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ERS Annual Congress Vienna

15 September 2012

Postgraduate Course 9 Progress on the treatment of COPD

Saturday, 1 September 2012 09:3013:00 Room: Lehar 3-4

Changes in the anti-inflammatory treatment of COPD

Prof. Peter J. Barnes Head of Respiratory Medicine Imperial College London Airway Disease National Heart & Lung Institute Dovehouse St SW3 6LY London United Kingdom p.j.barnes@imperial.ac.uk Introduction
COPD is associated with chronic inflammation affecting peripheral airways and lung parenchyma which is likely to be responsible for progressive fibrosis of small airways (chronic obstructive bronchiolitis) and alveolar destruction (emphysema) (1-3). This inflammatory response appears to progress with disease progression and flares up during exacerbations. Since this inflammation is likely to underlie disease progression, exacerbations and symptoms there is a strong case for the development of effective anti-inflammatory treatments. Furthermore, comorbidities of COPD may be due to systemic inflammation as a result of spill-over of peripheral lung inflammation into the systemic circulation, so effective treatment of lung inflammation may reduce the risk and improve comorbidities, including the risk of lung cancer (4; 5). Long-acting bronchodilators (anticholinergics, 2-agonists and their combination) are the most effective current treatment for COPD patients but do not affect disease progression or reduce mortality. As far as we know, these long-acting bronchodilators do not have significant antiinflammatory effects in COPD patients. Although corticosteroids are very effective in suppressing airway inflammation in patients with asthma, they are poorly effective in patients with COPD.

COPD inflammation is corticosteroid-resistant

Inflammation in COPD is largely corticosteroid-resistant and the molecular basis for this resistance is now understood (6). Corticosteroids switch off activated inflammatory diseases through the recruitment of histone deacetylase-2 (HDAC2), which is markedly reduced in COPD cells as a result of oxidative stress (7). High doses of inhaled and oral corticosteroids fail to reduce inflammatory cells and mediators in the sputum and airways of COPD patients (8-11). The exception is patients with COPD who have increased sputum eosinophils and these patients are likely to have coexistent asthma (overlap syndrome) (12). Inhaled corticosteroids (ICS) are now very widely used in high doses in the management of COPD patients. In sharp contrast to asthma, ICS provide little or no clinical benefit in COPD patients and may have long-term detrimental effects. High dose ICS are used in over 80% of patients with diagnosed COPD, although even following the guidelines that stipulate that ICS should be used only in patients with FEV1 <50% predicted with two or more exacerbations a year, which would amount to less than 20% of patients. High doses of ICS fail to reduce disease progression or mortality, even when combined with a longacting 2-agonist (LABA) (13; 14). Several large trials have demonstrated that ICS reduce exacerbations by ~20%, particularly in patients with more severe disease, but these studies are confounded by poor trial design and more appropriate analysis shows no benefit (15). Indeed, the benefit of combination inhalers seems to be largely explained by the effect of the LABA and longacting bronchodilators, including tiotropium bromide, provide matched benefits in reducing exacerbations, which do not appear to be additive between treatments.

29

There is now increasing evidence that high doses of ICS may have detrimental systemic side effects and may increase the risk of pneumonia in COPD patients (16). COPD patients are at particularly high risk for the development of systemic side effects of corticosteroids such as osteoporosis, cataracts, glaucoma and diabetes, as they are already at high risk for these diseases. This suggests that in the future the use of high dose inhaled corticosteroids should be far more restricted and perhaps only used in patients with eosinophilic inflammation, as evidenced by increased sputum eosinophils or exhaled nitric oxide.

Theophylline
Although theophylline used to be considered as a bronchodilator, in lower doses it has antiinflammatory effects in COPD patients (17), (18;19). Theophylline withdrawal increases symptoms in COPD patients (20) and low dose theophylline reduces exacerbations by ~50% (21). In addition to its anti-inflammatory effects theophylline is able to reverse corticosteroid resistance in COPD cells and in smoking models of COPD in mice by increasing HDAC2 (22-24); this is mediated through inhibition of oxidant-activate phosphoinositide-3-kinase- (PI3K) (24-26). In addition, low dose theophylline has a greater anti-inflammatory effect when added to inhaled corticosteroids than when given alone, suggesting that it may reverse corticosteroids resistance in COPD patients (27). Clinical trials of low dose theophylline combined with either inhaled or low dose oral corticosteroid are now in progress. Low dose theophylline also increases recovery from acute exacerbations and this is associated with increased HDAC activity in alveolar macrophages and a greater reduction in inflammatory mediators and neutrophils in sputum (28).

Macrolide antibiotics
Macrolides (erythromycin, azithromycin) reduce exacerbations in COPD patients (29; 30), which could be explained by their antibiotic effect or to an anti-inflammatory effect of macrolides. So far there is no evidence for any anti-inflammatory effect in COPD patients, but in vitro studies indicate that macrolides may increase HDAC2 and this reverse corticosteroid resistance.

Phosphodiesterase-4 inhibitors
The PDE4 inhibitor roflumilast is the first anti-inflammatory treatment that has been marketed specifically for COPD patients. PDE4 is the predominant phosphodiesterase expressed in neutrophils, T-cells and macrophages, suggesting that PDE4 inhibitors would be effective in treating inflammation in COPD (31; 32). PDE4 inhibitors reduce neutrophil chemotaxis, recruitment and activation, inhibit the activation of CD4+ and CD8+ T cells and inhibit monocyte chemotaxis. In addition, PDE4 inhibitors have effects on structural cells and inhibit mucus secretion, improve ciliary function and inhibit fibroblasts, Roflumilast prevents the development of emphysema in mice chronically exposed to cigarette smoke (33). In COPD patients, roflumilast reduces the numbers of neutrophils (by 36%) and CXCL8 concentrations in sputum (34). However, early clinical trials of roflumilast in COPD patients were disappointing, but analysis of the trial data identified that patients with severe disease (FEV1<50% predicted), frequent exacerbations (>2/year) and mucus hypersecretion (chronic bronchitis). In clinical trials of patients with these characteristics, roflumilast (500 g once daily) given over 12 months improves lung function in COPD patients (FEV1 increase ~50ml) and reduces exacerbations (by ~15%) (35). It is effective when added to long-acting bronchodilators (tiotropium or salmeterol) (36), so may be used as an additional treatment in patients with severe disease who have frequent exacerbations. A post-hoc analysis of roflumilast trials show that it is also effective when added to inhaled corticosteroids (37). The improvement in lung function in COPD patients cannot be explained by bronchodilatation as there is no immediate improvement in FEV1, so is presumably explained by the anti-inflammatory effects of the drug. The relatively small clinical efficacy of roflumilast (and other PDE4 inhibitors) reflects the fact that the dose after oral administration is limited by side effects, such as nausea, diarrhoea and headaches, which are mediated by PDE4 inhibition. Improving the therapeutic ratio of PDE4 inhibitors is

30

therefore now a major aim in drug development. The most obvious way to overcome the side effects of systemic PDE4 inhibitors is to deliver by inhalation and several inhaled PDE4 inhibitors have now been developed for the treatment of COPD. A PDE4 inhibitor UK-500,001 given twice daily as a dry powder inhaler had no effect on lung function or symptoms after 6 weeks of therapy in patients with a moderate-severe COPD (mean FEV1 ~50% predicted) and there were no adverse effects except at the highest dose delivered (38). Another potent inhaled PDE4 inhibitor GSK256066 that has antiinflammatory effects in animal models of pulmonary inflammation and a reduced likelihood of causing vomiting (39) is currently undergoing trials in COPD patients. Another approach to reducing side effects is to develop isoenzyme-selective inhibitors. In mice with PDE4 isoenzyme knock-out PDE4D inhibition appears to account for behaviour associated with nausea, whereas PDE4B inhibition may account for the anti-inflammatory effects, so that PDE4B selective inhibitors may be better tolerated. Selective PDE4B inhibitors have now been synthesised and these are in development for clinical studies (40). PDE7A is also expressed in the same inflammatory cells as PDE4, so inhibition of PDE7 may be beneficial in COPD patients. A selective PDE7 inhibitor has only a small anti-inflammatory effect in vitro, but potentiates the anti-inflammatory effects of a PDE4 inhibitor, suggesting that a combined PDE4/7 inhibitor may be a way of reducing side effects (41; 42). A combination of nebulised antisense oligonucleotides to block PDE4B and PDE7A is very effective at inhibiting cigarette smokeinduced inflammation in mice (43). PDE3 inhibitors, in contrast to PDE4 inhibitors, relax airway smooth muscle so that dual PDE3/4 inhibitors may combine bronchodilatation with anti-inflammatory activity (44). However, there are concerns about the potential cardiovascular toxicity of PDE3 inhibition so these drugs will have to be given by inhalation.

New anti-inflammatory treatments

There is a pressing need to discover new and safe anti-inflammatory therapies for COPD and several drugs are currently in development (45; 46).

CXCR2 antagonists
Promising drugs include CXCR2 antagonists, which block a key chemokine receptor involved in the recruitment of neutrophils and monocytes in COPD (47). One such antagonist, navarixin, reduces sputum neutrophils in COPD patients by almost 50%, but a reduction in circulating neutrophils may be a problem in some patients (48).

p38 MAPK inhibitors

p38 MAP kinase inhibitors are also promising, based on the finding that p38 MAPK is activated in COPD lungs and macrophages (49). Several small molecule inhibitors of p38 MAPK have been developed for oral administration and have previously been tested in rheumatoid arthritis. A potent inhibitor of p38 isoform, SD-282, is effective in inhibiting TNF- release from human lung macrophages in vitro (50) and in suppressing inflammation in cigarette smoke induced pulmonary inflammation in mice, which is corticosteroid-resistant (51). Over 20 oral small molecule p38 MAPK inhibitors have entered clinical trials (for rheumatoid arthritis and inflammatory bowel disease), but none of these drugs have reached phase III studies because of side effects (initial compounds has CNS side effects) and toxicity, as well as poor or transient efficacy (52). In a recent study in patients with COPD an oral p38 MAPK inhibitor (losmapimod) was well tolerated over a 12 week period, although there were no significant effects on lung function or on sputum neutrophils (53). There was a small effect on circulating fibrinogen but not on circulating cytokines or CRP. This may indicate underdosing of the drug, although circulating levels of phosphorylated heat shock protein (HSP)-27, a downstream target of p38 MAPK, were reduced by approximately 40% indicating a degree of enzyme inhibition. It may be possible to achieve higher levels of inhibition using inhaled p38 MAPK inhibitors. An inhaled p38 antisense oligonucleotide was effective in suppressing allergic inflammation on mice, indicating the feasibility of local p38 MAPK inhibition (54). Several potent and

31

selective inhaled p38 MAPK inhibitors, such as PF-03715455 and GSK610677) are now in clinical development for COPD (55).

Other anti-inflammatory drugs

Several other classes of small molecule kinase inhibitors, including IKK (NF-B), JAK and PI3K inhibitors are also in development, as well as blocking antibodies to cytokines implicated in the pathogenesis of COPD, including IL-1 (and NLRP3 inflammasome inhibitors), IL-6, IL-17, IL-18 and IL-23.

Reversing corticosteroid resistance in COPD

As discussed above, corticosteroids resistance in COPD may be explained by a reduction in HDAC2 as a result of inhibition of PI3K which has been activated by theophylline. This may be achieved with theophylline, but also with other drugs, including nortriptyline (56), curcumin (57) and selective PI3K inhibitors (24; 25). Inhaled Pi3K inhibitors are currently in clinical development. As oxidative stress is responsible for reduced oxidative stress via PI3K inhibition, as well as tyrosine nitration and cysteine nitrosylation of HDAC2 protein, then antioxidants should also be effective in reversing corticosteroid resistance in COPD. Current antioxidants, such as N-acetyl cysteine are poorly effective and they are inactated by oxidative stress (58), so that more effective and stable antioxidants are now needed. The most promising approach is activators of the transcription factor Nrf2, particularly since Nrf2 function is impaired in COPD cells (59; 60). An Nrf2 activator sulforaphane increases HDAC2 and reverses corticosteroid resistance in COPD cells (61). Clinical trials with sulforaphane are now underway but there is a search for more selective and less toxic Nrf2 activators.

References
1. Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol 2009; 4:435-59.:435-459. 2. McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG et al. Smallairway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011; 365(17):1567-1575. 3. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Immunol Rev 2008; 8:183-192. 4. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009; 33(5):1165-1185. 5. Barnes PJ. Chronic obstructive pulmonary disease: effects beyond the lungs. PLoS Med 2010; 7(3):e1000220. 6. Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet 2009; 342:1905-1917. 7. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Ann Rev Physiol 2009; 71:451464. 8. Keatings VM, Jatakanon A, Worsdell YM, Barnes PJ. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997; 155:542-548. 9. Culpitt SV, Nightingale JA, Barnes PJ. Effect of high dose inhaled steroid on cells, cytokines and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:1635-1639. 10. Hattotuwa KL, Gizycki MJ, Ansari TW, Jeffery PK, Barnes NC. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am J Respir Crit Care Med 2002; 165(12):1592-1596. 11. Loppow D, Schleiss MB, Kanniess F, Taube C, Jorres RA, Magnussen H. In patients with chronic bronchitis a four week trial with inhaled steroids does not attenuate airway inflammation. Respir Med 2001; 95(2):115-121. 12. Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2000; 356(9240):1480-1485.

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13. Yang IA, Fong KM, Sim EH, Black PN, Lasserson TJ. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007;(2):CD002991. 14. Barnes PJ. Inhaled corticosteroids in COPD: a controversy. Respiration 2010; 80:89-95. 15. Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J 2009; 34(1):13-16. 16. Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med 2009; 169(3):219-229. 17. Culpitt S, Maziak W, Loukides S, Keller A, Barnes PJ. Effect of theophylline on induced sputum inflammatory indices in COPD patients. Am J Respir Crit Care Med 1997; 157:A797. 18. Kanehara M, Yokoyama A, Tomoda Y, Shiota N, Iwamoto H, Ishikawa N et al. Antiinflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2008; 21(6):874-878. 19. Barnes PJ. Theophylline for COPD. Thorax 2006; 61(9):742-743. 20. Kirsten DK, Wegner RE, Jorres RA, Magnussen H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993; 104(4):1101-1107. 21. Zhou Y, Wang X, Zeng X, Qiu R, Xie J, Liu S et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology 2006; 11(5):603-610. 22. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM et al. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A 2002; 99(13):8921-8926. 23. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 2004; 200:689-695. 24. To Y, Ito K, Kizawa Y, Failla M, Ito M, Kusama T et al. Targeting phosphoinositide-3kinase- with theophylline reverses corticosteroid insensitivity in COPD. Am J Resp Crit Care Med 2010; 182:897-904. 25. Marwick JA, Caramori G, Stevenson CC, Casolari P, Jazrawi E, Barnes PJ et al. Inhibition of PI3K restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 2009; 179:542-548. 26. Marwick JA, Wallis G, Meja K, Kuster B, Bouwmeester T, Chakravarty P et al. Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun 2008; 377:797-802. 27. Ford PA, Durham AL, Russell REK, Gordon F, Adcock IM, Barnes PJ. Treatment effects of low dose theophylline combined with an inhaled corticosteroid in COPD. Chest 2010; 137:1338-1344. 28. Cosio BG, Iglesias A, Rios A, Noguera A, Sala E, Ito K et al. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of chronic obstructive pulmonary disease. Thorax 2009; 64:424-429. 29. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008; 178(11):1139-1147. 30. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Jr., Criner GJ et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365(8):689-698. 31. Diamant Z, Spina D. PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease. Pulm Pharmacol Ther 2011; 24(4):353-360. 32. Hatzelmann A, Morcillo EJ, Lungarella G, Adnot S, Sanjar S, Beume R et al. The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2010; 23(4):235-256. 33. Martorana PA, Beume R, Lucattelli M, Wollin L, Lungarella G. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 2005; 172(7):848-853.

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34. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 62(12):1081-1087. 35. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374(9691):685-694. 36. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374(9691):695-703. 37. Rennard SI, Calverley PM, Goehring UM, Bredenbroker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD. Respir Res 2011; 12:18.:18. 38. Vestbo J, Tan L, Atkinson G, Ward J. A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD. Eur Respir J 2009; 33(5):1039-1044. 39. Nials AT, Tralau-Stewart CJ, Gascoigne MH, Ball DI, Ranshaw LE, Knowles RG. In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor. J Pharmacol Exp Ther 2011; 337(1):137-144. 40. Naganuma K, Omura A, Maekawara N, Saitoh M, Ohkawa N, Kubota T et al. Discovery of selective PDE4B inhibitors. Bioorg Med Chem Lett 2009; 19(12):3174-3176. 41. Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG et al. Discovery of BRL 50481, a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages and CD8+ T-lymphocytes. Mol Pharmacol 2004; 66:1679-1689. 42. Giembycz MA. Phosphodiesterase-4: selective and dual-specificity inhibitors for the therapy of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005; 2(4):326-333. 43. Fortin M, D'Anjou H, Higgins ME, Gougeon J, Aube P, Moktefi K et al. A multi-target antisense approach against PDE4 and PDE7 reduces smoke-induced lung inflammation in mice. Respir Res 2009; 10:39. 44. Banner KH, Press NJ. Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol 2009; 157(6):892-906. 45. Barnes PJ. New therapies for chronic obstructive pulmonary disease. Med Princ Pract 2010; 19:330-338. 46. Barnes PJ. New anti-inflammatory treatmentsd for COPD. Nat Rev Drug Discov 2012. 47. Donnelly LE, Barnes PJ. Chemokine receptor CXCR2 antagonism to prevent airway inflammation. Drugs Future 2011; 36:465-472. 48. Magnussen H, Watz H, Sauer M, Khanskaya I, Gann L, Stryszak P et al. Safety and efficacy of SCH527123, a novel CXCR2 antagonist, in patients with COPD. Eur Resp J 2010; 36(suppl):38S. 49. Renda T, Baraldo S, Pelaia G, Bazzan E, Turato G, Papi A et al. Increased activation of p38 MAPK in COPD. Eur Respir J 2008; 31(1):62-69. 50. Smith SJ, Fenwick PS, Nicholson AG, Kirschenbaum F, Finney-Hayward TK, Higgins LS et al. Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol 2006; 149:393-404. 51. Medicherla S, Fitzgerald M, Spicer D, Woodman P, Ma JY, Kapoun AM et al. p38 selective MAP kinase inhibitor, SD-282, reduces inflammation in a sub-chronic model of tobacco smoke-induced airway inflammation. J Pharmacol Exp Ther 2007; 324:921-929. 52. Hammaker D, Firestein GS. "Go upstream, young man": lessons learned from the p38 saga. Ann Rheum Dis 2010; 69 Suppl 1:i77-i82. 53. Lomas DA, Lipson DA, Miller BE, Willits L, Keene O, Barnacle H et al. An Oral Inhibitor of p38 MAP Kinase Reduces Plasma Fibrinogen in Patients With Chronic Obstructive Pulmonary Disease. J Clin Pharmacol 2011. 54. Duan W, Chan JH, McKay K, Crosby JR, Choo HH, Leung BP et al. Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med 2005; 171(6):571-578.

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55. Millan DS. What is the potential for inhaled p38 inhibitors in the treatment of chronic obstructive pulmonary disease? Future Med Chem 2011; 3(13):1635-1645. 56. Mercado N, To Y, Ito K, Barnes PJ. Nortriptyline reverses corticosteroid insensitivity by inhibition of PI3K- . J Pharmacol Exp Ther 2011; 337:465-470. 57. Meja KK, Rajendrasozhan S, Adenuga D, Biswas SK, Sundar IK, Spooner G et al. Curcumin Restores Corticosteroid Function in Monocytes Exposed to Oxidants by Maintaining HDAC2. Am J Respir Cell Mol Biol 2008; 39:312-323. 58. Decramer M, Rutten-van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005; 365(9470):1552-1560. 59. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A et al. Decline in NRF2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am J Respir Crit Care Med 2008; 178:592-604. 60. Mercado N, Thimmulappa R, Thomas CM, Fenwick PS, Chana KK, Donnelly LE et al. Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. Biochem Biophys Res Commun 2011; 406:292-298. 61. Malhotra D, Thimmulappa RK, Mercado N, Ito K, Kombairaju P, Kumar S et al. Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J Clin Invest 2011;(121):4289-4302.

Evaluation
1. Which of these drugs have been shown to have anti-inflammatory effects in COPD? a. Tiotropium bromide b. Fluticasone propionate c. Theophylline d. Roflumilast e. Erythromycin 2. What are the effects of Inhaled corticosteroids in COPD patients? a. Reduce inflammation b. Reduce exacerbations c. Reduce disease progression d. Reduce mortality e. Increase pneumonia 3. Which of the following drugs have the potential to reverse corticosteroid resistance in COPD? a. Theophylline b. Roflumilast c. Tiotropium d. Nortriptyline e. Sulforaphane Please find all answers at the back of your handout materials.

35

CHANGES IN THE ANTI-INFLAMMATORY TREATMENT OF COPD

Peter Barnes FRS, FMedSci National Heart & Lung Institute Imperial College, London, UK
ERS PG Course: September 2012

Imperial College

Royal Brompton Hospital

AMPLIFICATION OF INFLAMMATION IN COPD

++++ +++ ++ + 0
Non-smokers Normal smokers Mild COPD Severe COPD Exacerbation

Inflammation

Neutrophils Macrophages Cytokines Mediators Proteases

What are the molecular mechanisms of amplification? Genetically determined? Epigenetic mechanisms?

CELLULAR MECHANISMS OF COPD

Barnes PJ: Nat Immunol 2008

COPD inflammation is corticosteroid-resistant (alternative anti-inflammatory treatments are needed)

36

COPD AND ASTHMA

COPD
Neutrophils Macrophages CD8+ cells Minimal AHR No atopy No steroid response ~10% Overlap syndrome

ASTHMA
Eosinophils Mast cells CD4+ cells AHR Atopy Steroid response

EX NO & SPUTUM EOS IN REVERSIBLE COPD

Reversible: >15% in FEV1 after b/d Exhaled NO Sputum eos

Papi A et al: AJRCCM 2000

LONG-TERM INHALED STEROIDS IN COPD

TRIAL n DURATION SEVERITY 3 yr 3 yr 3 yr mild mild moderate OUTCOME no effect no effect no effect no effect

Copenhagen City 290 EUROSCOP ISOLDE 1277 751

Lung Health 2 1116 3.5 yr moderate 1o outcome = decline in FEV1 over 3y Cochrane Review: >16,000 COPD patients No FEV1 decline (Yang IA et al 2007) No mortality

37

ICS AND COPD MORTALITY

TORCH STUDY

Calverley PM et al: NEJM 2007

INHALED CORTICOSTEROIDS IN COPD: SIDE EFFECTS

High doses used High risk of osteoporosis and fractures low mobility, poor nutrition, smoking, elderly Risk of cataracts Co-morbidity may be worsened diabetes, hypertension, peptic ulceration Increased risk of pneumonia, TB

TORCH STUDY: PNEUMONIA

25

Doctor-reported pneumonias
p < 0.001 vs placebo

Probability of event (%)

20 15 10 5 0

SALM/FP 19.6% FP 18.3% SALM 13.3% Placebo 12.3%

~6,000 patients

12

24

36

48 60 72 84 96 108 120 132 144 156 Time to event (weeks)

Crim C et al: ERJ 2009

38

TORCH STUDY: FACTORIAL ANALYSIS 2X2 Factorial Analysis

Yes (deaths) No (deaths) Crude RR 1.00 0.83 Adjusted RR 1.00` 0.83 (p=0.0043)

Fluticasone 439/3067 436/3045 Salmeterol 398/3054 477/3058

No interaction between FP and salmeterol: p=0.32 All of benefit provided by salmeterol

Suissa S et al: ERJ 2008

DESIGN FLAWS IN ICS TRIALS

ICS Prior ICS COPD Placebo

Reanalysis of OPTIMAL Trial

Aaron S et al: Ann Int Med 2007

Prior ICS users (n=335): No ICS users (n=114)

ICS exacerbations (HR 0.7, p=0.027)

Randomization
No Prior ICS ICS

ICS no exacerbations (HR1.11, p=0.68) Subsequent exacerbations: No effect of ICS in combined group (all effect due to 1st exacerbation)

Placebo

6 trials of ICS vs placebo: exacerbations with ICS Correlated with % patients on previous ICS
Suissa S et al: ERJ 2008

INHALED CORTICOSTEROIDS IN COPD

Treat associated asthma

(c.f. asthma)

(asthma and COPD may coexist in the same patient)

No significant effect on inflammation

No effect on progression of disease Reduction in severe exacerbations (small effect) Risk of adverse systemic effects (esp diabetes) Increased pneumonia, TB Expensive

39

INHALED CORTICOSTEROIDS IN COPD

Treat associated asthma

(asthma and COPD may coexist in the same patient)

No significant effect on inflammation (c.f. asthma) Inhaled corticosteroids recommended for patients with on severe diseaseof (FEV No effect progression disease 1<50% predicted) who have frequent exacerbations (>2/year) Reduction in severe exacerbations (small effect) <10% of patients (high dose ICS currently in >80%) Risk of adverse systemic effects (esp diabetes) The use of high dose inhaled steroids for COPD Increased pneumonia, needs to markedly reducedTB in the future Can we make steroids more effective? Expensive Are there alternative anti-inflammatory treatments?

EFFECT OF ORAL STEROID ON INDUCED SPUTUM INFLAMMATORY CELL PROFILE IN COPD

80 70 60 50 40 30 20 10 0 Neutrophils Eosinophils

COPD patients (n=8) 645.1yr; FEV1=48% predicted

FEV1=1.20L FEV1=1.27L FEV1=1.30L
Macrophages

Baseline
Keatings V et al: AJRCCM 1997

Placebo

(30mg daily x 14d)

Prednisolone

CYTOKINES IN INDUCED SPUTUM IN COPD: LACK OF EFFECT OF INHALED CORTICOSTEROID

COPD patients (n=14): age 65 1.1 yr; FEV1 = 35 1.3% Baseline
10 8 6 4 2 0

Placebo

Budesonide (800 g b.d.x 2 wk)

8

[IL-8 (nmol/mL)]

IL-8 IS THERE N.S. AN ACTIVE STEROID N.S. 6 RESISTANCE MECHANISM IN COPD?

4

TNF-

2 0

Keatings V et al: Am J Respir Crit Care Med 1997

40

REDUCED EFFECT OF CORTICOSTEROIDS IN COPD

Bronchoalveolar lavage macrophages
200

MIP-1 (ng/ml)

ALVEOLAR MACROPHAGES ARE STEROID-RESISTANT IN COPD (SIMILAR RESULTS WITH IL-8, MMP-9)

Non-smoker

COPD

100

NS LPS

10-10

10-8

10-6

NS

LPS

Dexamethasone (M)
Culpitt SV et al: Am J Respir Crit Care Med 2002

10-8M

Dex

AMPLIFICATION AND STEROID RESISTANCE

Cigarette smoke Oxidative stress

Corticosteroids

NF-B
Histone acetylation

Glucocorticoid receptor

HDAC2

Inflammatory genes
e.g. IL-8, MMP-9

Inflammation

AMPLIFICATION AND STEROID RESISTANCE

Cigarette smoke Oxidative stress

Corticosteroids

NF-B
Histone acetylation

Glucocorticoid receptor

HDAC2

Inflammatory genes
e.g. IL-8, MMP-9

Inflammation

41

AMPLIFICATION AND STEROID RESISTANCE

Cigarette smoke Oxidative stress

Ito K et al: N Engl J Med 2005

Inflammatory genes
e.g. IL-8, MMP-9

NF-B

Steroid resistance
HDAC2

Histone acetylation

Inflammation

REVERSAL OF CORTICOSTEROID RESISTANCE

Oxidative stress
Cell membrane

PI3K- P Akt P
HDAC2

Steroid resistance

REVERSAL OF CORTICOSTEROID RESISTANCE

Oxidative stress Antioxidants
Cell membrane

PI3K- P Akt Akt-1 P HDAC2 HDAC2 Reversal Steroid of steroid resistance resistance

THEOPHYLLINE PI3K- inhibitors

Cosio B et al: J Exp Med 2004

42

LOW DOSE THEOPHYLLINE IN COPD

Induced sputum Theophylline: 9.5 mg/L COPD patients: mean age 62 yr (n=25) FEV1 49% predicted
12

Neutrophils x106/ml)

2.5 2 1.5 1 0.5 0 0

Neutrophils
p<0.001

Interleukin-8

IL-8 (ng/mL)

P<0.001

Placebo

4 wk

4 weeks

Culpitt S et al: AJRCCM 2002

Theophylline

Placebo

Theophylline

4 weeks

ANTI-INFLAMMATORY EFFECT OF THEOPHYLLINE

COPD patients: FEV1 53% predicted, n=16
3

Theophylline
(plasma conc 6mg/ml)

Inhaled steroid N.S.

P<0.01

Pcbo Theo Hirano T et al: Thorax 2006

Pcbo

FP

THEOPHYLLINE 3-NITROTYROSINE
COPD patients: FEV1 53% predicted, n=16
3

NS

p<0.01
1

Theophylline 400 mg/day x 4wk

Fluticasone 400g/day x 4 wk

Hirano T et al: Thorax 2006

43

COPD PATIENTS: CORTICOSTEROIDS + THEOPHYLLINE

Fluticasone Placebo 0 4 F+T combination Theophylline 8 wk Induced sputum Plasma theophylline~8mg/L

n=30

Sputum neutrophils

Sputum neutrophil elastase

150

Neutrophils (%)

100

75

HNE (g/mL)

10 3

50

p<0.01
25

p<0.01 Baseline Ford P et al: Chest 2010

0

FP+T

Baseline

FP&T

EFFECT OF A MACROLIDE IN COPD

Time to first exacerbation
COPD: n=109, mean FEV1 50%, 1 year Erythromycin (~50%)

Placebo

No difference in: Sputum IL-6 L-8 MPO Serum CRP IL-6

Seemungal T et al: Am J Respir Crit Care Med 2008

EFFECT OF A MACROLIDE IN COPD

Proportion exacerbation free (27%)

Albert RK et al: NEJM 2012

Azithromycin (n=558)

Placebo (n=559)

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PDE4 INHIBITORS IN COPD

Cigarette smoke PDE4 inhibitors (and other irritants)

Epithelial cells TGF- CTG

CD8+ lymphocyte

Alveolar macrophage
Chemotactic factors

Fibroblast

Neutrophil

PROTEASES
Fibrosis Alveolar wall destruction (Sm airways) (Emphysema)

Monocyte Neutrophil elastase Cathepsins Matrix metalloproteinases

Mucus hypersecretion (Chronic bronchitis)

ANTI-INFLAMMATORY EFFECT OF ROFLUMILAST COPD patients: FEV1 61% predicted, n=38

Grootendorst DC et al. Thorax 2007

EFFECT OF ROFLUMILAST IN COPD

COPD patients: FEV1 <50%pred, frequent exacerbations, mucus hypersecretion

Calverley PMA et al: Lancet 2009

Add-on 40

post-FEV1

Little p<0.0001

effect on symptoms =No 55 ml effect on QoL n=1453 nausea, headaches, diarrhoea Weight loss

therapy for severe COPD with severe exacerbations, chronic bronchitis n=1500 Alternative to ICS? -4

45

PDE 4 INHIBITORS: SIDE EFFECTS

Nausea and vomiting Diarrhoea Headaches

(N.B. side effects of theophylline)

Central or peripheral effect? Subtype selective inhibitors?

- human PDE4A, 4B, 4C, 4D
Anti-inflammatory Nausea

PDE 4 INHIBITORS: SIDE EFFECTS

Nausea and vomiting Diarrhoea Headaches

(N.B. side effects of theophylline)

Central or peripheral effect? Subtype selective inhibitors? Cilomilast: 4D selective

- human PDE4A, 4B, 4C, 4D

Anti-inflammatory Nausea inhaled PDE4i Inhaled PDE4 inhibitors 3 have failed

Roflumilast: non-selective 4B-selective: now in development

NEW ANTI-INFLAMMATORY TREATMENTS

Specific mediator antagonists/inhibitors Anti-TNF: ineffective Anti-IL-8: ineffective LTB4 antagonists: ineffective CXCR2 antagonists: in clinical development

Broad spectrum anti-inflammatory treatments PDE4 inhibitors: roflumilast effective NF-B inhibitors: so far ineffective and toxic p38 MAP kinase inhibitors: in clinical development pan-JAK inhibitors: in clinical development PI3 kinase-/ inhibitors: in clinical development

46

CXCR2 ANTAGONIST IN COPD

CXCL1 CXCL8 CXCL5 (GRO-) (IL-8) (ENA-78) Navarixin (SCH527123) CXCR2

COPD patients: n=22; FEV1: 52% predicted

50 25 0 -25 -50 47%, p<0.035

Sputum neutrophils
Placebo

% Change from Baseline

-75 FEV1 91ml (NS) Sputum MMP9 59% (P<0.05)B/L Blood neutrophils 22% (P<0.001)

navarixin (30mg po)

2 4 6 8 10 12

Time (weeks)

Magnussen H et al: ERS 2010

p38 MAP KINASE INHIBITORS

LPS IL-1 TNF- Virus
6

Irritants

COPD MDMs
COPD

TNF- release (ng/mL)

TAK

p38 inhibitors SB203580 SB239063 SD-282 Losmapimod PH797804

Smith SJ et al: MKK3,MKK6 P-p38 Br J Pharmacol 2006 2 p38, p38 p38, p38
AP-1 0 Hsp-27 -6 -5 LPS -9 -8 -7 Smoker log [p38 inhibitor (M)]

TNF-, GM-CSF, Chemokines Renda et al: ERJ 2008

p38 MAP KINASE INHIBITORS IN COPD

COPD patients (n=294); Oral losmapimod (75mg b.d.) x12 weeks Oral p38 inhibitors Sputum neutrophils Similar results with PH-797804 No effect on: Other oral (for RA) , RV, IC FEV1toxicity Liver Lomas DA et al: Plasma CRP, IL-8, IL-6, MMP9, SPD Skin rashes J Clin Pharmacol Loss of efficacy Effect on: 2011 Inhaled p38 HSP-27 (inhibitors 39%): proof of mechanism PF-03715455 Plasma fibrinogen (11%) GSK Well610677 tolerated

47

CONCLUSIONS

Inflammation in COPD is corticosteroid-resistant so

so alternative anti-inflammatory therapies are needed and reverses corticosteroid resistance (PI3K inhibition)

Theophylline has anti-inflammatory effects in low doses Macrolides reduce exacerbations but no evidence that
this is through anti-inflammatory effects by side effects

PDE4 inhibitors are anti-inflammatory but the dose is limited New anti-inflammatory treatments include CXCR2 antagonists There is a need for safe and effective anti-inflammatory
therapies in COPD and p38 MAP kinase inhibitors

EARLY TREATMENT OF COPD

More reversibility (e.g. smoking cessation) More rapid decline of lung function: disease activity Less comorbidities to compromise therapy Early treatment to prevent future risk (exacerbations, disease progression, death, comorbidities) Analogous to treating hypertension, hypercholesterolaemia Screening (spirometry) to find early disease (high risk groups)

48