Emerging therapeutic strategies in COPD.

Drug Discovery Today Volume 00, Number 00 December 2014

REVIEWS

Reviews

Emerging therapeutic strategies in COPD Kesavan S. Babu1 and Jaymin B. Morjaria2 1 2

Dept of Respiratory Medicine, Queen Alexandra Hospital, Southwick Road, Cosham, Portsmouth PO6 3LY, UK Dept of Academic Respiratory Medicine, Hull York Medical School, University of Hull, Castle Hill Hospital, Castle Road, Cottingham HU16 5JQ, UK

Chronic obstructive pulmonary disease (COPD) management is changing with the advent of newer inhaled medications and devices that belong to the current group of therapies [i.e. inhaled corticosteroid (ICS), long-acting b2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs)], providing patients as well as physicians with a wider range of options. In this review, we examine Phase II studies currently underway in COPD patients. With improved understanding of the condition, the role for biological and immunomodulatory therapies in COPD patients is also an interesting and important aspect looked upon with great enthusiasm. It is indeed interesting to note that the future COPD treatment options could include novel interventional strategies in addition to innovative inhaled therapies, which have been the backbone of COPD management for the past couple of decades. Introduction Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterised by progressive airflow limitation caused by chronic airway inflammation which is normally in response to inhalation of noxious particles and gases mainly from tobacco smoking [1]. It is a multicomponent condition typified by a range of pathological airway and parenchymal changes including mucus hypersecretion, airway narrowing and fibrosis, as well as loss of alveoli [2]. It has systemic manifestations with loss of mean body mass, osteoporosis, cardiovascular and psychosocial effects [3]. Overall COPD affects millions, and globally mortality caused by COPD is expected to rise to become the third most common cause of death in the next two decades [1]. Hence, it is vital that preventative and treatment strategies are in place to avert depriving these patients of their quality of life, disease progression, worsening morbidity and reduced productivity as well premature mortality. The main goals of pharmacotherapy in COPD are to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status and increase exercise capacity. The Global Initiative for Chronic Obstructive Lung

Corresponding author: Morjaria, J.B. ([email protected]), ([email protected])

Disease (GOLD) recommends the use of long-acting bronchodilators as first-line maintenance therapy in moderate-to-severe COPD [1]. However, when patients remain uncontrolled despite being on bronchodilators, add-on therapies such as corticosteroids as well as phosphodiesterase (PDE) inhibitors have been cautiously employed [4,5]. With such high morbidity, mortality and economic implications researchers with a better understanding of the pathophysiology are exploring newer molecules and modalities to develop therapeutic strategies for this devastating condition. In this review, we discuss therapies in Phase II development for COPD. We conducted searches of newer therapeutic advances in the form of novel administration strategies, combinations and molecules, as well as improved efficacy and safety of conventional treatments. Relevant information pertaining to these new agents was made available by conducting detailed literature searches from PubMed, abstracts presented at international respiratory conferences, namely the American Thoracic and European Respiratory Societies (2009–2013), early stage compounds from the clinical trials websites and pharma industry websites. We have divided the review into conventional bronchodilators and anti-inflammatory therapies either as monotherapy or combination therapies, immunomodulatory therapies and subsequently other strategies for ease of reading.

www.drugdiscoverytoday.com Please cite this article in press as: Babu, K.S., Morjaria, J.B. Emerging therapeutic strategies in COPD, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.11.003

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DRUDIS-1534; No of Pages 9 REVIEWS

Bronchodilators Bronchodilators remain an important aspect of management of patients with COPD. Those in Phase II development are summarised in Table 1.

b2 Agonists

Reviews

Pearl Therapeutics (now part of Astra Zeneca, UK) has developed an alternative formulation of formoterol fumarate (FF), which generates a unique aerosol formulation of porous particles with aerodynamic advantages and minimised interaction between molecules, to be administered via a metered-dose inhaler (MDI). Studies of FF versus marketed Foradil1 Aerolizer1 (Merck, USA) administered twice-daily report comparable bioequivalence and efficacy in moderate-to-very-severe COPD patients [6,7]. This could provide an alternative device option for COPD patients who prefer MDIs. Abediterol (LAS100977; Almirall, Spain) is an inhaled ultra-LABA (long-acting b2 agonist) that has been reported from preclinical studies to be a full b2 agonist, with an increased affinity and functional sensitivity for b2-adrenoceptors over b1-adrenoceptors compared with licensed formoterol and indacaterol [8]. LAS100977 was ten-times more potent than salmeterol and similar to formoterol and indacaterol. The duration of action of LAS100977 was significantly longer (670 min) compared with formoterol and salmeterol (77 and 230 min, respectively). Furthermore, LAS100977 demonstrated higher b2 versus b1 selectivity than formoterol or indacaterol. In healthy subjects LAS100977 has a protracted increase in airway conductance of >24 h with a good tolerability profile [9]. In adult patients with COPD single doses of LAS100977 (0.625 mg, 2.5 mg, 5 mg and 10 mg via Genuair1), indacaterol (150 mg via Breezhaler1) and placebo were evaluated in a six-period crossover study. Single inhaled doses of LAS100977 0.625–10.000 mg induced and maintained significant bronchodilation versus placebo and were well tolerated [10]. LAS100977 once-daily in fixed-dose combination (FDC) with an inhaled corticosteroid (ICS) is now ready to move into Phase IIb clinical development worldwide for asthma and COPD. In a recent Phase I study in healthy volunteers, co-administration of LAS100977 and mometasone as a fixed-dose combination had minimal impact on the pharmacokinetic parameters of either drug within the predicted therapeutic range. LAS100977 belongs to a group dubbed as ultra-LABAs (i.e. the drug is retained in the lipid rafts of the plasma membrane for long periods achieving an effect that lasts up to 24 h). The other molecules being investigated include milveterol and carmoterol. Parenteral administered bedoradine (MN-221) (MediNova, USA), an ultra-selective b2 agonist, has been examined in two Phase I studies in moderate-to-severe COPD subjects (NCT01551316, NCT01013142) as an add-on therapy to current treatment (ICS, anticholinergics and b2 agonists). In one of these studies, following six i.v. infusions over 4 days, bedoradine was reported to improve forced expiratory volume in 1 s (FEV1), had no significant plasma accumulation, was well tolerated and had minimal safety issues (NCT01551316). Although not in Phase II development, bedoradine shows promise. Presently, there are limited data available as to its predicted future progression.

Anticholinergics Long-acting muscarinic antagonists (LAMAs). Glycopyrolate MDI (PT001) by Pearl Pharmaceuticals (now part of Astra 2


Zeneca, UK) has demonstrated comparable efficacy and safety to tiotropium in a randomised, double-blind, crossover study in patients with moderate-to-very-severe COPD [11]. Further trials are ongoing with combinations including formoterol (NCT01854658). The dissociation half-life of glycopyrrolate from M3 receptors is shorter than that of tiotropium or aclidinium [12], and in bronchial preparations in vitro its effect does not seem to be as long-lasting as that of tiotropium [13]. Clinical studies, however, have shown that its rapid bronchodilating effect is maintained over 24 h. With regard to its safety profile, glycopyrrolate was well tolerated with few drug class side-effects. Doses of 100 mg have also proved safe, probably owing to the greater selectivity of glycopyrrolate for M3 over M2 receptors. Theravance (USA), through the application of a multivalent design, has developed a novel inhaled LAMA: TD-4208. Preclinical data have shown enhanced affinity for the M3 compared with M2 receptors, and a prolonged duration of action of >16 h with no safety concerns [14,15]. In preclinical studies, TD-4208 has shown greater functional selectivity for the lung. Although there is limited information available from Phase I studies, in a dose-ranging, double-blind placebo-controlled (DBPC) including ipratropium bromide (IB), four-way crossover, Phase IIa study in moderateto-severe COPD subjects, nebulised TD-4208 was well tolerated and had similar onset of action to IB. However, unlike IB, TD-4208 had sustained bronchodilatory activity as measured by FEV1 at 12 h and 24 h [16]. Recently, it has been shown that single doses of nebulised TD-4208 at 350 mg and 700 mg have minimal systemic exposure and M3 receptor occupancy [17]. Theravance has proposed that nebulised TD-4208 might not only be considered for use as monotherapy but also in combination with other agents [18]. AZD8683 (AstraZeneca, UK), after rigorous preclinical evaluation for onset of action, efficacy and safety, was selected for formal assessment in clinical studies [19]. Phase I studies reported no safety concerns (NCT00979849) and, more recently, Phase II studies in COPD subjects (NCT01205269, NCT01708057) at various doses of AZD8683 versus placebo and tiotropium have been conducted and results are awaited. Sunovion Pharmaceuticals (USA) and Pari Pharma (Germany) have produced a nebulised solution, SUN-101, which is a proprietary inhaled solution formulation of glycopyrrolate (GP), a wellknown and widely used LAMA, that can be administered using the customised eFlow1 nebuliser system. This novel nebuliser system offers the benefits of a reduced administration time compared with the conventional nebuliser and a more portable size with minimal noise levels. In a Phase IIb, multicentre, DBPC, four-period, crossover study 140 moderate-to-severe COPD subjects were randomised to receive SUN-101 (placebo, 25 mg, 50 mg, 100 mg and 200 mg o.d.), open-label tiotropium 18 mg o.d. and open-label IB 500 mg t.i.d. via a jet nebuliser (GOLDEN-1 study) [20]. SUN-101 was well tolerated with no significant safety concerns. There were significant clinical improvements in 24 h FEV1 area under the curve (AUC) in favour of all the SUN-101 doses. Another dose-ranging, six-period crossover, DBPC study in 42 moderate-to-severe COPD subjects assessed the safety and efficacy of single doses of SUN-101 (12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg and 400 mg) and placebo [11]. Besides reporting similar positive outcomes in favour of SUN101 in the Fogarty et al. study [20], SUN-101 had a rapid onset of


DRUDIS-1534; No of Pages 9 Drug Discovery Today Volume 00, Number 00 December 2014

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TABLE 1

Bronchodilator and corticosteroid (inhaled, nebulised, oral, intravenous) compounds in current Phase II development and their efficacy endpoints Company

Delivery mode

Efficacy endpoints

Progression of compound

Inhaled via MDI

TD-4208[16,17]

Theravance

AZD8683[19]

AstraZeneca

Inhaled DPI via TurbohalerW o.d.

SUN-101[11,20]

Sunovion Pharmaceuticals & Pari Pharma

Nebulised using the eFlowW system

Bioequivalent and efficacious compared with ForadilW AerolizerW (currently approved DPI) Doses of 2.5, 5 and 10 mg of abideterol showed superior bonchodialtion compared with placebo and 150 mg of indacaterol Compared with placebo improved bronchodilation but with IB Similar onset of action but longer duration of bronchodilation compared with IB No safety concerns and comparable AEs to placebo and IB Compared with placebo showed significant improvements in peak and trough FEV1 and FVC, but not with formoterol 9 mg b.i.d. No benefits in reliever use, symptom scores, AEs or safety concerns compared to placebo and formoterol Improvements in 24 h FEV1 AUC and a rapid onset of action compared with inhaled tiotropium, nebulised IB and placebo No safety concerns or significant numbers of AEs

Yes

Abediterol (LAS100977)[10]

Pearl Therapeutics (now AstraZeneca) Almirall

MABAs GSK961081[25,26]

GlaxoSmithKline

Inhaled

Yes

AZD2115

AstraZeneca

Inhaled

Day 29 FVC measurements and reliever use was improved compared with placebo Compared with tiotropium, salmeterol and placebo there was a rapid onset of action and significantly improved FEV1 measurements No safety concerns or increased AEs reported Undergoing assessment (NCT01498081)

NK

Monotherapy Formoterol furoate[6,7]

Inhaled DPI via GenuairW inhaler o.d. Nebulised

Yes

Yes Reviews

Drug name

Yes

Yes

Phosphodiesterase (PDE) inhibitors Tetomilast (OPC-6535) Otsuka Pharmaceuticals CHF6001[30-36] Cheisi Farmaceutici

Oral

Undergoing assessment (NCT00874497)

NK

Inhaled

Undergoing assessment (NCT01730404)

NK

LABA/LAMA combinations PT003

Pearl Therapeutics

Inhaled via MDI

Yes

BI 1744[37-40]

Boehringer Ingelheim

RespimatW Soft MistTM inhaler

Significantly superior 12 h AUC FEV1 at day 7, morning and evening PEF, and reliever use compared to OL tiotropium and components of PT003 (GB and FF) No safety concerns on cardiovascular and metabolic assessment No marked numbers of AEs compared with other assessed groups BI 1744 compared with tiotropium has improved 24 h bronchodilation Compared with olodaterol, BI 1744 had incremental improvements in the trough FEV1 and AUC 0–6 h No safety concerns or increased AEs No results available

NK (although currently in Phase III)

Triple therapy (ICS/LAMA/LABA) Cheisi Farmaceutici CHF1535

Inhaled

Yes

Abbreviations: AEs, adverse events; AUC, area under curve; BDI, baseline dyspnoea index; b.i.d., twice daily; CRP, C-reactive protein; DPI, dry powder inhaler; FF, formoterol furoate; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GB, glycopyrronium bromide; IB, ipratropium bromide; MDI, metered dose inhaler; o.d., once daily; OL, open label; NK, not known; PD, pharmacodynamics; PK, pharmacokinetics; SAEs, serious adverse events; TDI, transitional dyspnoea index.


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bronchodilation of 5 min. Hence, in COPD patients who are unable to benefit effectively from inhaler therapies, there is possibility of a new once-daily administered therapy with a rapid onset of action that is clinically efficacious with a good safety profile. Pulmatrix (USA) has developed PUR0200, an inhaled dry powder formulation of a LAMA enabled by a non-lactose approach using Pulmatrix iSPERSETM delivery technology. The Phase Ib study evaluated pharmacokinetics and pulmonary function after administration of four single ascending doses of PUR0200 in 24 patients with moderate COPD. All doses of PUR0200 were generally well tolerated and were associated with increases in lung function, as measured by peak and trough FEV1 from baseline compared with placebo dosing. PUR0200 is currently in clinical testing in a Phase Ib/IIa study with moderate COPD patients. Muscarinic receptor antagonist and b2 adrenoceptor agonists (MABAs). Dual-pharmacology MABA molecules present an interesting new approach to the treatment of COPD by combining muscarinic anticholinergic antagonism and b2 agonism in a single entity. They have the potential to demonstrate additive or synergistic bronchodilation over the pharmacological action alone [21]. Based on this premise, GlaxoSmithKline has developed GSK961081 (GlaxoSmithKline, UK). It is a bifunctional molecule with muscarinic antagonistic activity at one end separated by an inert linker portion from the b2 agonist at the other end. MABAs provide a fixed ratio of muscarinic antagonist and b2 agonist activity at a cellular level, have a single pharmacokinetic profile and deliver a fixed ratio of muscarinic antagonist and b2 agonist to the whole lung, simplifying combination delivery and clinical development programmes. Preclinical and Phase I studies have shown GSK961081 functionality and safety comparable to tiotropium and salmeterol [22–24]. There have been two Phase II studies with this molecule [25,26]; the first in 436 moderate-tosevere COPD subjects which showed that it was safe and there were statistical (and clinical) significant improvements in forced vital capacity (FVC) and reliever use [25] compared with placebo. In the second DBPC, crossover, 14-day study by Bateman et al., 50 moderate COPD subjects were treated with GSK961081 400 mg and 1200 mg o.d., tiotropium18 mg o.d. plus salmeterol 50 mg b.i.d. (T + S) and placebo [26]. GSK961081 was well tolerated and demonstrated sustained bronchodilation similar to tiotropium plus salmetrol with a quicker onset of action. Currently, there are no ongoing clinical trials with this molecule but the identification and its clinical use in patients with COPD does open up future opportunities. AZD2115 (AstraZeneca, UK) is an inhaled MABA that has been assessed for safety, tolerability, good pharmacodynamics and pharmacokinetics in Phase I studies (NCT01283984, NCT01445782). There is an ongoing DBPC, crossover, randomised Phase II study, assessing bronchodilatory efficacy outcomes and safety (NCT01498081 and NCT02109406) of AZD2115. The other novel MABAs being evaluated include THRX-198321 (Theravance, USA) and LAS190792 (Almirall, Spain), which are currently in preclinical stages.

PDE inhibitors The PDE family of enzymes hydrolyses cyclic (c)AMP and cGMP, which regulate a variety of cellular processes including smooth muscle relaxation and inflammatory mediator release [27]. Eleven 4


PDE gene families have been identified denoted PDE1–11 and they differ in their primary structure and affinities to cAMP and cGMP. PDE3 and PDE4 are believed to play a part in COPD. Roflumilast, a selective PDE4 inhibitor is currently available for the treatment of patients with COPD [5]. Tetomilast (OPC-6535) developed by Otsuka Pharmaceuticals (Japan) is an oral PDE4 inhibitor being investigated in patients with COPD. It is believed that tetomilast could inhibit the development of emphysema by attenuating pulmonary inflammation and apoptosis caused by oxidative stress [28]. Presently, a Phase II study is underway in patients with COPD and emphysema (NCT00874497) to assess these postulations. Chiesi Farmaceutici (Italy) has developed an inhaled PDE4 inhibitor, CHF6001, which is being evaluated for safety, tolerability and pharmacokinetics in healthy individuals (NCT01703052). This is currently being evaluated in COPD GOLD stage 2 and 3 subjects for tolerability and efficacy (NCT01730404). Although not at the Phase II COPD assessment stage, Verona Pharma (UK) has developed RPL554 (EudraCT2010-023573-1): an inhaled PDE3/4 inhibitor. It has mainly been assessed in asthma but in a small study in mild-to-moderate COPD has been shown to be safe, well tolerated and have a rapid onset of bronchodilation. The bronchodilation was equivalent to salbutamol and significantly better than placebo [29]. Overall, RPL554 was well tolerated and adverse events were generally mild and of equal frequency between placebo and active treatment groups. In patients with COPD RPL554 improved the mean maximum FEV1 by 17.2%.

Combination therapy Currently, various combinations are available for patients with COPD including LABA/ICS and LABA/LAMA. Newer combinations are being evaluated and these are summarised in Table 2.

LABA/LAMA combinations COPD guidelines suggest benefit in combining bronchodilators of different classes [1]. PT003 (Pearl Therapeutics, now part of AstraZeneca, UK) is an inhaled LAMA/LABA combination bronchodilator comprising GP and FF (GFF) delivered via a hydrofluoroalkane (HFA)-MDI. In a dose-ranging study (1.2 mg GP + 9.6 mg FF, 2.4 mg GP + 9.6 mg FF, 4.6 mg GP + 9.6 mg FF, 9.0 mg GP + 9.6 mg FF, 18.0 mg GP + 9.6 mg FF) involving 132 moderate-to-severe COPD patients, except for the lowest dose, GFF MDI administered twicedaily was significantly superior in 12 h AUC FEV1 at day 7 to openlabel tiotropium (18 mg) and its components: GP MDI (18 mg) and FF MDI (9.6 mg) [30]. Moreover, the bronchodilatory response with GFF 18.0:9.6 mg was larger and clinically relevant than the lower doses as well as open-label tiotropium. The higher doses of GFF MDI (36.0:9.6 mg and 72.0:9.6 mg) also proved better than its MDI monocomponents (GP 36 mg, FF 9.6 mg), open-label tiotropium and FF in morning and evening mean pre-dose and post-dose PEF at day 7 as well as rescue medication requirements [31]. With the possible risk of cardiovascular and systemic adverse events using LABAs, pooled analyses of efficacy and safety studies have reported no major concerns at various doses with GFF MDI [32–35]. More recently, a further pooled analyses confirmed that the dose of 18.0:9.6 mg should be used in taking GFF MDI into Phase III development [36]. PT003, with its efficacy and safety profile, holds potential as a good combination bronchodilator candidate.


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TABLE 2

Novel anti-inflammatory agents in current Phase II development and their efficacy endpoints achieved Delivery mode

Efficacy endpoints

Progression of compound

Mitogen-activated protein (MAP) kinase inhibitors PH-797804[44] –Pfizer

Oral

NK

Losmapimod (GW856553X)[45]

GlaxoSmithKline

Oral

JNJ49095397 (RV568)[53]

Janssen Research & Development

Oral

Improvements from baseline TDI total focal score at week 6 with the 3 mg and 6 mg doses Significant increase in trough FEV1 compared with placebo in patients administered 3 mg and 6 mg doses No safety or increases in AEs noted No significant increase in 6MWT or lung function compared to placebo Improvement in hyperinflation compared with placebo but not versus salmeterol/fluticasone Significant reductions in plasma fibrinogen No safety concerns Superior to placebo in FEV1 Marked reduction in serum and sputum inflammatory markers No safety concerns

Novartis

Intravenous

No

MedImmune and AstraZeneca MedImmune and AstraZeneca

Intravenous

No available outcome data; although had lack of efficacy in COPD patients No data available (NCT01448850)

Subcutaneous

Depletion of peripheral and sputum eosinophils No difference in rate reduction of acute exacerbations of COPD compared to placebo Significant improvement in FEV1 compared with placebo

NK

Other agents CRTH2 antagonism – AZD1981[60]

AstraZeneca

Oral

NK

NE antagonism – AZD9668[62]

AstraZeneca

Oral

EGFR kinase inhibition – BIBW2948 BS[64]

Boehringer Ingelheim

Inhaled

No improvement in any objective or subjective parameters assessed compared to placebo No safety concerns and significant AEs No improvements in any objective or subjective, or time to first exacerbation No safety concerns or significant AEs No significant decrease in epithelial mucin stores Poorly tolerated

Monoclonal antibodies IL-1b antagonism – canakinumab[56] IL-1 receptor antagonism – Medi-8968 IL-5 receptor antagonism – benralizumab[59]

Company

NK

Reviews

Drug name

Yes

NK

NK

NK

Abbreviations: AEs, adverse events; b.i.d., twice daily; COPD, chronic obstructive pulmonary disease; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; EGFR, epidermal growth factor receptor; FEV1, forced expiratory volume in 1 s; FEV6, forced expiratory volume in 6 s; IC, inspiratory capacity; IL, interleukin; 6MWT, 6 minute walk test; NE, neutrophil elastase; NK, not known; TDI, transitional dyspnoea index.

Tiotropium and olodaterol (BI 1744) (Boehringer Ingelheim, Germany), both with 24 h duration of action in [37,38], have been assessed in combination through the Respimat1 Soft MistTM inhaler. When compared with tiotropium 5 mg monotherapy, tiotropium plus olodaterol (5:10 mg) proved to be superior in 24 h bronchodilation and was safe following 4 weeks of once-daily dosing in moderate-to-severe COPD patients [39]. Similarly, in a dose-optimisation study conducted recently the tiotropium and olodaterol combination therapy resulted in incremental improvements in lung function (trough FEV1 and AUC0–6 h) compared with olodaterol monotherapy after 4 weeks of treatment with no safety issues of note [40]. Other combinations that have been assessed for safety and efficacy in COPD patients, however not in Phase II development, include a combination of darotropium (GSK233705) -a LAMA and GSK642444 -a LABA (GlaxoSmithKline, UK) [41].

formoterol furoate (6 mg) (CHF5993) versus dual therapy of beclomethasone propionate (100 mg) plus formoterol furoate (6 mg) (CHF1535) in an MDI to assess the safety and efficacy in moderateto-severe COPD subjects (NCT01584505, EudraCT 2011-00358831, EudraCT 2011-004759-37). Although we have no outcome data, currently Phase III trials are underway with CHF5993 (NCT01917331). GSK961081 (LAMA/LABA) (GlaxoSmithKline, UK) has been evaluated as a twice-daily fixed combination with fluticasone propionate (FP) from a single DPI device [i.e. triple therapy compared to using separate DPI devices comparing its components (GSK961081 and FP) in healthy volunteers (NCT01449799)]. Although not in Phase II development, the combination of GSK961081 and FP, like CHF5993, holds promise in COPD patients who benefit from triple therapy.

Triple therapy (ICS/LABA/LAMA)

Novel anti-inflammatory agents (Table 2) Mitogen-activated protein kinase (MAPK) inhibitors

Chiesi Farmaceutici (Italy) have conducted two Phase II, doseranging studies using varying doses of triple therapy of glycopyronnium (12.5 mg) with beclomethasone propionate (100 mg) and

MAPKs are highly conserved protein kinases activated by stress. p38 MAPK pathways are activated by environmental stimuli, like


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tobacco smoke, by endogenous signals such as cytokines and growth factors in patients with COPD. The p38 MAPK pathway activation leads to enhanced inflammatory gene transcription, thereby promoting inflammation. Mucus hypersecretion in COPD is thought to be driven by interleukin (IL)-13 produced by immune cells. p38 MAPK has been implicated in signalling pathways responsible for controlling IL-13 gene expression [42]. Therefore development of MAPK inhibitors to treat COPD seems a logical step forward [43]. MacNee and colleagues investigated the efficacy and safety of an oral p38 MAPK inhibitor, PH-797804 (Pfizer, USA), in patients with COPD [44]. In this randomised, DBPC, multicentre trial, 230 patients were randomised to receive placebo, 0.5 mg, 3 mg, 6 mg or 10 mg PH-797804 o.d. for 6 weeks. PH-797804 was well tolerated and 3 mg and 6 mg doses showed an improvement in the dyspnoea index/transition dyspnoea index (TDI) total focal score. There was also a statistically significant improvement in trough FEV1 at week 6 compared with placebo in patients administered 3 mg and 6 mg of PH-797804. The most commonly reported treatment-related adverse effect was acneiform rashes. The entry criteria for this study required patients with moderate-to-severe COPD. Phenotyping and use of biomarkers to identify the subset of responders would provide a therapeutic breakthrough for the use of disease-modifying agents in COPD. Losmapimod (GW856553X; GlaxoSmithKline, UK) is an orally administered potent and selective inhibitor of p38 MAPK which was evaluated in 602 patients with moderate-to-severe COPD. Patients were randomly assigned (1:1:1:1) to one of losmapimod 2.5 mg, 7.5 mg or 15 mg or placebo, twice daily for 24 weeks [45]. There was no significant difference in the 6-minute walk test (6MWT) or lung function between the losmapimod and placebo groups. Losmapimod was well tolerated in patients with COPD. In another study oral losmapimod (7.5 mg) b.i.d. was compared to inhaled salmeterol/fluticasone 50:500 mg or placebo in 302 patients with GOLD II COPD [46]. The lack of benefit with losmapimod in COPD has not deterred this drug entering Phase III trials in acute coronary syndrome. JNJ49095397 (also called RV568; Janssen Research & Development, Johnson and Johnson, USA) is a narrow-spectrum inhaled MAPK inhibitor which has anti-inflammatory activity. Various preclinical studies have reported its efficacy in inhibiting proinflammatory cytokine gene expression, histamine-induced hyperresponsiveness and human rhinovirus (HRV) 16 inflammation and replication [47–52]. In 28 GOLD II/III COPD subjects it was reported that RV568 was superior to placebo in FEV1 measurements, serum and sputum inflammatory markers and was safe [53]. With these safety, pharmacokinetic and pharmacodynamic profiles, inhaled RV568 has been advanced into further Phase II clinical studies in COPD subjects (NCT01867762). AZD7624 is also an inhaled p38 MAPK inhibitor currently in early trials for COPD (NCT01817855).

Other anti-inflammatory agents EpiGenesis Pharmaceuticals (EPI-12323) has developed a molecule that does not bind to glucocorticoid receptors thereby avoiding corticosteroid-related adverse events, with a prolonged duration of action and hence suitable for once-daily use. There is a reference of this molecule being evaluated in COPD however there are no 6


available data relating to any studies or outcomes at present [54]. Similarly, PUR118 has anti-inflammatory efficacy (improvements in biomarkers of inflammation and mucus clearance) and is safe in healthy and COPD subjects (NCT01333904, NCT01690949). PUR118 uses small molecule iSPERSETM (inhaled small particles easily respirable and emitted) technology, using proprietary cationic salt formulations rather than carrier lactose molecules. This is a novel dry powder delivery platform. Both these molecules (EPI-12323 and PUR118) have been proposed to undergo Phase II assessment [54]. The advantages of iSPERSETM technology would accommodate delivery of high drug payloads per powder volume and large drug molecules in highly dispersible particles, yielding superior drug delivery capabilities compared with conventional dry powder technologies that rely on the use of lactose blending or low-density particles.

Monoclonal antibodies (Table 2) IL-1b antagonism IL-1b is a proinflammatory cytokine that acts as mediator of the peripheral immune response during infection and inflammation [55]. The levels of IL-1b are elevated in patients with COPD. Canakinumab (Novartis, Switzerland) is a human IgGk monoclonal antibody targeting IL-1b that was assessed in a 45-week Phase I/ II study (NCT00581945) in 130 adult patients with COPD. Canakinumab was ineffective and hence its development has ceased [56]. Medi-8968 (MedImmune/AstraZeneca, UK) is a monoclonal antibody directed against IL-1 receptor. This is currently being evaluated in a 52-week Phase II study in patients with moderate-tovery-severe COPD where subjects receive a single 600 mg i.v. infusion of Medi-8968 on a 4-week basis (NCT01448850).

IL-5 antagonism IL-5 is a eosinophilopoeic cytokine involved in the differentiation, maturation, migration, development, survival, trafficking and effector function of blood and local tissue eosinophils [57]. Benralizumab (MedImmune/AstraZeneca, UK) is an anti IL-5 monoclonal antibody that binds to receptors with a high affinity to IL-5Ra and thereby reduces eosinophilic inflammation [58]. In a Phase IIa study in moderate-to-severe COPD subjects with a prior exacerbation of their COPD in the past 12 months and sputum eosinophilia, subcutaneous bendraluzimab did not achieve its primary endpoint of reduction in exacerbations compared to placebo. However, there were significant improvements in the pre-bronchodilator FEV1 [59]. On a similar note, another antiIL-5 monoclonal antibody, mepolizumab (GlaxoSmithKline, UK), is currently undergoing Phase III evaluation in COPD patients with eosinophilia (NCT02105961).

Other agents Chemoattractant-receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonism CRTH2 is a G-protein-coupled receptor expressed by Th2 lymphocytes, eosinophils and basophils. CRTH2 receptor activation mediates the activation and chemotaxis of these cell types in response to prostaglandin D2 (PGD2), the major prostanoid produced by mast cells. The efficacy and tolerability of the selective CRTH2 (DP2) receptor antagonist AZD1981 at a dose of 1000 mg twicedaily (n = 61) (AstraZeneca, UK) has been compared with placebo


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(n = 57) in a DBPC study in patients with moderate-to-severe COPD [60]. There were no significant differences in the mean difference in change from baseline to end of treatment between AZD1981 and placebo for the co-primary endpoints of prebronchodilator FEV1 and Clinical COPD Questionnaire Score. Furthermore, there were no observed differences between treatments for the other outcomes of lung function, COPD symptom score, 6MWT, BODE index and use of reliever medication. AZD1981 was well tolerated. With the lack of obvious clinical benefit with AZD1981 in COPD patients further studies are unlikely.

REVIEWS

EGFR signalling is a complex pathway and its inappropriate activation leads to excessive airway proliferation, mucus overproduction and hypersecretion, and progressive distal lung fibrosis. It is increasingly accepted that the EGFR signalling pathway is a central regulator of airway mucus production and secretion [63]. The safety and efficacy of an inhaled EGFR inhibitor, BIBW2948 BS (Boehringer Ingelheim, Germany), was examined in 48 patients with COPD. Four weeks of treatment with BIBW2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggested that higher doses might be more effective at EGFR inhibition and decreasing mucin stores but the observed adverse events should be expected (NCT00423137) [64]. Other molecules in early evaluation in COPD include nuclear factor (NF)-kB inhibitors and IkB inhibitors.

There were no safety concerns or worsening of COPD with the use of ProchymalTM. Although there were no improvements in subjective or objective parameters of COPD assessed, the use of allogenic MSCs attenuated circulating C-reactive protein (CRP) levels in patients who had an elevated CRP at baseline. These observations provide the basis for subsequent cell therapy investigations. BioMarck Pharmaceuticals has developed BIO-11006, a myristolylated alanine-rich c-kinase substrate (MARCKS) protein inhibitor that blocks the release of mucus. In preclinical studies, BIO-11006 had a half-life of >1.9 h permitting sufficient pulmonary deposition by inhalation to result in pharmacological antiinflammatory effects in the lungs [66,67]. A Phase II safety and efficacy study has been completed using BIO-11006 (NCT00648245) and results are awaited. Inhaled bimosiamose (Revotar Biopharmaceuticals, now TPA Biotech, Germany) is a pan-selectin antagonist that has been evaluated in patients with COPD [68]. Selectins are a family of cell adhesion molecules involved in leukocyte extravasation to sites of inflammation. In a crossover, DBPC, multicentre trial, inhaled bimosiamose (10 mg) or placebo twice-daily was administered via breath actuated nebuliser for 28 days on top of standard bronchodilator therapy. Compared with placebo there was a decrease of sputum IL-8, neutrophil and macrophage numbers in the bimosiamose arm. There were small improvements in the lung functions. SH2-containing inositol-50 -phosphatase 1 (SHIP1) metabolises PI(3,4,5)P3 to PI(3,4)P2. AQX-1125 (Aquinox Pharmaceuticals, Canada) is an activator of SHIP1, which controls the PI3K cellular signalling pathway. If the PI3K pathway is overactive, immune cells can produce an abundance of proinflammatory signalling molecules and migrate to and concentrate in tissues, resulting in excessive or chronic inflammation. In humans, AQX-1125 has shown pharmacokinetic properties suitable for once-daily dosing. AQX-1125 demonstrated compelling activity in cigarettesmoke-related airway inflammation [69]. Currently, AQX-1125 is currently undergoing Phase II evaluation in COPD subjects (NCT01954628). Amarillo Biosciences (USA) sought to determine whether interferon (IFN)-a lozenges could have an antitussive effect in patients with COPD and idiopathic pulmonary fibrosis; however the study was terminated owing to insufficient patient accrual (NCT00690885). No further studies are planned on this compound in the literature. Other molecules like oral danirixin, a CXCR antagonist, are in early Phase II trials (NCT02130193). Retinoic acid is known to increase alveolar septation during lung development. A clinical trial with palovarotene failed to show significant benefit on lung density in moderate-to-severe emphysema patients with a1 antitrypsin deficiency [70].

Other molecules and/or therapies

Concluding remarks

The characteristics and biological activity as well as safety of ProchymalTM (remestemcel-L) (Osiris Therapeutics, USA) ex vivo cultured adult human mesenchymal stem cells (MSCs) suggest that it might be a good candidate for treating COPD subjects. In a Phase II, DBPC study 62 moderate-to-severe COPD patients were randomised to receive 4-monthly i.v. infusions of allogenic MSCs or placebo, and subsequently followed up for 2 years for safety [65].

COPD is a major health and economic burden to many individuals and societies throughout the world. The currently available medications predominantly target airways for bronchodilation and the inflammatory cascade with corticosteroids. Newer bronchodilators in the form of LABAs and LAMAs and the various newer combinations combined with newer inhaler devices are a great step forward for patients with COPD. Combination inhalers tend

Neutrophil elastase (NE) inhibitors NE is a serine protease secreted by neutrophils and macrophages during inflammation. Restoring the balance between NE and endogenous antiproteases by inhibiting NE could be a possible therapeutic option in patients with COPD where there is an overexpression of these enzymes. AZD9668 (AstraZeneca, UK) is a reversible and selective inhibitor of NE. In a DBPC, Phase IIb trial the efficacy and safety of AZD9668 (60 mg b.i.d.) versus placebo in 615 patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol showed no effect in favour of AZD9668 on lung function, respiratory signs and symptoms, SGRQ-C score or time to first exacerbation compared to placebo. The side-effect profile was similar to placebo [61]. Similar results were found when AZD9668 was evaluated in patients with COPD on tiotropium. Although AZD9668 was well tolerated, it showed no clinical benefit and no effect on biomarkers of inflammation or tissue degradation when added to tiotropium in patients with COPD [62]. Although both these studies did not have promising outcomes in patients with COPD, identification of biomarkers and selective targeting does offer exciting therapeutic opportunities in the management of COPD.

Epidermal growth factor receptor (EGFR) kinase inhibitors


7

Reviews



Reviews

to aid patient compliance and in some instances provide additive or synergistic effects for the medications. Molecules like PDE4 inhibitors, which were relegated in view of the side-effects, are being revaluated with a focus on local delivery of the medications to reduce the side-effect profile. The identification of nonsteroidal glucocorticoid receptor agonists, if found to have similar clinical efficacy to corticosteroids without the well known side-effect profile, would be suitable for these patients because ICS in COPD have clear risk reduction benefits in terms of exacerbation rates [4]. If these molecules prove to be efficacious then it is likely that we will have an anti-inflammatory drug without the corticosteroidrelated side-effects. With improved understanding of the pathophysiology underpinning COPD, modulating the inflammatory pathways with cytokine inhibitors has created newer therapeutic potentials (Table 2). The development of orally active MAPK inhibitors is an encouraging start for the role of cytokine modulation in COPD. MAPK inhibitors have been evaluated in other conditions like rheumatoid arthritis but unfortunately the efficacy has been short lived [71]. Although losamapimod did not show promising results in patients with COPD, the other two molecules, namely PH797804 and JNJ49095397, have the potential to be a therapeutic option in COPD patients. These studies were short in duration and long-term studies to evaluate the efficacy will shed further light on these molecules and their effectiveness in COPD. Most of the available MAPK inhibitors target the a-isoform which is highly expressed on immune cells. It is possible that MAPK inhibitors targeting the other isoforms (b, g and d) could serve as a therapeutic tool in patients with COPD. Identification of biomarkers and easy bedside diagnostic testing to identify responders does open up the gateway to stratified medicine. This would also give the provision of individualising


therapies for each and every patient based on their inflammatory profile and phenotypes [72]. Although there is a cautious optimism on the role of cytokine modulation, we have seen in the past that patients with rheumatological and inflammatory bowel disease benefit from the use of monoclonal antibodies. Newer innovative approaches of identifying drug targets, collaborative work with the pharmaceutical industry and academia and early, safe, robust and reliable clinical trials will pave the way for early introduction of newer molecules into clinical practice with an aim to reduce the morbidity and mortality of COPD.

Conflicts of interest K.S.B. has received honoraria for speaking at (and financial support to attend) meetings from Teva, GSK Wyeth, Chiesi and AstraZeneca. J.B.M. has received honoraria for speaking at (and financial support to attend) meetings and/or advisory boards from Wyeth, Chiesi, Pfizer, MSD, Boehringer Ingelheim, Teva, GlaxoSmithKline/Allen & Hanburys, Napp, Almirall, AstraZeneca and Novartis.

Acknowledgments The authors should like to highlight the following references. The first MDI LABA monotherapy assessed in the USA with similar bioequivalence, safety and efficacy compared to a licensed DPI [6]. First study showing the use of a single molecule with bifunctional properties being efficacious in objective and subjective COPD parameters [23]. An excellent review examining the possibilities of MAPK inhibitors as a therapeutic modality in COPD [40]. This study, although not reporting positive outcomes, shows that there could be a role for human MSCs in COPD safely [62].

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10 Beier, J. et al. (2013) Efficacy and safety of abediterol (LAS100977) in patients with COPD: Phase II, randomised, crossover study. Am. J. Respir. Crit. Care Med. 42, A183 11 Singh, D. et al. (2011) Efficacy and safety of nebulized glycopyrrolate (EP-101) for administration using high efficiency nebulizer in patients with COPD. Eur. Respir. J. 38 (Suppl. 55), 147 A865 12 Casarosa, P. et al. (2009) Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs. J. Pharmacol. Exp. Ther. 330, 660–668 13 Villetti, G. et al. (2006) Pharmacological assessment of the duration of action of glycopyrrolate vs tiotropium and ipratropium in guinea-pig and human airways. Br. J. Pharmacol. 148, 291–298 14 Pulido-Rios, M.T. et al. (2009) TD-4208: a novel, lung-selective muscarinic antagonist with sustained bronchoprotective activity in preclinical models. Am. J. Resp. Crit. Care Med. 179, A4557 15 Steinfield, T. et al. (2009) In vitro characterisation of TD-4208, a lung-selective and longacting muscarinic antagonist bronchodilator. Am. J. Respir. Cell Mol. Biol. 179, A4553 16 Potgieter, P. et al. (2012) A randomised, crossover study to examine the pharmacodynamics and afety of a new antimuscarinic (TD-4208) in COPD. Eur. Respir. J. 40 (Suppl. 56), 524 A2878 17 Baldwin, M. et al. (2013) Single-dose pharmacokinetics of TD-4208, a novel longacting muscarinic antagonist, in patients with COPD. Am. J. Resp. Crit. Care Med. 187, A1496 18 (2012) Theravance initiates TD-4208 Phase 2b dose ranging study. Pharma. Business Rev. http://drugdelivery.pharmaceutical-business-review.com/news/theravanceinitiates-td-4208-phase-2b-dose-ranging-study-121212 19 Mete, A. et al. (2013) The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD. Bioorg. Med. Chem. Lett. 23, 6248–6253


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J. 42 (Suppl. 57), P4141 33 Fabbri, L. et al. (2013) Pooled analyses of QTcF across six Phase 2b studies with glycopyrrolate-formoterol fumarate (GFF) MDI, its components and active comparators. Eur. Respir. J. 42 (Suppl. 57), P759 34 Reisner, C. et al. (2013) Pearl Therapuetics’ combination LAMA/LABA (GFF MDI, PT003) provides comparable safety as measured by 24-hour Holter monitoring to its components (GP MDI, PT001 And FF MDI, PT005) and Foradil1 Aerolizer1. Am. J. Respir. Crit. Care Med. 187, A1485 35 Reisner, C. et al. (2012) Pearl Therapeutics’ combination LAMA/LABA MDI (GFF MDI, PT003) provides comparable metabolic and ECG safety to Spiriva1 Handihaler1 and placebo in patients with COPD. Am. J. Respir. Crit. Care Med. 185, A2925 36 Reisner, C. et al. (2013) Pooled analyses of five Phase 2b studies support dose selection of glycopyrrolate-formoterol (GFF) MDI (PT003) 18/9.6 mg for Phase III development. Eur. Respir. J. 42 (Suppl. 57), A4153 37 van Noord, J.A. et al. 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Cell Biol. 2014, 272689 43 Buhler, S. and Laufer, S.A. (2014) p38 MAPK inhibitors: a patent review (2012– 2013). Expert Opin. Ther. Pat. 24, 535–554 44 MacNee, W. et al. (2013) Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax 68, 738–745

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45 Watz, H. et al. (2014) Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet Respir. Med. 2, 63–72 46 Lomas, D.A. et al. (2012) An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J. Clin. Pharmacol. 52, 416–424 47 Charron, C. et al. (2011) Superior effects of RV568, a novel narrow spectrum kinase inhibitor, to BIRB796, a P38MAPK inhibitor, on pro-inflammatory cytokine roduction in macrophages. Am. J. Resp. Crit. Care Med. 183, A3088 48 Kizawa, Y. et al. (2011) Effects of RV568, a narrow spectrum kinase inhibitor, on airway inflammation and hyperresponsiveness in tobacco-smoke exposed mice. Am. J. Resp. Crit. Care Med. 183, A3103 49 Charron, C. et al. 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9

Reviews


Emerging Molecularly-Targeted Therapeutic Strategies in Brain Cancer. Introduction.

Metabolic reprogramming: the emerging concept and associated therapeutic strategies.

TNF biology, pathogenic mechanisms and emerging therapeutic strategies.

Emerging pharmaceutical therapies for COPD.

Necrotizing enterocolitis in newborns: update in pathophysiology and newly emerging therapeutic strategies.

Current and Emerging Therapeutic Strategies for the Treatment of Meibomian Gland Dysfunction (MGD).

Mysteries of α1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease.

Emerging immunotherapy strategies in breast cancer.

Identification of Novel Therapeutic Targets in COPD.

Emerging nanotherapeutic strategies in breast cancer.

Opinion paper: emerging markets, emerging strategies under the genomic revolution.

Therapeutic strategies in lymphangioleiomyomatosis (LAM).

Theme 11 therapeutic strategies.

New therapeutic strategies emerge.

New therapeutic strategies emerge.

Strategies for therapeutic hypometabothermia.

MAP4K4: an emerging therapeutic target in cancer.

Emerging therapeutic targets in esophageal adenocarcinoma.

Emerging therapeutic targets in bladder cancer.

Phytotherapy: emerging therapeutic option in urologic disease.

Emerging treatment strategies for glioblastoma multiforme.

Emerging strategies to deplete the HIV reservoir.

Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies.

[Therapeutic strategies: Ways to remission].