The Novartis View on Emerging Drugs and Novel Targets for the Treatment of Chronic Obstructive Pulmonary Disease

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Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573

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Pulmonary Pharmacology & Therapeutics

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The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease

C. Compton*, D. McBryan, E. Bucchioni, F. Patalano

Novartis Pharma, Basel, Switzerland

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Article history: Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow Received 23 May 2013 limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented Accepted 27 May 2013 by long-acting bronchodilators, an important aspect of Novartis’ development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the Keywords: LAMA/long-acting b2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide Long-acting bronchodilators significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, Once-daily health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits Inhaled corticosteroids Inflammation provided by these new treatment options, prevention of disease progression and control of exacerbations Fixed-dose combinations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These com- mitments are central to the Novartis’ final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD. Ó 2013 The Authors. Published by Elsevier Ltd. Open access under CC BY-NC-SA license.

1. Introduction for patients whose symptoms are not effectively controlled by single bronchodilators. Inhaled glucocorticosteroids (ICS), which Chronic obstructive pulmonary disease (COPD) is a debilitating are associated with several side effects, including increase risk of lung disease characterized by airflow limitation that is usually pneumonia, osteoporosis and early onset of diabetes [3], are rec- progressive and associated with an enhanced inflammatory ommended only as add-on therapy in patients with severe and very response to noxious particles and gases [1]. COPD is a multicom- severe COPD and frequent exacerbators that are not controlled by ponent disease characterized by a range of pathological changes, long-acting bronchodilators [1]. Given the importance of long- which include mucus hypersecretion, airway narrowing and loss of acting bronchodilators in the management of COPD as mono- or alveoli in the lungs, and loss of lean body mass and cardiovascular combination therapy, Novartis has made such agents a key part of effects at a systemic level [2]. its development program. As complex inhaler devices and a Bronchodilators are the mainstay of pharmacological therapies frequent dosing schedule may contribute to poor adherence [4,5], for COPD. The recent revision to the Global Initiative for Chronic Novartis has focused its effort on trying to provide patients with Obstructive Lung Disease (GOLD) strategic document recommends new agents with a prolonged duration of action, which permits long-acting inhaled bronchodilators as first-line maintenance once-daily dosing, as well as fixed-dose combinations of broncho- therapy for COPD [1]. Treatment options include long-acting dilators and bronchodilators/ICS in a single, easy-to-use inhaler, muscarinic antagonists (LAMAs) and long-acting b2-agonists with the aim of simplifying COPD management. (LABAs), which could be used as monotherapy or in combination Despite the important benefits provided by new treatment options to patients with COPD, there are no currently available therapies able to ensure full symptom control and more remains to be achieved to optimize quality of life. In addition, control and prevention of exacerbations continue to be major challenges that need * Corresponding author. Novartis Pharmaceuticals UK Limited, Wimblehurst to be further addressed in order to slow decline in lung function Road, Horsham, West Sussex RH12 5AB, UK. Tel.: þ44 1403 324285; fax: þ44 1403 323054. and disease progression, while potentially reducing mortality. E-mail address: [email protected] (C. Compton). Novartis is committed to addressing these unmet needs by

1094-5539 Ó 2013 The Authors. Published by Elsevier Ltd. Open access under CC BY-NC-SA license. http://dx.doi.org/10.1016/j.pupt.2013.05.009 C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573 563 developing innovative therapies aimed at improving the standard 6.1 2.1 min for inhibition of methacholine-induced calcium of care in respiratory medicine. release e approximately five times faster than that of tiotropium This review will summarize the therapeutic advances and (t1/2 29.4 4.2 min) [26]. Taken together, these results suggested benefits provided by new long-acting bronchodilators developed potential for a more favorable tolerability profile and faster onset of by Novartis as mono- or combination therapy, and discuss the most action for glycopyrronium versus tiotropium, providing the ratio- promising targets in COPD beyond bronchodilation. nale for further investigating glycopyrronium in clinical trials. Phase II studies have shown that once-daily glycopyrronium 2. Long-acting bronchodilators (12.5e200 mg) is well tolerated and provides sustained 24-hour bronchodilation in patients with moderate-to-severe COPD [28e 2.1. Currently available long-acting bronchodilators for the 30]. The Phase III GLycopyrronium bromide in COPD airWays treatment of COPD (GLOW) program further evaluated the efficacy and safety of 50 mg glycopyrronium once daily (50 mg refers to the quantity of the Long-acting bronchodilators are the preferred option for main- glycopyrronium moiety present in the capsule, which corresponds tenance treatment of COPD [1]. Two classes of long-acting inhaled to a delivered dose of 44 mg) taken in the morning in patients with bronchodilators are available e LABAs and LAMAs. LABAs directly moderate-to-severe COPD. GLOW1 evaluated the efficacy, safety induce bronchodilation by relaxing airway smooth muscle through and tolerability of glycopyrronium compared with placebo over 26 stimulation of b2-receptors, whereas LAMAs prevent acetylcholine- weeks. GLOW2 evaluated the efficacy and safety of glycopyrronium induced bronchoconstriction by acting as competitive antagonists compared with placebo and open-label (OL) tiotropium 18 mg once on muscarinic receptors [6]. daily (as an active comparator) over 52 weeks and GLOW3 assessed Until recently, the twice-daily LABA salmeterol and formoterol the effects of glycopyrronium versus placebo on exercise tolerance. were widely used maintenance bronchodilators. Indacaterol, the first once-daily LABA providing 24-hour bronchodilation, was 2.2.1. Lung function developed by Novartis and has been available for use in patients In GLOW1 FEV1 at Week 12 (primary endpoint) was significantly with COPD since 2009. The efficacy of indacaterol in improving lung higher in patients receiving glycopyrronium compared with pa- function has been demonstrated in four pivotal trials [7e10] and tients receiving placebo, with a least squares means (LSM) treat- several supportive Phase III studies [11e13]. Indacaterol has also ment differences versus placebo of 108 mL (p < 0.001; Fig. 1A) [31]. been shown to improve several important clinical outcomes; when Similarly, in GLOW2 glycopyrronium significantly improved trough compared with the twice-daily LABAs salmeterol and formoterol, FEV1 at Week 12 (primary endpoint) versus placebo, with a LSM indacaterol produced significantly superior improvements in dys- treatment difference of 97 mL (p < 0.001; Fig. 1B) [32]. The efficacy pnea and reduced the use of rescue medication [7,10,12]. Several of glycopyrronium versus placebo in lung function improvement studies have also shown that indacaterol improves health status was similar to that of OL tiotropium (83 mL versus placebo and exercise endurance time and reduces the frequency of COPD p < 0.001; Fig. 1B). The bronchodilation achieved with glyco- exacerbations compared with placebo [14e16]. In addition to pyrronium was sustained over 26 weeks (GLOW1) and 52 weeks improving several meaningful clinical outcomes, indacaterol, with (GLOW2) (Fig. 1A and B). its once-daily dosing, simplified the management of COPD, providing a significant advantage over previously available twice- 2.2.2. Onset of bronchodilation daily LABAs. In addition to being as effective as OL tiotropium in improving Tiotropium was the first once-daily LAMA marketed for the lung function, glycopyrronium displayed a rapid onset of action on treatment of COPD. Despite being effective in improving a range of Day 1. In GLOW1, a significant increase in FEV1 was already apparent important clinical outcomes [17e22], a study in patients with sta- shortly after the first dose on Day 1, with a difference in mean FEV1 of ble COPD has shown that tiotropium has a relative slow onset of 93 mL at 5 min and 144 mL at 15 min versus placebo (p < 0.001). In action, taking up to 3 h to achieve optimal bronchodilation, in GLOW2, the mean FEV1 treatment difference on Day 1 for glyco- particular after the first administration [23]. pyrronium versus placebo was 87 mL at 5 min post-dose, while the difference for OL tiotropium versus placebo was 45 mL at 5 min (all 2.2. Glycopyrronium: a new long-acting muscarinic antagonist for p < 0.001). FEV1 was significantly higher at all measured timepoints the treatment of COPD from 5 min to 4 h post-dose compared with placebo (p < 0.001) and OL tiotropium (p < 0.01) (Fig. 2). In GLOW2 on Day 1 and at Week 26, The once-daily LAMA glycopyrronium bromide (NVA237) has glycopyrronium produced early bronchodilation following morning recently been approved as a once-daily treatment for COPD. Like dosing, with significantly greater peak FEV1 and FEV1 area under the other LAMAs, glycopyrronium acts as a competitive antagonist by curve (AUC) from 0 to 4 h (AUC0e4h) post-dose compared with binding to muscarinic type-1 (M1) and type-3 (M3) receptors in the tiotropium and placebo. The peak FEV1 LSM treatment difference for bronchial smooth musculature, thereby preventing acetylcholine- glycopyrronium-placebo and tiotropium-placebo was 200 and induced bronchoconstriction [24]. Blockade of muscarinic type-2 152 mL (p < 0.001) at Day 1 and 177 and 127 mL at Week 26, (M2) receptors, which modulate cardiac sinus activity and respectively (p < 0.001); the treatment difference for glyco- contraction force in the heart [25], has the potential to cause car- pyrronium versus tiotropium was 47 mL (p < 0.001). The FEV1 AUC0e diac side effects. It has been shown that glycopyrronium has a 4hLSM treatment difference for glycopyrronium-placebo and higher kinetic selectivity for M3 versus M2 receptors than tio- tiotropium-placebo was 197 mL and 141 mL at Day 1 and 177 and tropium and a shorter residence time than tiotropium on M1 re- 127 mL at Week 26 (all p < 0.001); the treatment difference for ceptors, which are expressed in exocrine glands and central glycopyrronium versus tiotropium was 56 and 50 mL at Day 1 and nervous system and are associated with anticholinerigic adverse Week 26, respectively (p < 0.001 and p < 0.01). events such as dry mouth and gastrointestinal disturbances [26].In This rapid and early onset of bronchodilation of glycopyrronium preclinical studies, glycopyrronium displayed an improved in vivo compares favorably against tiotropium. The rapid onset of action of therapeutic index, particularly for cardiovascular side effects, glycopyrronium could have important implications in COPD, as it compared with tiotropium [27]. Notably, glycopyrronium also dis- may provide early relief of morning symptoms, a recognized issue played a rapid onset of action in vitro, with a half-life (t1/2)of for patients [33]. This may result in improvement in the ability to 564 C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573

A 2.2.3. Symptoms and health-related quality of life In both GLOW1 and GLOW2, glycopyrronium also significantly reduced symptoms such as breathlessness, one of the cardinal symptoms of COPD, as measured by the transition dyspnea index (TDI). In GLOW1, glycopyrronium significantly improved TDI focal score at Week 26, with a treatment difference of 1.04 versus placebo (p < 0.001), which exceeded the 1-point treatment difference considered as clinically important (Fig. 3A) [35]. In GLOW2, both glycopyrronium and tiotropium significantly improved TDI focal scores compared with placebo at Week 26 with treatment differences of 0.81 and 0.94, respectively (both p ¼ 0.002) (Fig. 3B). In both studies glycopyrronium improved health-related quality of life, as assessed by the St George’s Respiratory Questionnaire (SGRQ). In GLOW1, the SGQR total score was significantly better (lower) in patients receiving glycopyrronium compared with pla- B cebo (p ¼ 0.004) at Week 26, with a treatment difference of 2.81. A significantly higher percentage of patients achieved a clinically meaningful improvement in SGRQ (4-point reduction) with glycopyrronium compared with placebo (OR 1.58, 95% CI: 1.14; p ¼ 0.006). At Week 52 in GLOW2, SGRQ total score was significantly improved in patients receiving glycopyrronium and OL tiotropium versus placebo, with treatment differences of 3.32 (p < 0.001) and 2.84 (p ¼ 0.014). A numerically higher proportion of patients receiving glycopyrronium or OL tiotropium achieved clinically meaningful improvements in SGRQ compared with placebo.

2.2.4. Exacerbations Glycopyrronium signiﬁcantly reduced the risk of a ﬁrst moderate or severe exacerbation by 31% compared with placebo over 26 weeks in GLOW1 (p ¼ 0.023) and by 34% over 52 weeks in GLOW2 (p < 0.001; Fig. 4). In the GLOW2 study, the risk reduction versus

Fig. 1. Glycopyrronium steady state improvement in trough FEV1 achieved on Day 1 and sustained until (A) Week 26 (GLOW1) [31] and (B) Week 52 (GLOW2) [32]. Data are least squares means (LSM) standard errors (SE); *p < 0.001 versus placebo; A yp ¼ 0.007 versus tiotropium; FEV1 ¼ forced expiratory volume in 1 s. perform morning activities [33]. It is interesting to note that an analysis investigating the impact of morning symptoms in patients receiving an ICS/LABA ﬁxed-dose combination has recently shown that patients with morning symptoms had signiﬁcantly more exacerbations in the previous twelve months than those without (p ¼ 0.005) [34].

Fig. 2. FEV1 at each timepoint up to 4 h post-dose on Day 1: GLOW2 [32]. Data are least square means; p < 0.001 for glycopyrronium and tiotropium versus placebo at all Fig. 3. Improvements in dyspnea with glycopyrronium versus placebo in GLOW1 [31] timepoints 5 min to 4 h; p < 0.01 for glycopyrronium versus tiotropium at all time- (A) and GLOW2 (B) [32]. Data are least squares (LS) means standard errors (SE); points 5 min to 4 h; FEV1 ¼ forced expiratory volume in 1 s. TDI ¼ Transition Dyspnea Index. *p < 0.01. C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573 565 placebo observed with glycopyrronium was similar to that for tio- controlled by monotherapy. As previously mentioned, the GOLD tropium (Fig. 4). 2013 update recommends combination therapy with LAMA and LABA to optimize symptoms benefits [1]. 2.2.5. Exercise tolerance Although the nature of interaction between cholinergic and In GLOW3, morning dosing of glycopyrronium improved exer- adrenergic pathways in airway smooth muscle has not been fully cise endurance time measured 1 h post-dose by 10% on Day 1 and understood, there is pharmacological evidence to suggest that the 21% on Day 21 versus placebo (p < 0.001; Fig. 5) [36]. This was combination of muscarinic antagonists and b2-agonists could have accompanied by sustained reductions in lung hyperinflation, as an additive effect on bronchodilation. The activation of b2-receptors indicated by significant improvements in inspiratory capacity (IC) with a b2-agonist reduces release of Ach by modulating cholinergic at isotime (Fig. 5), which was also seen in the longer GLOW1 and neurotransmission [37e39] thereby amplifying the bronchodila- GLOW2 studies. Glycopyrronium was also found to reduce exer- tion produced by muscarinic antagonists [6]. b2-receptors are tional dyspnea versus placebo 1 h post-dose on Day 1 and Day 21 abundant in the small airways [40], whereas M3 receptors are (p < 0.05; Fig. 5) as measured by the Modified Borg Dyspnea score predominantly found in the lower trachea and bronchi [41]. Thus, at isotime. the combination of b2-agonists and muscarinic antagonists could result in a better coverage of the airways compared with mono- 2.2.6. Safety therapy and provide maximal bronchodilation in all regions of the Pooled data of GLOW1 and GLOW2 demonstrated that glyco- human lungs. pyrronium was well tolerated with a low frequency of cardiac and LABA/LAMA combinations have been shown to improve lung antimuscarinic side effects which was comparable to that of pla- function (formoterol plus tiotropium [42e44]; tiotropium plus cebo and OL tiotropium. Antimuscarinic side effects, such as dry indacaterol [45]), symptoms and reduce the need for daytime mouth, gastrointestinal disturbances, urinary retention and urinary rescue medication compared with monotherapy (formoterol plus tract infections, occurred with a low frequency in the glyco- tiotropium [42e44]). Safety data from all these studies have sug- pyrronium, placebo and tiotropium treatment groups. The per- gested that combination therapy does not increase the risk of side centage of patients with newly occurring or worsening clinically effects compared with monotherapy. In addition to providing notable QTcF values (QT interval with Fridericia’s correction) was greater bronchodilation, fixed-dose combinations of LABAs and low across all treatment groups. The number of deaths reported in LAMAs may simplify treatment and potentially lead to increased each group was low and similar across treatments, and none were adherence, particularly for patients with several comorbities who considered to be related to study medication. are likely to be taking other medications. Given these multiple potential benefits, QVA149 is currently in 2.2.7. Glycopyrronium as an alternative choice to tiotropium development at Novartis as a once-daily fixed-dose combination of Overall, these results suggest that glycopyrronium is well the established LABA indacaterol and the new efficacious LAMA tolerated and as effective as tiotropium in improving lung function, glycopyrronium, administered in a single inhaler, which affords the health status and exercise tolerance, and reducing dyspnea and risk additional benefit of simplifying treatment regimens and hence of exacerbations in patients with COPD. Glycopyrronium, with its opportunity to improve adherence. fast onset of action, represents a useful alternative to tiotropium. 3.2. QVA149 (indacaterol/glycopyrronium) 3. Combination therapy in COPD Although several LABA/LAMA combinations are currently under 3.1. Combining long-acting bronchodilators investigation [46], QVA149, which contains a fixed-dosed combination of indacaterol (110 mg) and glycopyrronium (50 mg), is the A single bronchodilator may not be optimal for COPD manage- once-daily dual bronchodilator in the most advanced stage of ment especially for patients whose symptoms are not effectively development. In a Phase II study, QVA149 had a rapid onset of

Fig. 4. Glycopyrronium prolong time to ﬁrst COPD exacerbation (moderate-to-severe) compared with placebo 52 weeks (GLOW2) [32]. 566 C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573 A B

Fig. 5. Improvements in (A) exercise endurance, (B) lung function during exercise and (C) exertional dyspnea after 3 weeks of treatment with glycopyrronium versus placebo: GLOW3 [36].IC¼ inspiratory capacity. Data are LSM either SE or 95% CI. *p < 0.05; ***p < 0.001 versus placebo.

action and significantly increased 24-hours post-dose FEV1 placebo (LSM difference 3.01; p < 0.01) and tiotropium (LSM compared with placebo and indacaterol alone on Day 1 and Day 7 difference 2.13; p < 0.05; Table 1). [47]. In a study primarily designed to assess cardiovascular safety, In the ILLUMINATE study, QVA149 was compared with the QVA149 was tolerated with an adverse event (AE) rate similar to LABA/ICS combination of twice-daily SFC in terms of efficacy, safety, that of placebo [48]. and tolerability in patients with moderate-to-severe COPD and no QVA149 is undergoing investigation in the ongoing IGNITE history of exacerbations in the previous year [51]. This particular clinical trial program, one of the largest Phase IIIa program in COPD patient population was chosen to provide new evidence to support involving more than 7000 patients with moderate-to-severe COPD the recommended approach of treating patients with moderate-to- [49]. The IGNITE program is evaluating the safety and efficacy of severe COPD with bronchodilators, while reserving ICS for patients QVA149 on lung function, rate of exacerbations, exercise endurance with severe disease and high risk of exacerbation. Despite this and dyspnea, versus indacaterol, glycopyrronium, tiotropium, sal- recommendation, the side effects associated with their use, and meterol/fluticasone (SFC) and placebo. their relative narrow approved indications in many countries, SHINE, a 26-week, double-blind, parallel-group study was combination inhalers containing ICS are often prescribed to pa- designed to compare QVA149 with placebo, indacaterol 150 mg, tients with more moderate disease [52]. The results of this study glycopyrronium 50 mg and OL tiotropium 18 mg in 2144 patients highlighted the potential benefits of dual bronchodilation over with moderate-to-severe COPD [50]. QVA149 significantly LABA/ICS combination in patients with moderate-to-severe COPD. improved trough FEV1 at Week 26 (primary endpoint) compared FEV1 AUC from 0 to 12 h (AUC0e12 h) was significantly higher with with placebo and all active treatments (mean difference versus QVA149 versus SFC at Day 1 and Weeks 12 and 26 (primary placebo, indacaterol, glycopyrronium and tiotropium: 200, 70, 90 endpoint) (LSM difference: 70,120 and 140, respectively; p < 0.001; and 80 mL, respectively; all p < 0.001; Table 1). QVA149 provided Fig. 6). Serial spirometry showed significantly higher and clinically 24-hour bronchodilation with a rapid onset of action from Day 1, as meaningful improvements in FEV 1 with QVA149 versus SFC at all shown by significantly higher FEV1 and FEV1 AUC0e4hcompared timepoints from 0 to 12 h at Day 1 and Weeks 12 and 26 (p < 0.001 with placebo and all the active comparators (all p < 0.01; Table 1). at all timepoints). QVA149 significantly improved the TDI focal At Week 26, TDI focal score was significantly improved with score versus SFC (treatment mean: 2.16 versus 1.41; p ¼ 0.003) and QVA149 compared with placebo (LSM difference 1.09; p < 0.001) reduced the use of rescue medication. and tiotropium (LSM difference 0.51; p < 0.05; Table 1). At Week 26, In the BRIGHT study, QVA149 also improved exercise tolerance QVA149 also significantly improved SGRQ total score versus versus placebo in patients with moderate-to-severe COPD [53]. C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573 567

Table 1 Improvements in lung function, symptoms, health-related quality of life and rescue medication use with QVA149 versus placebo, indacaterol, glycopyrronium and tiotropium: the SHINE study [50].

Least squares mean treatment difference

Day 1 QVA149ePBO QVA149eIND QVA149eNVA237 QVA149eTIO

Trough FEV1 (mL)þ 190a 80a 80a 80a FEV1 AUC0e4h(mL) 220a 60a 30a 80a Week 26

Trough FEV1 (mL) 200a 70a 90a 80a FEV1 AUC0e4h(mL) 340a 110a 140a 130a FEV1 AUC0e24 h (mL) 320a 110a 110a 110a Peak FEV1 (L) (0e4 h) 330a 120a 130a 130a Transition Dyspnea Index focal score 1.09a 0.26 0.21 0.51c St George’s Respiratory Questionnaire 3.01b 1.09 1.18 2.13c total score Rescue medication use 0.96a 0.30c 0.66c 0.54c

a b c þ End of Day 1; p < 0.001; p < 0.01; p < 0.05. FEV1 ¼ forced expiratory capacity in 1 s; AUC0e4h¼ area under the curve (AUC) from 0 to 4 h; AUC0e24 h ¼ area under the curve (AUC) from 0 to 24 h.

SPARK, which is also part of the IGNITE program and involved 3.3. ICS/LABA combinations 2224 patients over a period of 64 weeks, showed that QVA149 reduced the risk of moderate/severe exacerbations by 12% The use of ICS plus LABA therapy is recommended in patients compared with glycopyrronium (primary endpoint; p < 0.05) and with severe COPD and high risk of exacerbation [1]. In contrast to the risk of all (mild, moderate and severe) exacerbations versus their effectiveness in controlling the underlying chronic inflam- both glycopyrronium and tiotropium (p ¼ 0.001 and p < 0.01, mation in asthma, the efficacy of ICS in COPD is less well established respectively) [54]. and the debate over their clinical use continues. Evidence from a Overall, these studies demonstrated that QVA149 provides a number of clinical trials suggest that ICS as monotherapy failed to significant advantage versus LABA and LAMA monotherapy in prevent disease progression in patients with COPD [55e57]. Several terms of improvement in lung function, relief from symptoms and long-term clinical studies have shown that high-dose ICS had no reduction in the number of exacerbations. In addition, there were effect on the annual decline of FEV1 [55,57]. A meta-analysis of six incremental benefits in lung function, dyspnea and rescue medi- long-term studies, involving 3571 patients with COPD, also failed to cation use compared to LABA/ICS combination therapy in patients show any effect on the rate of FEV1 decline [55,56]. The limited without history of an exacerbation in the previous year, therefore efficacy of ICS treatment in COPD could be explained by its inability highlighting the importance of dual bronchodilation in moderate- to suppress inflammation in lungs and airways due to an active to-severe COPD. resistance mechanism [58].

Fig. 6. Improvement in lung function with QVA149 versus SFC: the ILLUMINATE study [51]. Data are LSM SE; FEV1 ¼ forced expiratory volume in 1 s; ***p < 0$0001 for comparisons between QVA149 and SFC; AUC0e12 h ¼ area under the plasma concentrationetime curve from 0 to 12 h; LSM ¼ least squares means; SE ¼ standard error; SFC ¼ salmeterol/ﬂuticasone. n numbers shown represent patient number per treatment group at each timepoint. 568 C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573

Ò Despite their limited efficacy in COPD as monotherapy, ICS have very severe COPD [71]. The Twisthaler device has been replaced Ò shown a greater clinical effect when used in combination with by the Breezhaler device, which is able to ensure a higher lung long-acting bronchodilators. The TORCH (Towards a Revolution in delivery [72], in the QMF149 development program. COPD Health) study compared all-cause mortality among patients Ò with COPD between SFC, fluticasone propionate, salmeterol, and 3.5. The Breezhaler device: a common platform for the delivery of placebo [59]. Although not effective in reducing mortality, SFC Novartis COPD pipeline products provided greater symptom control, improvement in pulmonary function and reduction in exacerbations, compared with either of As inhalation is the preferred route of administration in COPD, the individual components [59].Apost hoc analysis of the results of the characteristics of inhalation devices play a vital role in ensuring this study showed a small but significant reduction in the annual an effective management of this disease. An ideal inhaler for use in rate of FEV1 decline by SFC compared with placebo in severe pa- COPD should be easy to use and provide optimal and consistent tients [60], suggesting that the use of ICS/LABA combination could drug delivery over a wide range of inspiratory flow rates. The in- potentially have a positive impact on disease progression. More- ternal resistance of the inhaler determines the effort patients have over, ICS/LABA combinations appear to have anti-inflammatory to make to achieve adequate inspiratory flows for effective and effects not seen with ICS alone [61]. ICS have also been shown to reproducible dose delivery [73,74]. This is particularly relevant in enhance the bronchodilator effect of LABAs [62], suggesting that light of the results of recent studies showing that older patients and additional pro-contractile agents, the release of which could be those with severe COPD have difficulty generating sufficient mediated by the activation of pro-inflammatory pathways, may inspiratory flow for correct use of dry-powder inhalers [75,76].In contribute to the airflow limitation observed in COPD. Even though order to overcome these limitations, Novartis has chosen to deliver the molecular mechanism of such a synergistic effect is yet fully all its COPD products by a low-resistance single-dose, dry-powder Ò understood, it is now acknowledged that the pathways activated by inhaler known as the Breezhaler device. Studies with the Ò ICS and LABAs interact at several different levels [63]. Breezhaler device have shown that it delivers a consistent dose of In light of these findings, complementing the bronchodilator indacaterol, irrespective of disease severity and is easy to use and effect of LABAs with adjunctive ICS therapy is a valuable option for well accepted by patients [77,78]. patients with more severe COPD and frequent exacerbations. In In addition to the characteristics mentioned above, an ideal order to meet the treatment needs of these patients, Novartis is inhaler for use in COPD should also generate optimal particle size for investing significant resources in developing QMF149, a new ICS/ lung delivery and retention at the required site. The aerodynamic LABA combination. size of drug particles generated by inhalers is one of the most important factors in defining the distribution and deposition of drug 3.4. QMF149 (indacaterol/mometasone) within the lung, with a particle size of less than 4.7 mm in diameter generally considered optimal for deposition in the bronchi and Ò QMF149, administered via the Breezhaler device, is a once- alveoli [79]. A high fine particle fraction (FPF), defined as fraction of daily ICS/LABA fixed-dose combination of mometasone furoate particles of less than 4.7 mm in diameter, indicates that a significant and indacaterol currently in development at Novartis for the proportion of the inhaled dose is likely to reach the pulmonary re- maintenance treatment of asthma and COPD. Although in early gion [80]. A recent in vitro study has also revealed that the Ò stages of clinical development for the treatment of COPD, QMF149 Breezhaler device delivers a high FPF across a wide range of with its once-daily dosing has the potential to provide important inspiratory flows, further suggesting that it may be suitable for pa- benefits over the two currently available twice-daily ICS/LABA tients with COPD of different severities, including severe COPD [81]. Ò fixed-dose combinations fluticasone propionate/salmeterol and The Breezhaler device also offers continuity across the Novartis budesonide/formoterol. In addition, evening dosing is expected to COPD portfolio, as it will be used to deliver glycopyrronium, ensure peak efficacy of QMF149 during early morning hours when QVA149 and QMF149. This will simplify the management of COPD, lung function and symptoms are worst [33]. as patients will not need to learn the use and handling of a new This new ICS/LABA combination could also represent an advance device when switching from one inhaled treatment to another. in therapy as it combines the efficacy and rapid onset of action of the established LABA indacaterol with the anti-inflammatory ac- 4. Emerging anti-inflammatory strategy for COPD tivity of mometasone furoate. Mometasone furoate, alone or in combination with formoterol, is licensed for the treatment of 4.1. Role of inflammation in COPD asthma and COPD, where it has been shown to have a favorable safety and tolerability profile [64e66]. In a 52-week, placebo- Inflammation in the lungs leads to the airway structural changes controlled clinical trial in patients with COPD, mometasone furo- and associated airflow limitation characteristic of COPD (Fig. 7) ate significantly increased FEV1 from baseline and reduced the risk [82]. Macrophages and epithelial cells in the respiratory tract are of exacerbations [67]. The study demonstrated comparable AE rates activated by inhaled irritants, such as cigarette smoke, occupational between mometasone furoate and placebo groups, with a low dust and environmental pollution, to release inflammatory medi- incidence of pneumonia, a side effect associated with some ICS/ ators, including tumor necrosis factor (TNF)-a and other CXC che- LABA combinations [68]. mokines, which in turn attract different types of inflammatory cells Ò The efficacy and safety of QMF149 via the Twisthaler device to the airways [82]. Neutrophils produce proteases, which are was assessed in a randomized, double-blind, active-comparator potent stimulants of mucus secretion [83], and are believed to be (mometasone furoate) study in patients with persistent asthma associated with chronic bronchitis, one of the main features of [69,70]. QMF149 significantly improved trough FEV1 and reduced COPD. T-lymphocytes, which have the capacity to cause cytolysis the risk of a serious exacerbation versus mometasone furoate with and apoptosis of alveolar epithelial cells [84], contributes to the an incidence of AEs comparable to that of mometasone furoate emphysema associated with COPD [85]. Macrophages not only alone. The efficacy and safety of QMF149 (150 mg/160 mg once-daily) orchestrate the inflammatory response in COPD, but can also cause compared with salmeterol xinafoate/fluticasone propionate (50 mg/ emphysema by producing elastolytic enzymes, such as matrix 500 mg twice-daily) will be investigated in a randomized, double- metallopeptidase 9 (MMP-9) [86], able to break down connective blind, 12-week parallel group study in patients with moderate-to- tissue in the lung parenchyma. C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573 569

with a long-acting bronchodilator (tiotropium or salmeterol) were investigated in four long-term, large clinical trials [102e105]. Although in all these studies roflumilast significantly improved post-bronchodilator FEV1 compared with placebo, its effect on exacerbations was inconclusive. Two post-hoc, pooled analysis of trials involving patients with COPD, revealed that roflumilast reduced exacerbation frequency in a subset of COPD patients with chronic bronchitis, particularly in those taking concomitant ICS [103,106]. Based on the results of these analyses, the effect of roflumilast plus an ICS/LABA fixed-dose combination on exacerbations will be investigated in a 1-year randomized, double-blind, placebo-controlled Phase III/IV study [107]. Several inhaled PDE4 inhibitors are currently in development to maximize efficacy and reduce side effects associated with oral administration [108]. GSK256066 demonstrated potent and long- lasting anti-inflammatory effects in animal models of pulmonary inflammation, with a low rate of gastrointestinal side effects [109]. A Phase II trial in COPD patients has recently been completed but no data are currently available [110]. Despite the potential of GSK256066, failures in clinical trials have been reported for other inhibitors in development such as tofimilast [111]. PDE3 is important in mediating airway smooth muscle relaxa- tion, as confirmed by the observation that PDE3 inhibitors cause Fig. 7. Inflammatory response in COPD. Adapted from Ref. [146]. bronchodilatation in subjects with asthma [112]. Combined PDE3/4 inhibitors, such as RPL554, could therefore have the ability to relax airway smooth muscle and suppress inflammation and are Evidence from a number of studies has shown that COPD is currently under investigation for the treatment of COPD. RPL554 fl intimately linked to in ammation, both locally and systemically. The has been shown to exhibit a broad range of both bronchoprotective fl number of in ammatory cells in bronchial biopsies and induced and anti-inflammatory activities in animal models [113]. The results sputum has been correlated with COPD disease severity and rate of of a Phase II clinical trial in COPD patients have recently become e fl decline in lung function and health status [87 89].In ammatory available and showed that a single dose of nebulized RPL554 pro- cells and mediators have also been shown to increase during an duced a rapid bronchodilator response, with increase in FEV e 1 exacerbation [90 92], suggesting that treatments that suppress significantly greater than that obtained with placebo and equiva- fl in ammation in COPD could potentially reduce exacerbations. In lent to that achieved with the active comparator salbutamol [114]. addition, several studies have shown that serum biomarkers of In addition, RPL554 was well tolerated and did not cause any sig- fl in ammation including TNF-a and MMP-9 are increased in patients nificant adverse effects. fl with COPD and correlate with the degree of air ow obstruction as New approaches in development to target PDE enzymes also e well as with important clinical outcomes including mortality [93 include oligonucleotide therapy, which aims at reducing protein 95]. This may account for the observation that patients with COPD expression levels by targeting messenger RNA [115]. Several oli- also present with systemic symptoms and comorbid conditions, gonucleotides are currently in late preclinical or clinical stage including muscle weakness, weight loss, cardiovascular disease, development for the treatment of COPD. osteoporosis, hypertension, depression, cognitive decline [96,97]. fl Given the central role played by in ammation in COPD, target- 4.3. Chemokine antagonists ing relevant pathways is key to developing innovative therapies, in particular to slow disease progression and better control exacer- Expression of several chemokines is increased in patients with fi bations. In order to achieve these goals, the identi cation of novel COPD; this has generated a lot of interest in developing small- fl fl anti-in ammatory drugs is vital, as in ammation in COPD is molecule chemokine receptor antagonists [116,117]. Chemokines resistant to the effect of ICS monotherapy [58]. In this review we secreted by activated macrophages play a pivotal role in inflam- will focus on phosphodiesterase-4 (PDE4) inhibitors, chemokine mation as they recruit neutrophils and monocytes to the lungs, antagonists and p38 mitogen-activated protein kinase (MAPK) in- thereby amplifying the inflammatory response [82]. CX chemokine hibitors, which represent the most promising classes of anti- receptor 2 (CXCR2) is expressed by monocytes and neutrophils and fl in ammatory drugs currently in development for the treatment mediates the activity of secreted chemokines such as CXCL1, CXCL5, of COPD. CXCL7 and CXCL8 [82]. Interestingly, CXCR2 has been found to be up regulated in bronchial biopsies of patients with COPD with se- 4.2. PDE4 inhibitors vere exacerbations [118]. Two oral CXCR2 inhibitors, SCH527123 and SB656933, are in early clinical development. Studies in healthy PDE4 is a specific phosphodiesterase predominantly expressed volunteers have demonstrated that both inhibitors caused attenu- by inflammatory cells, including those important to the patho- ation of ozone-induced neutrophil recruitment to the lungs and genesis of COPD, which makes it an attractive target for the displayed good tolerability profiles [119,120]. Moreover, SB656933 development of new drugs [98]. PDE4 inhibitors are effective anti- had also an effect on peripheral blood neutrophils and inhibited inflammatory agents in animal models and have been shown to agonist (CXCL-1)-mediated expression of the integrin CD11d, which reduce markers of inflammation in COPD [99,100]. enables transmigration of circulating neutrophils into the lung Roflumilast is an oral PDE4 inhibitor approved in the EU and in parenchyma [120]. A clinical trial in patients with asthma has the US for patients with severe COPD and a history of exacerbations recently shown that SCH527123 was well tolerated and effective in [101]. The efficacy and safety of roflumilast alone or in combination reducing sputum neutrophils [121]. A study evaluating the safety 570 C. Compton et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 562e573 and dose ranging of SCH527123 in patients with moderate-to- defined as ‘a single or combination of disease attributes that severe COPD has been completed although data are not currently describe differences between individuals with COPD as they relate available [122]. to clinically meaningful outcomes’ [145]. CX chemokine receptor 3 (CXCR-3) and CX3C chemokine re- Novartis is committed to identifying novel phenotypes in COPD ceptor 1 (CX3CCR1), which respectively mediate the recruitment of and is actively involved in several collaborations including T-lymphocytes and leukocytes in small airways and lung paren- COPDGene, COPDMAP, SPIROMICS and the COPD Foundation chyma, are also under investigation as new molecular targets in Biomarker Qualification Consortium with the aim of identifying COPD [123,124]. underlying genetic factors, new clinical outcomes and biomarker in COPD. This will allow the classification of patients into distinct 4.4. p38 MAPK inhibitors subgroups and potentially drive the development of individualized therapy, which could be matched more closely to patients’ needs, as The p38 MAPK family comprises four different isoforms (a, b, g well as helping to further clarify the underlying pathophysiology of and d) that are activated in response to cellular stress [125]. The p38 COPD. MAPK pathway, which is activated in macrophages, CD8 lymphocytes and bronchial epithelial cells in patients with COPD [126,127], 6. Conclusions regulates the expression of inflammatory cytokines including CXCL8, TNF-a and MMPs, and therefore plays a key role in Long-acting bronchodilators remain the cornerstone of the fl in ammation [128,129]. In particular, p38a, the most important management of symptomatic COPD. Given their importance in the fl isoform in the in ammatory response in COPD, is directly involved COPD treatment algorithm, Novartis has focused considerable in the migration of neutrophils and eosinophils into the lungs effort on developing novel once-daily dosing agents such as the e [129 131]. Evidence suggests that inhibition of p38 MAPK kinase LABA indacaterol, the LAMA glycopyrronium and the LAMA/LABA fi pathway could potentially have therapeutic bene ts on many as- fixed-dose combination QVA149, which have been shown to pro- fl pects of COPD, in addition to reducing the in ammatory response vide significant benefits to patients with COPD in terms of that contributes to the pathogenesis of this disease. p38 MAPK improvement in lung function, exercise tolerance, health-related family mediates airway smooth muscle contraction and may also quality of life, symptoms and reduction in the rate of exacerba- fl contribute directly to the air ow limitation observed in COPD tions. The new Novartis’ ICS/LABA combination QMF149, which is e [132 134]. Additionally, p38 MAPK activation has been shown to in early clinical development, offers potential as a new treatment contribute to corticosteroid insensitivity [135] and may play an option for patients at high risk of exacerbations. In order to ensure important role in mediating the effect of respiratory viruses, the continuity across the COPD Novartis portfolio, Novartis has further most common cause of exacerbations, on airways cells such as invested significant resources in developing the low-resistance, e Ò macrophages and respiratory epithelium [136 138]. dry-powder inhaler Breezhaler device, which represents a com- A number of small-molecule inhibitors of p38 MAPK have now mon platform for the delivery of all the COPD products. been developed. Although several oral p38 MAPK inhibitors have Despite these recent advances in the treatment of COPD, there is been associated with liver toxicity, mainly due to off-target effects still a pressing medical need to develop new therapies targeted at fi [135], two novel compounds had encouraging ef cacy and safety preventing disease progression and reducing mortality and exac- fi pro les in short-term studies in COPD. A single oral dose of the erbations. In this context, targeting inflammation represents the p38a-selective inhibitor dilmapimod (SB681323) reduced the most promising approach; Novartis is fully committed to devel- levels of phosphorylated heat shock protein 27 (p-HSP27), a marker oping novel anti-inflammatory drugs able to address different as- of p38 MAPK activation, and TNF-a in whole blood derived from pects of the pathophysiology of COPD. Novartis is also actively patients with COPD [139]. A reduction in sputum neutrophils, involved in several collaborations with the aim of gaining new in- accompanied by an improvement in FVC but not in FEV1, was also sights into the complexity of COPD and identifying novel COPD reported in a 4-week treatment using this compound [140].Ina6- phenotypes. This commitment is central to the achievement of week study different doses of PH797804, another inhibitor of p38a, Novartis’ final goal: developing innovative therapies in COPD to fi signi cantly increased FEV1 with concomitant improvement in improve patients’ lives. dyspnea score and IC [141]. The efficacy, safety and tolerability of the oral Novartis inhibitor BCT197 are under evaluation in a randomized, double-blind, placebo-controlled study in patients with Acknowledgments an acute COPD exacerbation [142]. Inhaled p38 inhibitors, are currently under development for the The authors were assisted in the preparation of the manuscript treatment of COPD, with the aim of improving efficacy and further by Roberta Sottocornola, a professional medical writers contracted fi reducing systemic effects [143]. to CircleScience (Maccles eld, UK), and Mark J Fedele (Novartis). Writing support was funded by the study sponsor. 5. The future of COPD management: tailoring therapies to phenotypes References

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