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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

Improving COPD management through maximising bronchodilation

Dr. Roland Buhl Pulmonary Department, III. Medical Center Johannes Gutenberg University Mainz Langenbeckstrasse 1D55131 Mainz Germany Roland.Buhl@unimedizin-mainz.de Summary
Recent guidelines for symptomatic COPD patients recommend long-acting bronchodilators, 2agonists and anticholinergics, as first line pharmacological treatment of COPD in Global initiative for chronic Obstructive Lung Disease (GOLD) stages II IV and as a second choice even in GOLD stage I patients [1]. A wealth of clinical data supports this recommendation, demonstrating clinically relevant beneficial effects of both classes of drugs on COPD symptoms, lung function, exercise capacity, exacerbation frequency as well as health related quality of life [2]. The long-acting 2agonists (LABAs) formoterol and salmeterol, the ultralong-acting 2-agonist indacaterol, and the ultralong-acting anticholinergic (muscarinic antagonist, LAMA) tiotropium are widely used maintenance treatments for COPD [3]. A combination of an inhaled muscarinic antagonist with an inhaled 2-agonist is recommended when symptoms are not adequately controlled by single drugs [1, 2]. The complementary mechanisms of action of 2-agonists and anticholinergics significantly improve treatment outcomes compared with monotreatment with either drug. Many clinical trials confirm that treatment with combinations of long-acting 2-agonists and tiotropium provide clinically relevant improvements in lung function control and patient-related outcomes that are superior to treatment results of either agent used alone [4]. Most of the studies published to date report on the free combination of a LABA administered twice-daily with a short-acting muscarinic antagonist [5] or a twice-daily LABA with once-daily tiotropium bromide [6-15]. However, combining LABAs and LAMAs with a 24 hour duration of action is an equally attractive perspective, more so from a real-life clinical point of view [16, 17]. Consequently, combining bronchodilators of both classes of drugs is a convenient strategy to obtain superior treatment results at least in patients with moderate to very severe COPD with symptoms not adequately controlled by bronchodilator monotherapy, paving the way for fixed combinations of LAMAs and LABAs.

Fixed combinations of long-acting anticholinergics and long-acting 2-agonists

From a pharmacological point of view the combination of LABAs with LAMAs makes perfect sense. 2-agonists decrease the release of acetylcholine leading to amplification of the bronchial smooth muscle relaxation directly induced by the anticholinergic agent. The addition of an anticholinergic agent can also reduce the peripheral bronchoconstrictor effects mediated by acetylcholine, amplifying the bronchodilation elicited by the 2-agonist through the direct stimulation of 2-adrenoceptors on airway smooth muscles. From the patient perspective, fixed combinations of 2-agonists and muscarinic antagonists with similar or equivalent posologies in the same inhaler device provide the opportunity of a simpler and more convenient administration regimen, likely improving treatment adherence. A further advantage may be that combining optimal doses of bronchodilators with different mechanisms of action rather than maximizing doses of a single drug reduces side effects [14]. Fixed LABA/LAMA combinations administered twice daily Aclidinium bromide and formoterol fumarate Aclidinium bromide is a novel, inhaled LAMA with a strong affinity and selectivity for all muscarinic receptor subtypes (M1-M5) and kinetic selectivity for the M3 receptor over the M2 receptor. The drug is in late stage clinical development as a twice-daily maintenance treatment for COPD [18]. Clinical

trials of twice-daily aclidinium demonstrated beneficial effects on airflow obstruction, lung hyperinflation, and exercise tolerance of the same order of magnitude as once-daily tiotropium (18 g once daily) [19], as well as a pharmacological profile characterized by a faster rate of onset of the smooth muscle relaxing activity than tiotropium. A rapid hydrolysis of aclidinium in human plasma to inactive metabolites may account for its favourable cardiovascular safety profile [20]. The European Medicines Agency (EMA) issued a positive opinion for approval of aclidinium at its meeting in May 2012. Based on randomised double-blind placebo-controlled phase II trials in patients with moderate-tosevere stable COPD to determine the optimal dose and to assess efficacy, safety and pharmacokinetics, the fixed aclidinium / formoterol combination is currently in clinical phase III development as an inhalation powder delivered by a breath-actuated dry powder inhaler [21]. Fixed LABA/LAMA combinations administered once daily Fixed dose combinations of LABAs and LAMAs with a once daily posology provide 24 hour bronchodilation and symptom control. This strategy is supported by a clinical trial investigating the combination of tiotropium and formoterol as proof-of-concept. Even though formoterol is not approved for once-daily treatment in COPD, a combination of tiotropium and formoterol given oncedaily provided additional benefit over either formoterol twice-daily or tiotropium once-daily [11]. The most effective bronchodilation was achieved with combination treatment with tiotropium / formoterol and significantly higher peak and average FEV1 and FVC responses were observed as compared with either drug alone. The concept of a combination of two ultralong-acting bronchodilators with different mechanisms of action and once-daily dosing is further supported by two randomized, double-blind studies over 12 weeks in patients with moderate-to-severe COPD. Both trials evaluated the free combination of 2 drugs with a true duration of action of 24 hours, tiotropium and indacaterol. Patients were treated with indacaterol (150 g once-daily) plus open-label tiotropium (18 g once daily) or open-label tiotropium (18 g once daily) plus placebo. All drugs were administered via dry powder inhalers. As expected, the addition of indacaterol to tiotropium led to significantly greater increases in FEV1 (area under the curve and trough) and inspiratory capacity with greater reductions in use of rescue medication (salbutamol) compared with tiotropium alone. The addition of tiotropium did not increase the frequency of adverse events, safety and tolerability profiles were similar in both treatment groups [17]. Indacaterol maleate and glycopyrronium bromide Indacaterol maleate (QAB149) is an ultralong-acting inhaled 2-adrenergic receptor agonist recommended for once-daily treatment in COPD patients. Indacaterol has an efficacy profile similar to tiotropium, providing an advantage over the two long-acting inhaled 2-receptor agonists formoterol and salmeterol [22-25]. Glycopyrronium bromide (NVA237) is a quaternary ammonium antimuscarinic agent characterized by a greater potency at the M1 and M3 receptor subtypes than at the M2 receptor subtype predominant in cardiac tissue. These properties partially explain the favourable cardiovascular safety profile. Glycopyrronium has a fast onset of action and a prolonged bronchodilatory effect over 24 hours [3, 26-28]. The EMA has recently issued a positive opinion for approval of glycopyrronium bromide. QVA149, an inhaled fixed combination containing the two 24-hour bronchodilators indacaterol and glycopyrronium is currently in phase III clinical development for once-daily treatment of COPD [16]. A randomised, double-blind, placebo-controlled, four-period crossover study assessed the efficacy and safety of once-daily QVA149 in patients with moderate-to-severe COPD. 154 patients entered the trial to receive QVA149 (indacaterol 300 g / glycopyrronium 50 g), indacaterol (300 g), indacaterol (600 g), or placebo once-daily for 7 days. On day 1 and at the end of the 7 day treatment phase QVA149 showed sustained 24-hour bronchodilation which was significantly more pronounced than what was achieved with indacaterol or placebo. The mean trough FEV1 improvements for QVA149 versus placebo and indacaterol exceeded the pre-defined minimal clinically important differences. The onset of action of QVA149 was rapid. Compared with placebo and indacaterol, FEV1 values in the indacaterol / glycopyrronium arms were significantly higher at 5 min post-dose on days 1 and 7. Similar significant improvements in all other spirometry results (FEV1 AUC, peak FEV1 and FVC) were seen in the QVA149 arms compared with indacaterol or placebo. Importantly, QVA149

treatment resulted in statistically significant improvements in inspiratory capacity [16]. A second randomised, double-blind, placebo-controlled, parallel-group study evaluated 257 patients with moderate-to-severe COPD who received QVA149 (indacaterol / glycopyrronium 600 g / 100 g, 300 g / 100 g or 150 g / 100 g), indacaterol (300 g) or placebo once daily for 14 days. In this trial no clinically significant differences in the 24-hour mean heart rate or QTc interval (Fridericia's) were observed between the three doses of QVA149 and placebo or indacaterol. It appears that fixed combinations of ultralong bronchodilators do not increase the burden of adverse events compared with bronchodilators with a 12 hour duration of action [29]. Tiotropium bromide and olodaterol hydrochloride The ultralong-acting inhaled anticholinergic bronchodilator tiotropium is characterized by a superior muscarinic receptor subtype selectivity profile and duration of action compared with ipratropium. Tiotropium is approved as an inhalation powder with a once-daily posology in many countries worldwide. An alternative aqueous formulation for use in the Respimat device (2x 2.5 g oncedaily) has recently been approved in Europe [30]. Olodaterol is an ultralong-acting 2-adrenoceptor agonist with 24-hour duration of bronchodilation that is currently in phase III development in patients who require maintenance bronchodilator therapy for the management of COPD symptoms [3, 31]. Olodaterol has an optimized inhaled profile of topical lung selectivity, high 2-receptor selectivity, almost full intrinsic activity at 2-adrenoceptors and low intrinsic activity at 1-adrenoceptors. Significantly greater bronchodilation compared with placebo over 24 hours post-dose FEV1 and a clear dose-response relationship over the range of doses tested (2 g, 5 g, 10 g and 20 g) is confirmed by preliminary clinical evidence. Olodaterol was well tolerated with no apparent dose relation in terms of adverse events [32, 33]. The fixed combination of tiotropium and olodaterol in the Respimat single inhaler device is a rational new approach to optimize bronchodilator treatment in COPD. Phase II studies in COPD patients demonstrated the additional bronchodilator efficacy of a fixed combination of both drugs compared with monotreatment with tiotropium and olodaterol, without relevant safety or tolerability concerns. Further, preliminary evidence suggests that the protection against histamine-induced bronchoconstriction mediated by olodaterol is synergistically augmented and prolonged in the presence of tiotropium, indicating an important role for endogenous acetylcholine in the regulation of airway responsiveness to 2-agonists [34]. Vilanterol trifenatate and GSK573719 The once-daily inhaled 2-agonist vilanterol trifenatate and the once-daily inhaled muscarinic receptor antagonist GSK573719 (GSK573719 / vilanterol) are part of a fixed combination in an advanced stage of clinical development. The fixed GSK573719 / vilanterol combination will be administered via a new dry powder inhalation device.

Perspective
For many years to come inhaled anticholinergics and 2-adrenoceptor agonists will remain the workhorses of symptomatic COPD treatment. Once- or twice-daily dosing of fixed LABA / LAMA combinations may provide clinically relevant bronchodilatory and symptomatic benefits compared with free combinations of two bronchodilators in separate inhalation devices. Putative mechanism(s) behind these additive effects may be independent effects on sympathetic and parasympathetic pathways, a differential distribution of 2-adrenergic and muscarinic receptors within the airways and / or (a) receptor interaction(s), with potentiation of 2-receptor activation by muscarinic (M3) receptor blockade. Crucial questions that require further investigation are a potential discrepancy between superior effects of LABA / LAMA combinations on pulmonary function parameters versus modest / inconsistent effects on patient-reported outcomes, and the potential additive benefits of LAMAs and LABAs alone or in combination with an inhaled corticosteroid in reducing exacerbations. Long-acting bronchodilators reduce exacerbations almost certainly not due to an anti-inflammatory effect but more likely due to their property of increasing airway patency and reducing hyperinflation. Both mechanisms counteract the tendency of respiratory insults to worsen airflow obstruction and hyperinflation.

Fixed LAMA / LABA combinations may help to simplify COPD management in daily clinical practice. Clinical experience confirms that it is more convenient for many patients to inhale a drug from a single inhaler rather than using several devices with potentially different instructions for use. This may further improve treatment adherence and consequently treatment outcomes. This is even more so because adherence is a major obstacle to successful COPD management. It is therefore not surprising that in addition to indacaterol and olodaterol several other 2-adrenoceptor agonists with 24 hour duration of action are in advanced stages of clinical development (e.g. vilanterol, carmoterol, LAS100977, PF-610355, and AZD3199) [3]. The same is true for anticholinergics with a 24 hour duration of action (e.g. GSK573719). Physicians will soon be able to offer symptomatic COPD patients not adequately controlled on single bronchodilators a variety of free and fixed LAMA / LABA - combinations. A different, even more innovative approach is drugs with a bifunctional mechanism of action, combining antimuscarinic and 2-agonist activities in a single molecule. This approach has the advantage to always deliver an optimal fixed LABA / LAMA ratio into every part of the lungs, and may serve as a basis for fixed triple combinations by co-delivery with an inhaled corticosteroid or novel anti-inflammatory compounds, such as inhaled phosphodiesterase 4 inhibitors, that could deliver three complementary therapeutic effects in patients with COPD [35]. Likely target populations for this approach are COPD patients with concomitant asthma and possibly patients with asthma or COPD with frequent exacerbations. However, it is as yet unclear whether addition of an anti-inflammatory compound to the LABA / LAMA combination will provide additional clinical value for most patients.

Conclusion
Many clinical trials support the recommendation of current treatment guidelines that in patients with COPD whose symptoms are not adequately controlled by bronchodilator monotherapy, bronchodilators of different classes can be combined. Free and fixed combinations of LABAs and LAMAs provide statistically significant and clinically relevant improvements in bronchodilation, COPD symptoms and other patient-related outcomes over each individual bronchodilator without increasing the frequency or intensity of side effects. Fixed combinations of LABAs and LAMAs offer simplified, more convenient dosing along with the potential to improve patient compliance compared with taking the two compounds as separate agents from different inhalation devices.

References
1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease. NHLBI/WHO workshop report. Bethesda, National Heart, Lung and Blood Institute, April 2001; GOLD website (www.goldcopd.com). Date updated: November 2011 2. Niewoehner DE. Clinical practice. Outpatient management of severe COPD. N Engl J Med 362(15), 1407-1416 (2010) 3. Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 64(3), 450-504 (2012) 4. Cazzola M, Matera MG. Emerging inhaled bronchodilators: an update. Eur Respir J 34(3), 757-769 (2009) 5. D'Urzo AD, De Salvo MC, Ramirez-Rivera A, Almeida J, Sichletidis L, Rapatz G, Kottakis J. In patients with COPD, treatment with a combination of formoterol and ipratropium is more effective than a combination of salbutamol and ipratropium : a 3-week, randomized, doubleblind, within-patient, multicenter study. Chest 119(5), 1347-1356 (2001) 6. Tashkin DP, Donohue JF, Mahler DA, Huang H, Goodwin E, Schaefer K et al. Effects of arformoterol twice daily, tiotropium once daily, and their combination in patients with COPD. Respir Med 103(4), 516-524 (2009) 7. Tashkin DP, Littner M, Andrews CP, Tomlinson L, Rinehart M, is-Mize K. Concomitant treatment with nebulized formoterol and tiotropium in subjects with COPD: a placebocontrolled trial. Respir Med 102(4), 479-487 (2008) 8. Tashkin DP, Varghese ST. Combined treatment with formoterol and tiotropium is more efficacious than treatment with tiotropium alone in patients with chronic obstructive

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18. 19. 20. 21. 22. 23. 24. 25. 26.

pulmonary disease, regardless of smoking status, inhaled corticosteroid use, baseline severity, or gender. Pulm Pharmacol Ther 24(1), 147-152 (2011) van Noord JA, Aumann JL, Janssens E, Smeets JJ, Zaagsma J, Mueller A, Cornelissen PJ. Combining tiotropium and salmeterol in COPD: Effects on airflow obstruction and symptoms. Respir Med 104(7), 995-1004 (2010) van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJ. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 129(3), 509-517 (2006) van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J, Disse B et al. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 26, 214-222 (2005) Cazzola M, Centanni S, Santus P, Verga M, Mondoni M, Di Marco F, Matera MG. The functional impact of adding salmeterol and tiotropium in patients with stable COPD. Respir Med 98, 1214-1221 (2004) Tashkin DP, Pearle J, Iezzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD 6(1), 17-25 (2009) Vogelmeier C, Kardos P, Harari S, Gans SJ, Stenglein S, Thirlwell J. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Respir Med 102(11), 1511-1520 (2008) Richter K, Stenglein S, Mucke M, Sieder C, Schmidtmann S, Harnest U et al. Onset and duration of action of formoterol and tiotropium in patients with moderate to severe COPD. Respiration 73(4), 414-419 (2006) van Noord JA, Buhl R, LaForce C, Martin C, Jones F, Dolker M, Overend T. QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease. Thorax 65(12), 1086-1091 (2010) Mahler DA, D'Urzo A, Bateman ED, Ozkan SA, White T, Peckitt C et al. Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax (2012), epub ahead of print Sims MW, Panettieri RA, Jr. Profile of aclidinium bromide in the treatment of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 6, 457-466 (2011) Fuhr R, Magnussen H, Sarem K, Llovera AR, Kirsten AM, Falques M et al. Efficacy of Aclidinium Bromide 400 mug Twice Daily Compared With Placebo and Tiotropium in Patients With Moderate to Severe COPD. Chest 141(3), 745-752 (2012) Cazzola M. Aclidinium bromide, a novel long-acting muscarinic M3 antagonist for the treatment of COPD. Curr Opin Investig Drugs 10(5), 482-490 (2009) Singh D, Magnussen H, Kirsten A, Mindt S, Caracta C, Seoane B et al. A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. Pulm Pharmacol Ther 25(3), 248-253 (2012) Dahl R, Chung KF, Buhl R, Magnussen H, Nonikov V, Jack D et al. Efficacy of a new oncedaily long-acting inhaled {beta}2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax 65(6), 473-479 (2010) Korn S, Kerwin E, Atis S, Amos C, Owen R, Lassen C. Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: A 12-week study. Respir Med 105, 719726 (2011) Buhl R, Dunn LJ, Disdier C, Lassen C, Amos C, Henley M, Kramer B. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. Eur Respir J 38(4), 797-803 (2011) McKeage K. Indacaterol: a review of its use as maintenance therapy in patients with chronic obstructive pulmonary disease. Drugs 72(4), 543-563 (2012) Vogelmeier C, Verkindre C, Cheung D, Galdiz JB, Guclu SZ, Spangenthal S et al. Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Pulm Pharmacol Ther 23(5), 438-444 (2010)

27. Fogarty C, Hattersley H, Di SL, Drollmann A. Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients. Respir Med 105(3), 337-342 (2011) 28. D'Urzo A, Ferguson GT, van Noord JA, Hirata K, Martin C, Horton R et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res 12(1), 156 (2011) 29. van de Maele B, Fabbri LM, Martin C, Horton R, Dolker M, Overend T. Cardiovascular safety of QVA149, a combination of indacaterol and NVA237, in COPD patients. COPD 7(6), 418-427 (2010) 30. van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Respir Med 103(1), 22-29 (2009) 31. Casarosa P, Kollak I, Kiechle T, Ostermann A, Schnapp A, Kiesling R et al. Functional and biochemical rationales for the 24-hour-long duration of action of olodaterol. J Pharmacol Exp Ther 337(3), 600-609 (2011) 32. van Noord JA, Smeets JJ, Drenth BM, Rascher J, Pivovarova A, Hamilton AL, Cornelissen PJ. 24-hour bronchodilation following a single dose of the novel beta(2)-agonist olodaterol in COPD. Pulm Pharmacol Ther 24(6), 666-672 (2011) 33. Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp A. Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther 334(1), 53-62 (2010) 34. Smit M, Zuidhof AB, Bos IST, Maarsingh H, Gosens R, Zaagsma J et al. The bronchoprotective effect of olodaterol against histamine is synergistically enhanced and prolonged by tiotropium bromide. Am J Respir Crit Care Med 183, A1379. 2011 35. Barnes PJ. Triple inhalers for obstructive airways disease: will they be useful? Expert Rev Respir Med 5(3), 297-300 (2011)

10

Improving COPD Management through Maximizing Bronchodilation

Roland Buhl Pulmonary Department Mainz University Hospital

Statement of interest Dr R. Buhl has received reimbursements for attending scientific conferences, and/or fees for speaking and/or consulting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Nycomed, and Roche and Talecris.

GOLD Revision 2011

COPD COPD, a common preventable

and treatable disease, is
GOLD, Update 2011

characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases

11

Improving COPD management through maximizing bronchodilation

Bronchodilators in COPD: Are we schizophrenic ? Bronchodilators are central to symptom management inhaled therapy is preferred The choice between bronchodilators depends on individual response and side effects Bronchodilators are given regularly or as-needed Long-acting bronchodilators are more effective Combining bronchodilators of different phamacological classes may improve efficacy and decrease the risk of side effects
GOLD Report 2011
Global Initiative for Chronic Obstructive Lung Disease 2011 Available at: http://www.goldcopd.org

Bronchodilator responsiveness in COPD

UPLIFT: COPD (n=5756) Ipratropium 80 g
60 min.

FEV1 12% + 200 mL

[%]
60 40 20 0

Salbutamol 400 g
30 min.

II

spirometry

III IV GOLD stages

Tashkin et al., ERJ 31:742-750, 2008

Goals of pharmacologic COPD therapy

improve / prevent symptoms reduce frequency and severity of exacerbations improve health status improve exercise tolerance
GOLD 2011

12

Therapy at each stage of COPD

I: Mild
FEV1/FVC < 0.70 FEV1 80% pred.

II: Moderate
FEV1/FVC < 0.70

III: Severe
FEV1/FVC < 0.70

IV: Very severe

FEV1/FVC < 0.70

50% FEV1< 80% pred. 30% FEV < 50% pred. FEV1 < 30% pred. or 1 FEV1 < 50% plus chronic respiratory failure

Active reduction of risk factor(s); influenza vaccination

Add

Short-acting bronchodilator (when needed) Regular treatment with one or more Add long-acting bronchodilators (when needed)
Add

Rehabilitation
Add

Inhaled glucocorticosteroids if repeated exacerbations

Add

GOLD, 2010 www.goldcopd.com

Long-term O2 if chronic resp. failure Consider surgical treatments

GOLD COPD 2012: Spirometry, symptoms, exacerbations and future risk

COPD Diagnosis and Management At-AGlance Desk Reference
http://www.goldcopd.org/guide lines-copd-diagnosis-andmanagement.html

GOLD COPD 2011

Pharmacological COPD management

www.goldcopd.org/.../GOLD2011_summary.pdf

13

Bronchodilators in COPD
2 - agonists
short-acting long-acting

Theophylline

Anticholinergics
short-acting long-acting

receptors

Cholinergic receptor

Clinical effects of bronchodilators in COPD

Lung function

obstruction hyperinflation

Control of symptoms

breathlessness exercise capacity

Quality of life Exacerbations Systemic parameters

body mass index

Composite scores

Bronchodilators in COPD

Ipratropium salbutamol
534 COPD patients

1.2 1 0.8 0.6 0.4 0.2

Day 1

Day 85

Ipratropium
42 g q.i.d. 200 g q.i.d.

Ipratropium + salbutamol
85 days

FEV1 [AUC0-4]
Combivent Study Group, Chest 1994

FEV1 [AUC0-4]

Salbutamol

0
IPRA SALB IPRA +SALB IPRA SALB IPRA +SALB

14

2 - agonists for COPD

Regular
53 COPD patients

vs. as-needed therapy

[puffs / day]
15 6 5

Ipratropium Salbutamol BDP

40 g qid as-needed 500 g bid

Dyspnea

200 g qid

Salbutamol use

Salbutamol Placebo
3 months

10

4 3

[Score]

2 1

Salbutamol use
Cook et al., AJRCCM 2001

2 - agonists for COPD

Regular
6 minute walk

vs. as-needed therapy

Dyspnea after walk SF-36 physical score

Cook et al., AJRCCM 2001

Improving COPD management through maximizing bronchodilation

Improvement in outcome Duration of action (hours)1 Salbutamol Ipratropium bromide 46 68 Lung function28 Exercise endurance*1,2 Quality of life114 Exacerbations13,5,714 NA NA

Breathlessness28

evidence of effectiveness; evidence of effectiveness over SABA or SAMA; evidence of effectiveness over LABA *Outcome demonstrated by all bronchodilators, lack of evidence of significant differences between them evidence depending on formulation5,10,11 Evidence of numerical improvements over shorter acting comparator4,8 on dose; NA = evidence not available
Equivocal

Dependent

1. GOLD 2008; 2. Celli B et al. ERJ 2004; 3. Mahler D et al. Chest 1999; 4. Rennard S et al. AJRCCM 2001; 5. Dahl R et al. AJRCCM 2001 6. Wadbo M et al. ERJ 2002; 7. Vincken W et al. ERJ 2002; 8. Brusasco V et al. Thorax 2003; 9. Rutten van-Molken MPMH et al. Eur J Health Econ 2007; 10. Szafranski W et al. ERJ 2003; 11. Calverley PM et al. ERJ 2003; 12. Calverley PM et al. NEJM 2007 13. Niewoehner D et al. Ann Intern Med 2005; 14. Tashkin D et al. NEJM 2008

SF-36 [Score]

Score

Meter

15

Long-acting bronchodilators
Aqueous biphase

Salmeterol / Formoterol1

Lipophilic (fat soluble) Retained in lipid membrane Slow release from cell membrane 12 hours duration of action3

1. Anderson Life Sci 1993; 2. Lombardi Eur J Pharm Sci 2009; 3. Battram, et al. JPET 2006

Bronchodilators for the treatment of COPD

Study Day 1
0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time (hours) Placebo Salmeterol Ipratropium 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time (hours)

Study Day 84
Placebo Salmeterol Ipratropium

Change from baseline in FEV1 (L)

Mahler et al., Chest 115:957-965, 1999

Bronchodilation following single doses of formoterol and salmeterol

Formoterol 24 g

Kottakis et al. Figure 2. Faster onset of bronchodilation Results of a randomized, doubleblind clinical study Can Respir J 2002

Formoterol 12 g Salmeterol 100 g Salmeterol 50 g

Placebo

Time post-dose (minutes)

16

Dynamic pulmonary hyperinflation

The critical target in COPD

Lung volume (% pred. TLC)
140 120 100 80 60 40 20 0 0 20 40 60 80 End expiratory lung volume IRV* Inspiratory capacity

Healthy

Lung volume (% pred. TLC)

140 120 100 80 60 40 20 0 0 20

COPD

Inspiratory capacity

40

60

80

Ventilation (L/min)
ODonnell, et al. Am J Respir Crit Care Med 2001

Ventilation (L/min)
*IRV: Inspiratory reserve volume

Bronchodilator - induced lung deflation in COPD

23 COPD patients
static FRC

[%]
15 10

hyperinflation 120% pred.

Salmeterol
50 g bid

Placebo
2 weeks

FRC
0 -5 -10 -15

Inspiratory capacity

Constant work rate exercise

(75 % of Wmax)

ODonnell et al., ERJ 2004

Salmeterol vs. placebo in COPD

Reduction in dyspnoea during exercise

Dyspnoea (Borg) Placebo Salmeterol
p = 0.07

ODonnell et al., ERJ 2004

Exercise endurance (minutes)

17

Long-acting brochodilators interrupt Vicious circle in COPD the vicious cycle in COPD
Flow limitation Airflow limitation Air trapping Air trapping Hyperinflation Hyperinflation Dyspnea Dyspnea

Long-acting bronchodilators

Activity De-conditioning

Quality of life

TORCH: Post-bronchodilator FEV1

Calverley et al., N Engl J Med 356:775-789, 2007

Bud-Form in COPD: Quality of life

The Szafranski study The Calverley study

p=0.001 Bud-Form vs Bud, p=0.014 Bud-Form vs Form *p<0.05, **p<0.01 vs placebo *p<0.05, **p<0.01, ***p<0.001 vs placebo

18

TOwards a Revolution in COPD Health

TORCH: Salmeterol and fluticasone in COPD

6112 COPD patients
FEV1 60%

SFC combination
Exacerbations [%] Mortality

SFC 2x 50/500 g Salm FP 2x 50 g 2x 500 g -10

Placebo 3 years

-20

- 17.5%
p=0.052

Mortality Exacerbations

-30

- 25%
p<0.001

Calverley et al., NEJM 2007

Improving COPD management through maximizing bronchodilation

Improvement in outcome Duration of action (hours)1 Salbutamol Ipratropium bromide Salmeterol Formoterol 46 68 12 12 Lung function28 Exercise endurance*1,2 Quality of life114 Exacerbations13,5,714 NA () NA

Breathlessness28

evidence of effectiveness; evidence of effectiveness over SABA or SAMA; evidence of effectiveness over LABA *Outcome demonstrated by all bronchodilators, lack of evidence of significant differences between them evidence depending on formulation5,10,11 Evidence of numerical improvements over shorter acting comparator4,8 on dose; NA = evidence not available
Equivocal

Dependent

1. GOLD 2008; 2. Celli B et al. ERJ 2004; 3. Mahler D et al. Chest 1999; 4. Rennard S et al. AJRCCM 2001; 5. Dahl R et al. AJRCCM 2001 6. Wadbo M et al. ERJ 2002; 7. Vincken W et al. ERJ 2002; 8. Brusasco V et al. Thorax 2003; 9. Rutten van-Molken MPMH et al. Eur J Health Econ 2007; 10. Szafranski W et al. ERJ 2003; 11. Calverley PM et al. ERJ 2003; 12. Calverley PM et al. NEJM 2007 13. Niewoehner D et al. Ann Intern Med 2005; 14. Tashkin D et al. NEJM 2008

Tiotropium
Vagus nerve

M1

+
M2

Long-acting inhaled anticholinergic

M1 / M3 receptor selective 24 h duration of action

M3

+
smooth muscle

19

Tiotropium versus Salmeterol

F E V1
1,35 1,30 1,25 1,20 1,15 1,10 1,05 1,00 0,95 0,00
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12

Tiotropium (n = 202)

Dose: 1 x 18 g Tiotropium [/ day] 2 x 50 g Salmeterol 1 or 2 x Placebo

FEV1 [L]

*/# * Salmeterol (n = 203)

*

Placebo (n = 179)

Day 1 Day 169 Hours post inhalation

#p

*p < 0,001 vs. Placebo, all time points < 0,05 Tiotropium vs. Salmeterol, all time points on day 169

Donohue et al., Chest 122:47-55, 2002

Tiotropium improves the effectiveness of pulmonary rehabilitation in COPD

Endurance (min)
24 20 16 12 8 0 2 4 6 8 10 12 14 16 18 20 22 24 26

Study medication Rehabilitation

32%* 42%*

16%
*p<0.05

Tiotropium (n=55) Placebo (n=53)

Weeks
Casaburi, et al. Chest 2005

UPLIFT: Tiotropium in COPD

Pre- und post-bronchodilator FEV1

Tashkin et al., NEJM 359:1543, 2008

20

POET: Tiotropium significantly delayed time to first exacerbation

Vogelmeier, et al. N Engl J Med 2011

INSPIRE: Salm-FP vs. tiotropium in COPD

1323 COPD patients
Post-BD FEV1 39% 1.4 1.2 1.0 0.8

[%]

Exacerbations

Salm-FP 2x 50/500 g Tiotropium 1x 18 g 2 years

0.6 0.4

Exacerbations
Wedzicha, et al. AJRCCM 2008

0.2

Salm-FP

Tiotropium

Aclidinium bromide
Inhaled long acting anticholinergic M1 / M3 - receptor selective

Aclidinium bromide

21

Lipophilicity was associated with 12 hours duration of action: interaction with lipid raft may provide 24 hours
Aqueous biphase

Salmeterol1

Indacaterol2

Lipophilic (fat soluble) Retained in lipid membrane Slow release from cell membrane 12 hours duration of action3

Lipophilic (fat soluble) Retained in raft domain of lipid membrane Ultra slow release from cell membrane 24 hours duration of action3

1. Anderson Life Sci 1993; 2. Lombardi Eur J Pharm Sci 2009; 3. Battram, et al. JPET 2006

Indacaterol: Bronchodilation over 24 hours

LaForce, et al. Pulm Pharmacol Ther 2011

p<0.001 for indacaterol vs placebo at all time points; p<0.05 for salmeterol vs placebo at all time points; p<0.05 for indacaterol vs salmeterol

Indacaterol 300 g provided significant improvement in trough FEV1 over 52 weeks, superior to formoterol

Dahl et al. Thorax 2010

*p<0.05, ***p<0.001 vs placebo; p<0.05, p<0.001 vs formoterol Data are LSM in the modified intent-to-treat population Trough = average of 23 h 10 min and 23 h 45 min post-dose values

22

Indacaterol vs. tiotropium

Trough FEV1 at week 12

Trough FEV1*
1.5
1.44 L

FEV1
140

[L]
1.0

1.43 L

[mL]
100 80 60

130 ml 120 ml

0.5

40 20

Indacaterol
*p<0.001 for non-inferiority

Tiotropium

Buhl, et al. Eur Respir J 2011

Indacaterol

Tiotropium

Compared with placebo, indacaterol 300 g improved exercise endurance time

Placebo Indacaterol 300 g

Study B23181

INABLE 12 1.68 p<0.001 1.46 min p=0.0032* Time (min)

8.47 9.75
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0

1.85 p=0.011
9.77

10.0 9.5

0.52 min

Time (min)

9.0 8.5 8.0 7.5 7.0 6.5 6.0

8.07

7.92

7.46 6.93 7.01

*difference of least squares means (90%-KI) Indacaterol 300 g and placebo

1. Beeh et al. COPD 2011; 2. ODonnell et al. Respir Med 2011

Indacaterol reduces the exacerbation risk over 52 weeks

Dahl, et al. Thorax 2010

23

New bronchodilators provide more consistent improvements in outcomes for COPD patients
Improvement in outcome
Duration of action (hours)1 Lung function28 Breathlessness28 Exercise endurance*1,2 Quality of life114 Exacerbations13,5,714

Salbutamol Ipratropium Salmeterol Formoterol Tiotropium Indacaterol

46 68 12 12 24 24

NA () ()

NA

evidence of effectiveness; evidence of effectiveness over SABA or SAMA; evidence of effectiveness over LABA *Outcome demonstrated by all bronchodilators, lack of evidence of significant differences between them Equivocal evidence depending on formulation5,10,11 Evidence of numerical improvements over shorter acting comparator4,8 on dose; NA = evidence not available

Dependent

1. GOLD 2008; 2. Celli B et al. ERJ 2004; 3. Mahler D et al. Chest 1999; 4. Rennard S et al. AJRCCM 2001; 5. Dahl R et al. AJRCCM 2001 6. Wadbo M et al. ERJ 2002; 7. Vincken W et al. ERJ 2002; 8. Brusasco V et al. Thorax 2003; 9. Rutten van-Molken MPMH et al. Eur J Health Econ 2007; 10. Szafranski W et al. ERJ 2003; 11. Calverley PM et al. ERJ 2003; 12. Calverley PM et al. NEJM 2007 13. Niewoehner D et al. Ann Intern Med 2005; 14. Tashkin D et al. NEJM 2008

Glycopyrronium in COPD [GLOW2]

1066 COPD patients FEV1 post-BD 56%
NVA237 50 g Tirtropium 18 g (open) Placebo 2:1:1 randomisation

Trough FEV1 vs. placebo

140 120 100 80 60 [mL]

1 year

Trough FEV1 at week 12 Time to 1st exacerbation

Kerwin, et al. AJRCCM 183:A2920, 2012

40 20

Day 1

Week 12

Week 26

Week 52

Once-daily treatments in development for COPD

24 hr LABA

24 hr LAMA

24 hr inhaled steroid

LAMA = long-acting anticholinergic

24

Combining indacaterol with tiotropium

1134 and 1142 COPD pts. GOLD stages II - IV
FEV1 48%, FEV1 16 - 19% [ml]
200 160 120 80 40

Trough FEV1 at week 12

[Change from baseline]

Tiotropium
18 g od

plus Indacaterol
150 g od

Placebo 12 weeks

Trough FEV1 at week 12 Mahler, et al. Thorax 2012

Indacaterol + tiotropium

Tiotropium

Indacaterol plus tiotropium improves inspiratory capacity versus tiotropium alone

Inspiratory capacity at serial timepoints post-dose at Week 12

Mahler, et al. Thorax 2012

Fixed indacaterol / glykopyrronium combination in COPD stages II - III

135 COPD patients FEV1 post-BD 52%
Indacaterol/NVA237 300 / 50 g Indacaterol 300 g Indacaterol 600 g Placebo

FEV1 [L]
[L] 1.5 226 ml
p<0.001

X X X

1.4

1.3

7 days 1.2 FEV1 on day 7 van Noord, et al. Thorax 2010 Indacaterol Indacaterol NVA237 300 g 600 g Placebo

25

Fixed indacaterol / glykopyrronium combination in COPD stages II - III

van Noord, et al. Thorax 2010

Olodaterol: 24-hour bronchodilation following a single dose in COPD

36 COPD patients FEV1 post-BD 4512%
Olodaterol 2, 5, 10 and 20 g Placebo [ml]
120 100 80 60 40 20

FEV1 at 24 hr post dose

[Difference from placebo]

7 days

FEV1 van Noord, et al. Pulm Pharmacol Ther 2011

2 5 10 20

Olodaterol [g]

Improving COPD management through maximizing bronchodilation

Enhanced efficacy of combining bronchodilators of different pharmacological classes Putative mechanism(s) for additive effect independent effects on sympathetic and parasympathetic pathways differential distribution of 2-adrenergic and muscarinic receptors within the airways receptor interaction, with potentiation of 2-receptor activation by muscarinic (M3) receptor blockade Discrepancy between superior effects on pulmonary function parameters and modest / inconsistent effects on patient-reported outcomes
Mahler, et al. Thorax 2012

26

Response to inhaled 2-agonists is poorly reflected by increase in FEV1

FEV1 [%] 60
40

20

-20 -20 0 20 40 60 80 100

Taube, et al. Am J Respir Crit Care Med 162:216-220, 2000

VAS Score

Single, double, or triple therapy for COPD ?

Exacerbations
Pts 1 exac. [%] 60 40 20
p = n.s.

Hospitalisations for COPD exacerbations

[n] 60 40 20 0
p = 0.01

0 Tio Tio + Salm Tio + Salm-FP

Tio

Tio + Salm

Tio + Salm-FP

Aaron et al., Ann Intern Med 2007

Single, double, or triple therapy for COPD ?

Health-related quality of life
SGRQ. [Score] 0 -2 -4 -6 -8 -10
p = 0.02 p < 0.001

Discontinued study drug

[%]
p < 0.001

Tio

Tio + Salm

Tio + Salm-FP

40

20

0 Tio Tio + Salm Tio + Salm-FP

Aaron et al., Ann Intern Med 2007

27

Goals of COPD treatment

improve / prevent symptoms reduce frequency and severity of exacerbations improve health status improve exercise tolerance

GOLD, Update 2010

Natural course of COPD

100

FEV1 (% of FEV1 at age 25)

75

Smoking cessation Smoking cessation plus bronchodilators

50 Invalidity 25 Death 0 25 30 35 40 45 50 55 60 65 70 75 80 85

Age (years)

28