Indacaterol The First Once-daily Long-acting Beta2 Agonist for COPD
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2 Milestones in Drug Therapy Series Editors: Michael J. Parnham Jacques Bruinvels Alexandre Trifilieff Editor Indacaterol The First Once-daily Long-acting Beta2 Agonist for COPD
3 Milestones in Drug Therapy Series Editors Michael J. Parnham, Fraunhofer IME & Goethe University Frankfurt, Germany Jacques Bruinvels, Bilthoven, The Netherlands Advisory Board J.C. Buckingham, Imperial College School of Medicine, London, UK R.J. Flower, The William Harvey Research Institute, London, UK A.G. Herman, Universiteit Antwerpen, Antwerp, Belgium P. Skolnick, National Institute on Drug Abuse, Bethesda, MD, USA For further volumes:
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5 Alexandre Trifilieff Editor Indacaterol The First Once-daily Long-acting Beta2 Agonist for COPD
6 Editor Alexandre Trifilieff Respiratory Diseases Area Novartis Institutes for BioMedical Research Basel, Switzerland ISBN ISBN (ebook) DOI / Springer Basel Heidelberg New York Dordrecht London Library of Congress Control Number: Springer Basel 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (
7 Preface Chronic obstructive pulmonary disease (COPD) is a multicomponent disease (including emphysema and chronic bronchitis which may or may not coexist in the same individual) leading to a disease state characterized by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lung. This disease constitutes a major public health burden worldwide, and the World Health Organization estimates COPD to be the world s fifth most common disease and fourth leading cause of death. Very few effective therapies are available, and bronchodilatator therapy, such as long-acting inhaled β2-agonists or inhaled anticholinergic agents, is the mainstay of the management of this disease. Onbrez Breezhaler is a newly approved once-daily inhaled β2-agonist for the treatment of COPD. This book has been put together in order to provide the reader with a comprehensive review of the development of Onbrez Breezhaler from the chemical design of the molecule up to the clinical program that was performed for registration. A review of current pharmacotherapy for COPD is covered by J. Donohue and colleagues. R Fairhurst et al. summarized the chemical design and the preclinical pharmacology of the molecule. The early clinical development of Onbrez is reviewed by J. Beier and K-M Beeh. D. Lawrence et al. described the INHANCE study that provides a successful example of the use of an adaptive design in the confirmatory setting. The phase III clinical efficacy is presented by R. Dahl and D. Mahler, while D Young et al. described the history and performance of the Breezhaler device. Finally, P. Barnes has put together a list of emerging targets that could well be the future treatments for COPD. I would like to express my gratitude to all the contributors and hope the reader will benefit from reading this special issue on COPD. Basel, Switzerland Alexandre Trifilieff v
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9 Contents Current Pharmacotherapy for COPD... 1 James F. Donohue, Matthew C. Miles, and Jill A. Ohar The Preclinical Pharmacology of Indacaterol Alexandre Trifilieff, Steven J. Charlton, and Robin A. Fairhurst The Design of the Indacaterol Molecule Robin A. Fairhurst, Steven J. Charlton, and Alexandre Trifilieff The Early Clinical Development of Indacaterol Jutta Beier and Kai M. Beeh INHANCE: An Adaptive Confirmatory Study with Dose Selection at Interim David Lawrence, Frank Bretz, and Stuart Pocock Phase 3 Clinical Efficacy Studies: Lung Function Ronald Dahl Phase III Clinical Efficacy of Indacaterol: Patient-Centered Outcomes Donald A. Mahler The History and Performance of the Breezhaler Device David Young, Lee Wood, Dilraj Singh, and Juergen Dederichs What Does the Future Hold for the Therapy of COPD? Peter J. Barnes vii
10 Current Pharmacotherapy for COPD James F. Donohue, Matthew C. Miles, and Jill A. Ohar Abstract In this chapter, we are reviewing the current pharmacotherapy available for the treatment of chronic obstructive pulmonary disease (COPD). Both shortacting and long-acting bronchodilators have been used for many years for the treatment of COPD. Use of long-acting beta-agonists/long-acting muscarinic agents alone or together, often with inhaled corticosteroids, is commonplace in COPD. Long-acting anticholinergics are more effective in COPD because they improve the airflow and reduce air trapping at the same time. Oral methylxanthines, the precursors of phosphodiesterase type 4 (PDE4) inhibitors, also have a therapeutic role and are widely used in developing nations. PDE4 inhibitors (roflumilast being the only currently available agent) have a role limited to the severe and very severe patient with frequent exacerbations. Recent evidence suggests that maintenance antibiotic therapy may be additive to the effect of bronchodilators in reducing exacerbation frequency. The choice of agents may be based primarily on individual response, cost, side-effect profile, and availability. J.F. Donohue (*) University of North Carolina at Chapel Hill, CB# 7020, 130 Mason Farm Road, 4125 Bioinformatics Building, Chapel Hill, NC 27599, USA jdonohue@med.unc.edu M.C. Miles Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA mmiles@wakehealth.edu J.A. Ohar Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA johar@wakehealth.edu A. Trifilieff (ed.), Indacaterol, Milestones in Drug Therapy, DOI / _1, Springer Basel
11 2 J.F. Donohue et al. 1 Introduction Both short-acting and long-acting bronchodilators have been used for many years for the treatment of chronic obstructive pulmonary disease (COPD). Use of longacting beta agonists (LABAs)/long-acting muscarinic agents (LAMAs) alone or together, often with inhaled corticosteroids (ICS), is commonplace in COPD. The role of the beta-receptor genotype in affecting beta-agonist response is unclear but could hold promise in the future for optimal patient management. Long-acting anticholinergics are more effective in COPD because of their so-called volume dominant response [1] which means that they are as apt to improve FVC as FEV 1 (Fig. 1). Bronchodilators improve FEV 1 by improving airflow but improve FVC by reducing air trapping. Oral methylxanthines, the precursors of PDE4 inhibitors, also have a therapeutic role and are widely used in developing nations. PDE4 inhibitors (roflumilast being the only currently available agent) have a role limited to the severe and very severe patient with frequent exacerbations. Recent evidence suggests that maintenance antibiotic therapy may be additive to the effect of bronchodilators in reducing exacerbation frequency [2]. This review focuses on the LABAs, LAMAs, ICS, theophylline, roflumilast, and their combinations when used in COPD (Tables 1 and 2). 2 Beta2-Adrenoceptor Agonists 2.1 Pharmacology β 2 -adrenergic receptor (β 2 -AR) agonists act through binding to the β 2 -adrenergic receptor which is a member of the seven transmembrane domains, G-proteincoupled family of receptors. Adenyl cyclase is activated via the signal-transducing G s protein, which results in a rise in cellular cyclic AMP (camp) levels and activation of protein kinase A (PKA) when ligand binds to the β 2 -AR. The precise PKA phosphorylation targets mediating bronchial smooth muscle relaxation are not fully understood but are likely to include myosin light-chain kinase and Ca ++ - dependent K + (K ca ) channels [3]. Although β 2 -ARs are present in high density in airway smooth muscle cells, they are also present in submucosal glands; vascular endothelium; ciliated epithelium; mast cells; circulating inflammatory cells, such as eosinophils and lymphocytes; Clara cells; type II pneumocytes; and cholinergic ganglia. β 2 -AR agonists are delivered through the inhaled or oral route, although use of the latter is limited because of the increased risk of adverse effects. There are several important pharmacological differences among the existing agents [3, 4]. The onset of action is short (1 5 min) with albuterol and formoterol, while it is more prolonged with salmeterol (30 45 min). The difference in onset of action is related to the lipophilicity of each of these agents and their ability to activate the β 2 -AR in the aqueous phase (albuterol and formoterol). Albuterol has a
12 Current Pharmacotherapy for COPD 3 Fig. 1 Rationale for the use of bronchodilators in COPD 1) Physiologic Effects a) Airway smooth muscle relaxation Bronchodilation: Improve FEV1, lung volumes Decreased air trapping and dynamic hyperinflation b) Non-bronchodilator Effects 2) Clinical Effects Breathlessness ( airway resistance, hyperinflation) Exercise tolerance ( dynamic hyperinflation) Sleep quality ( nocturnal bronchospasm) Health-related quality of life Frequency of acute exacerbations Table 1 Summary of the effects of commonly used bronchodilators on clinical outcomes in COPD Bronchodilator FEV 1 Lung volume Dyspnea HRQoL Exercise endurance Short-acting β 2 -AR agonist Yes a Yes b Yes a Yes b Ipratropium bromide Yes a Yes b Yes a No b Yes b Long-acting β 2 -AR agonist Yes a Yes a Yes a Yes a Yes b Tiotropium Yes a Yes a Yes a Yes a Yes b Theophylline Yes a Yes b Yes a Yes b Yes b Adapted from [64] a Randomized clinical trial, substantial numbers of studies with large study populations b Randomized clinical trial, few studies or studies with small study populations short duration of action lasting less than 6 h, while the duration of action of salmeterol and formoterol is approximately 12 h. These agents also differ significantly in their ability to active the β 2 -AR (intrinsic efficacy) which is dependent on their affinity and potency [3]. While formoterol has a high intrinsic efficacy (strong agonist), albuterol and salmeterol have a very low intrinsic efficacy (weak agonists). The clinical relevance of this difference needs to be further explored in future trials. 2.2 Clinical Benefits Because of their rapid onset of action, short-acting beta2-adrenoceptor agonists are very effective for rescue from symptoms of COPD. Albuterol is the most commonly used agent. In addition to their bronchodilatory properties, these agents are
13 4 J.F. Donohue et al. Table 2 Commonly used bronchodilators in COPD Short-acting agents β 2 -AR agonists Albuterol (MDI, NS) Terbutaline Levalbuterol (MDI, NS) Pirbuterol (MDI) Anticholinergic Ipratropium bromide (MDI, NS) Fixed combination Albuterol/ipratropium (MDI, NS) Long-acting agents β 2 -AR agonists Salmeterol (DPI) Formoterol (DPI) Arformoterol (NS) Anticholinergic Tiotropium bromide (DPI) Fixed combination Salmeterol/fluticasone a (DPI, MDI) Formoterol/budesonide b (DPI, MDI) Methylxanthines Theophylline (PO) MDI metered-dose inhaler, DPI dry powder inhaler, NS nebulized solution, PO oral preparation a Only one dose formulation (250/50) approved for COPD in the USA b Not currently approved for COPD in the USA effective in increasing mucociliary clearance. A systematic review showed that regular use of short-acting β 2 -AR agonists in COPD was associated with improvement in lung function and dyspnea [5]. Both salmeterol and formoterol were initially introduced and approved for use in asthma. The COPD indications came at a later date. These two currently available LABAs have been shown in most COPD studies to significantly improve lung function, health status, and symptom reduction, compared with both placebo [6 9] and ipratropium [10, 11]. These agents also extend the duration of exercise and reduce hyperinflation, but effects can be modest. However, a recent Cochrane meta-analysis concluded that while salmeterol is more effective in improving lung function variables than ipratropium, there was no significant difference in these agents effect on quality of life, exacerbation frequency, or symptoms [12]. Because of formoterol s fast onset of action, it has a potential role as monotherapy or in combination with another bronchodilator in the management of acute COPD exacerbations [13 15] and for use as both a rescue and maintenance medication [16]. A recent study demonstrated a superior effect of formoterol compared to tiotropium bromide in improving FEV 1 in the first 2 h after administration; however, the area under the curve (AUC) FEV 1 over 12 h was similar between these two agents [17]. Several systematic reviews of LABAs reveal that these agents can reduce the rate of COPD exacerbations [18, 19]. This has been confirmed by a recent Cochrane systematic review and metaanalysis of 27 trials [20]. This study went on to show that LABAs had significant benefits on airflow limitation measures, quality of life, and use of rescue medication [20]. In a study of 634 patients with COPD, the administration of salmeterol for 12 months improved health outcomes including exacerbations especially in patients who complied with therapy [21]. The effect of LABAs on all-cause mortality is contradictory with salmeterol being responsible for most of the LABA/ICS survival advantage in TORCH, while other meta-analyses conclude the opposite.
14 Current Pharmacotherapy for COPD Role of Stereoisomers The majority of currently used β 2 -AR agonists are racemic compounds which contain a mixture of the R and S-enantiomers of the agonist. Recently, the R-enantiomer of albuterol (levalbuterol) [22, 23] and the R,R-enantiomer of formoterol (arformoterol) were approved for clinical use in the management of COPD [24]. Much of the pharmacological activity of the agonist usually resides in the effects of the (R)-enantiomer, the (S)-enantiomer is believed to have no bronchodilator effects but in fact may induce deleterious effects. An in vitro study suggests that S,S formoterol is not biologically inert, such that in racemic mixtures, it inhibited the beneficial effects of R,R (formoterol) on proliferation, anti-inflammatory cellular surface marker expression, and cytokine secretion [25]. The effectiveness and cost-effectiveness of isomeric vs. racemic β 2 -AR agonists in the management of airway diseases such as COPD remain controversial and need to be further explored [26, 27]. A recent trial investigating the efficacy and safety of different dose formulations of arformoterol nebulization solution administered over 12 weeks to patients with moderate to severe COPD demonstrated a significant sustained improvement in FEV 1 compared to placebo but comparable to salmeterol [28]. Carmoterol is a similar LABA. 2.4 Non-bronchodilator Effects of β 2 -AR Agonists Although the major action of β2-ar agonists on airways is relaxation of airway smooth muscles, they also exert several effects mediated through the activation of β2-ars expressed on resident airway cells such as epithelial cells and mast cells and circulating inflammatory cells such as eosinophils and neutrophils [29, 30]. These effects include inhibition of airway smooth muscle cell proliferation and inflammatory mediator release, as well as non-smooth muscle effects, such as stimulation of mucociliary transport [31], cytoprotection of the respiratory mucosa, and attenuation of neutrophil recruitment and activation [30]. Recently both formoterol and salmeterol have been shown to inhibit LPS (lipopolysaccharide)- stimulated release of tumor necrosis factor (TNF) and granulocyte/monocyte colony-stimulating factor (GMCSF) but not CXCL-8 from monocyte-derived macrophages in culture [32]. Budesonide inhibited the release of all three cytokines and when combined with formoterol inhibited TNF release in an additive manner. However, many of these effects have been described by in vitro studies, and in vivo studies are still needed to fully explore these effects.
15 6 J.F. Donohue et al. 2.5 Novel Beta2-Adrenoceptor Agonists A variety of β 2 -AR agonists with longer half-lives are currently under development with the hopes of achieving once-daily dosing [33]. These include carmoterol, indacaterol, GSK , GSK , GSK , GSK , and GSK These compounds are mainly (R,R)-enantiomers and have high intrinsic efficacy and quick onset of action. While a quick onset of action and a prolonged 24-h effect are desirable in the management of COPD, the use of agonists with high intrinsic efficacy may theoretically be associated with a rapid onset of tolerance, the fact that may limit their clinical use [3]. This needs to be taken in consideration in the evaluation of new agents under development. However, it is likely that once-daily dosing of a LABA will lead to enhancement of compliance with therapy and may have advantages leading to improved overall clinical outcomes in patients with COPD. 3 Anticholinergics 3.1 Pharmacology Parasympathetic activity in the large- and medium-size airways is mediated through the muscarinic receptors (M 1 and M 3 ) and results in airway smooth muscle contraction, mucus secretion, and possibly increased ciliary activity. M 2 receptors inhibit acetylcholine release from nerve terminals. Increased cholinergic tone is important in the pathogenesis of COPD, contributing both to increased bronchial smooth muscle tone and to mucus hypersecretion [34, 35]. Thus, anticholinergics reduce airway tone and improve expiratory flow limitation, hyperinflation, and exercise capacity in patients with COPD. Two anticholinergic bronchodilators are currently available in the USA for clinical use. These are ipratropium bromide and tiotropium. The short-acting anticholinergic agent, ipratropium bromide, acts on all three muscarinic receptors. Its short duration of action requires dosing every 6 h, and its delayed onset of action (peak at 45 min) precludes its use as rescue therapy. Tiotropium also binds to all three receptor subtypes; however, it dissociates rapidly from M 2 receptors. In contrast, its dissociation half-life from M 3 receptors is close to 35 h which results in a prolonged bronchodilatory effect. Its peak bronchodilatory effect is in 1 3 h and continues for up to 32 h with a dip between 16 and 24 h related to circadian change. However, its bronchoprotective effect against a bronchospastic agent continues up to 48 h [36].
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