacity for AstraZeneca, Boehringer Ingelheim, Novartis, and Nycomed/Takeda. 1
2
3
4 5
6
7
8
9
10 11
Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013; 1: 210–23. Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013; 1: 199–209. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–89. Calverley PM, Anderson JA, Celli B, et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax 2010; 65: 719–25. Gamble E, Grootendorst DC, Brightling CE, et al. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168: 976–82. Agusti A, Edwards LD, Rennard SI, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One 2012; 7: e37483. MacNee W, Allan RJ, Jones I, De Salvo MC, Tan LF. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax 2013; 68: 738–45. Albert P, Agusti A, Edwards L, et al. Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease. Thorax 2012; 67: 701–08. Watz H, Barnacle H, Hartley BF, Chan R. Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; published online Dec 5. http://dx.doi.org/10.1016/ S2213-2600(13)70200-5. O’Donnell DE, Bredenbroker D, Brose M, Webb KA. Physiological effects of roflumilast at rest and during exercise in COPD. Eur Resp J 2012; 39: 1104–12. Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the COPD frequent exacerbator phenotype. Chest 2013; 143: 1302–11.
7
Magnus P Ekström
5
Department of Clinical Sciences, Division of Respiratory Medicine and Allergology, Lund University, Lund, Sweden, and Department of Medicine, Blekinge Hospital, Karlskrona, Sweden [email protected]
6
I declare that I have no conflicts of interest. 1
2 3
4
Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095–128. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS medicine 2006; 3: e442. López-Campos JL, Ruiz-Ramos M, Soriano JB. Mortality trends in chronic obstructive pulmonary disease in Europe, 1994–2010: a joinpoint regression analysis. Lancet Respir Med 2013; Dec 6. http://dx.doi. org/10.1016/S2213-2600(13)70232-7. Moriyama I, Loy R, Robb-Smith A. History of the statistical classification of diseases and causes of death. Hyattsville, MD, USA: National Center for Health Statistics. 2011.
7 8
9
10
WHO. Manual of the International Statistical Classification of Diseases and Health Related Problems. 10th revision. Geneva, Switzerland: World Health Organization; 1992. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012; 380: 37–43. Jensen HH, Godtfredsen NS, Lange P, Vestbo J. Potential misclassification of causes of death from COPD. Eur Respir J 2006; 28: 781–85. Rothman KJ, Greenland S, Poole C, Lash TL. Rothman KJ, Greenland S, Lash TL, eds. Modern epidemiology. Philadelphia: Lippincott Williams and Wilkins, 2008: 5–31. Mladovsky P, Allin S, Masseria C, Hernández-Quevedo C, McDaid D, Mossialos E. Health in the European Union: trends and analysis. Observatory studies series, no 19. Copenhagen, Denmark: World Health Organization, European Observatory on Health Systems and Policies, 2009. Pirie K, Peto R, Reeves GK, Green J, Beral V. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 2013; 381: 133–41.
Astier/BSIP/Science Photo Library
New treatments for COPD: many miles still to go
Published Online December 5, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70242-X See Articles page 63
6
Primary and secondary preventive measures are of enormous importance for management of chronic obstructive pulmonary disease (COPD), but the residual disability associated with established COPD has led to much research on new ways to treat this intractable condition. At present, treatment focuses on decreasing airway smooth-muscle tone by bronchodilator drugs and modulating pulmonary inflammation with inhaled corticosteroids or the phosphodiesterase type 4 inhibitor roflumilast. Both approaches can improve lung function, as shown in recent trials of combined treatment,1,2 whereas evidence of a reduction of mortality3 and cardiac events4 is less consistent. However, at best, these drugs decrease the effect of COPD on health status, exercise capacity, and exacerbation frequency leaving the patients feeling better but not completely well. Modulating inflammation more effectively has been a particular target for COPD research. Data suggest that inhaled corticosteroids combined with longacting β-agonists or use of a phosphodiesterase type 4 inhibitor can decrease inflammatory cell infiltration in patients with COPD.5 Several other drugs that modulate anti-inflammatory pathways have been investigated and inhibition of the p38 mitogen-activated kinase (MAPK) is particularly promising according to evidence from in vitro studies. This pathway involves phosphorylation of several proteins involved in the generation of inflammatory cytokines. MAPK is a good
target because it is involved in multiple inflammatory pathways and might have a role in modulation of systemic inflammation, which occurs in some patients with COPD.6 Data from a 6-week study7 of a p38 MAPK inhibitor for treatment of patients defined as having moderate disease by spirometry reported an increase in forced expiratory volume in 1 s (FEV1) of 86–92 mL in the treated group. However, these data should be treated with caution, not least because of the modest size of the change but also because patients with less severe disease show a greater capacity to respond spirometrically to treatment interventions.8 A more robust test of the benefits of this type of antiinflammatory drug would involve more patients with more severe disease studied for longer, together with relevant symptomatic endpoints. In the Lancet Respiratory Medicine Henrik Watz and colleagues9 report the results of such a trial. They tested three doses (2·5 mg, 7·5 mg, and 15 mg twice daily) of the oral p38 MAPK antagonist losmapimod compared with placebo. They assessed the effects of the drug on patients with COPD (mean FEV1 postbronchodilator roughly 45% of that predicted) and measured lung function, health status by St George’s Respiratory Questionnaire (SGRQ), and exacerbations. The primary outcome was the difference in 6 min walking distance, which the investigators reasoned would be an integrated measure of the effect of COPD on patients and the response to treatment. www.thelancet.com/respiratory Vol 2 January 2014
Comment
The difference in 6 min walking distance between the placebo group and treatment groups was not significant for any of the doses: –6·7 m (95% CI –18·2 to 4·9) for losmapimod 2·5 mg, –4·7 m (–16·1 to 6·8) for losmapimod 7·5 mg, and –3·4 m (–15·1 to 8·2) for losmapimod 15 mg. Nor was the change in FEV1 at week 24 significantly different between groups, although small but significant differences in lung function were present at week 12 for the 15 mg dose. The drug was well tolerated, although rather more patients taking losmapimod complained of pruritus than did those taking placebo. Health status was somewhat better and fewer people had exacerbations in the losmapimod groups but these differences were a far from statistically significant, perhaps because only 20% of participants reported frequent exacerbations before study entry. With hindsight, the choice of walking distance as the primary outcome measure was unfortunate. Exercise capacity of patients with COPD is affected by many variables, especially disordered static and dynamic lung mechanics, cardiac function, peripheral muscle strength, and previous levels of daily activity. It is unlikely that any drug that does not directly affect one of these processes would change an integrated measurement like walking distance. Similar disappointing data about the effect of another antiinflammatory phosphodiesterase type 4 inhibitor— roflumilast—on exercise capacity have been published.10 In contrast to losmapimod, roflumilast reduces exacerbations in patients prone to these events11 and such an effect may be true of this class of drug as well. So, what does this well done but negative trial tell us about new drugs for COPD? First, any anti-inflammatory drug is unlikely to have a major effect on outcomes like exercise performance or breathlessness unless it modifies resting lung function at least as much as a bronchodilator. Second, choosing the correct endpoint is crucial when planning proof-of-concept and dose-ranging trials, which were combined in this case. Third, changes in anti-inflammatory markers such as fibrinogen—which was assessed by Watz and coworkers and was decreased in the treatment groups— do not translate readily into a clinically measureable
www.thelancet.com/respiratory Vol 2 January 2014
improvement detectable by present methods of assessment. Finally, exacerbations remain the most tractable outcome for anti-inflammatory treatment. Investigation of drugs that decrease less severe events— eg, combined bronchodilators—might give a better proof of concept trial to determine the clinical effect rather than studying endpoints that are easier to measure but less likely to be modified by treatment. We are still exploring the best options for COPD research but we need the courage not to abandon potentially valuable treatments because we took the wrong path. Only if we show this courage will we reach our goal of better patient care. Peter M A Calverley Clinical Science Centre, University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, UK [email protected] I have advised on the design and conduct of clinical trials done by GlaxoSmithKline and received honoraria for this work and for speaking at meetings supported by GlaxoSmithKline. I have also worked in a similar capacity for AstraZeneca, Boehringer Ingelheim, Novartis, and Nycomed/Takeda. 1
2
3
4 5
6
7
8
9
10 11
Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013; 1: 210–23. Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013; 1: 199–209. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–89. Calverley PM, Anderson JA, Celli B, et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax 2010; 65: 719–25. Gamble E, Grootendorst DC, Brightling CE, et al. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 168: 976–82. Agusti A, Edwards LD, Rennard SI, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One 2012; 7: e37483. MacNee W, Allan RJ, Jones I, De Salvo MC, Tan LF. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax 2013; 68: 738–45. Albert P, Agusti A, Edwards L, et al. Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease. Thorax 2012; 67: 701–08. Watz H, Barnacle H, Hartley BF, Chan R. Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; published online Dec 5. http://dx.doi.org/10.1016/ S2213-2600(13)70200-5. O’Donnell DE, Bredenbroker D, Brose M, Webb KA. Physiological effects of roflumilast at rest and during exercise in COPD. Eur Resp J 2012; 39: 1104–12. Wedzicha JA, Rabe KF, Martinez FJ, et al. Efficacy of roflumilast in the COPD frequent exacerbator phenotype. Chest 2013; 143: 1302–11.
7
