Title: The Role of Fixed-Dose Dual Bronchodilator Therapy in Treating COPD

Accepted Manuscript Title: The Role of Fixed-Dose Dual Bronchodilator Therapy in Treating COPD Author: Antonio Anzueto, Marc Miravitlles PII: S0002-9343(18)30006-8 DOI: https://doi.org/10.1016/j.amjmed.2017.12.018 Reference: AJM 14456 To appear in: The American Journal of Medicine Please cite this article as: Antonio Anzueto, Marc Miravitlles, The Role of Fixed-Dose Dual Bronchodilator Therapy in Treating COPD, The American Journal of Medicine (2018), https://doi.org/10.1016/j.amjmed.2017.12.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The Role of Fixed-Dose Dual Bronchodilator Therapy in Treating COPD Running head: Dual Bronchodilator Therapy in COPD Antonio Anzueto, MD, a Marc Miravitlles, MD b a University of Texas Health Science Center, and South Texas Veterans Health Care System, San Antonio, TX, USA; b Department of Pneumology, Vall d'hebron University Hospital, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain. AUTHOR INFORMATION: Author Full address Phone number (including country and area code) Antonio Anzueto University of Texas 001 201 617 Health Science Center, and South Texas 5256 Veterans Health Care System, 111E, 7400 Merton Minter Blvd, San Antonio, TX 78229, USA Marc Miravitlles Department of 0034 93 274 60 Pneumology, Vall d'hebron University 83 Hospital, Barcelona, Spain. Email address (if available) anzueto@uthscsa.edu mmiravitlles@vhebron.net Corresponding author: Antonio Anzueto MANUSCRIPT INFORMATION: Keywords: COPD, bronchodilation, LAMA, LABA Highlights Page 1 Page 1 of 34

Chronic obstructive pulmonary disease represents a significant cause of morbidity and mortality Physicians should optimize chronic obstructive pulmonary disease treatment to reduce symptoms and activity limitation There is a robust rationale for using dual long-acting bronchodilator therapy in chronic obstructive pulmonary disease Dual bronchodilator therapy allows for greater maximal bronchodilation versus monocomponent therapy Dual bronchodilator therapy may be optimal for preventing exacerbations in many chronic obstructive pulmonary disease patients Word count: 69 (maximum 70) Funding AstraZeneca LP (Wilmington, DE, USA) provided funding for medical writing and editorial support for this article. Authorship This manuscript is an original work; all authors participated in the drafting, reviewing, and final approval of this manuscript. Conflicts of interest Antonio Anzueto received consulting fees, lecture fees and travel support from AstraZeneca, Boehringer Ingelheim, Sunovion, GlaxoSmithKline and Novartis, and grant support from GlaxoSmithKline. Page 2 Page 2 of 34

Marc Miravitlles has received speaker fees from Almirall, Boehringer Ingelheim, Pfizer, AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Teva, Grifols, and Novartis, and consulting fees from Almirall, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Gebro Pharma, CLS Behring, Cipla, Medimmune, Teva, Takeda, Novartis and, Grifols. Abstract The incidence of chronic obstructive pulmonary disease (COPD) is rising in the United States, and the disease represents a significant source of morbidity and mortality. Primary care providers face many challenges in COPD diagnosis and treatment, as different clinical phenotypes require personalized treatment approaches. Patient adherence and inhaler technique also contribute to treatment outcomes. Around 48% of primary care providers are unaware of guidelines and recommendations for COPD diagnosis and treatment, which may lead to misdiagnosis or undertreatment of COPD symptoms. Inadequately treated COPD can impair patients quality of life and ability to perform everyday activities. Long-acting bronchodilator therapy is the cornerstone treatment for patients with COPD; combinations of bronchodilators of different pharmacological classes have shown improved efficacy versus monotherapy. We review the rationale behind fixeddose dual bronchodilator therapy, evidence for the four currently FDA-approved long-acting anticholinergic bronchodilators (LAMA)/ long-acting β 2 -agonists (LABA) fixed-combinations, patient suitability for the available inhaler devices, and practical guidance to optimize personalized care for patients with COPD. Page 3 Page 3 of 34

Introduction In the United States (US), more than 13 million people have been diagnosed with chronic obstructive pulmonary disease (COPD), with another 24 million suspected of having undiagnosed disease. 1,2 Improved disease awareness, increased diagnosis of the disease in women, and tobacco smoking all contribute to the rise in COPD incidence, 3,4 and the World Health Organization predicts that COPD will become the third most common cause of death worldwide by 2030. 5 COPD is preventable, treatable, and characterized by persistent airflow limitation that is usually progressive. 6 It is a complex and heterogeneous disease, with systemic manifestations and comorbidities contributing to many clinical phenotypes, each exhibiting different pulmonary and extra-pulmonary characteristics. 7 Primary care providers are the main point of contact for patients with COPD, and play a critical role in day-to-day care. 8 Diagnosis and treatment of COPD presents several challenges, with a growing understanding of various COPD phenotypes that require a personalized treatment approach. 9,10 Additional factors, including patient adherence and inhaler technique, also contribute to treatment outcomes. 11 Long-acting bronchodilator therapy is the cornerstone treatment for most patients with COPD; 4,12 for some patients with mild disease, and low symptom burden, shortacting bronchodilators may suffice for symptom control, 4 but in many cases they should be used only as rescue medications. Inhaled long-acting β 2 -agonists (LABAs) and long-acting anticholinergic (or antimuscarinic) bronchodilators (LAMAs) are regularly used for maintenance treatment. 5,12 Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared with higher doses of monocomponents. 13 Four fixed-dose LAMA/LABA Page 4 Page 4 of 34

combinations are now available in the US in a single delivery device; however, it may be unclear which patients would benefit more from dual rather than single bronchodilator therapy as initial treatment, and which inhaler device would be most appropriate for each patient. We review the rationale for fixed-dose dual bronchodilation, the evidence for LAMA/LABA combinations in patients with COPD, and the inhaler device options. Practical approaches to optimize personalized care for patients with COPD also are discussed. Burden of Disease in COPD Patients diagnosed with COPD may experience symptoms of differing severity that can vary from day to day, such as chronic and progressive dyspnea, cough, and sputum production, as well as nonspecific symptoms such as wheezing and chest tightness. 4,14 Several validated questionnaires have been developed that primary care providers can use to comprehensively assess COPD symptoms, such as the COPD Assessment Test or the COPD Control Questionnaire. 4 Many patients with COPD will have some degree of lung hyperinflation, defined as an increased volume of air remaining in the lung at the end of a spontaneous expiration. Hyperinflation is closely associated with dyspnea, limitation of physical activity, and exercise intolerance; thus, a reduction in hyperinflation may result in an improvement in physical activity, reduced dyspnea, and other clinical benefits. 15 The severity of dyspnea increases alongside COPD severity, and can cause strong emotional reactions of anxiety and distress. 15 Anxiety and depression, which are commonly reported in patients with COPD, have been shown to correlate with Page 5 Page 5 of 34

impaired quality of life. 15 It is therefore essential that dyspnea and hyperinflation, as well as related comorbidities, 16 are appropriately managed in patients with COPD. Although clinical trials often assess forced expiratory volume in 1 second (FEV 1 ) as a key endpoint, symptoms and activity levels are as important when determining the severity of disease, quality of life, and prognosis of COPD. Small sustained increases in physical activity may slow physical deterioration and improve quality of life in patients with COPD. 17 Quality of life improvements following completion of a pulmonary rehabilitation program were associated with reductions in dyspnea and leg fatigue in a study in patients with COPD. 18 Similarly, the substantial decrease in physical activity observed across all severity stages is associated with worsening lung function and health status. 19 In patients with COPD, it is necessary to prevent the spiral of decreasing lung function, increasing exacerbations, and worsening disease progression to improve quality of life and life expectancy. Evidence suggests that patients who maintain good physical activity levels have better long-term outcomes compared with those who maintain low activity. 20 Thus, physical activity limitation should be an important area of concern for patients with COPD, and treatments that ultimately reduce activity limitation should be considered. Guidelines-Based Treatment When Should a LABA be Added to a LAMA? An estimated 48% of primary care providers are unaware of guidelines for COPD diagnosis and treatment, and only 25% use them in decision-making. 8 Diagnosis of COPD based on clinical findings alone can lead to misdiagnosis and suboptimal treatment. 8 Page 6 Page 6 of 34

Many countries have developed and implemented evidence-based treatment guidelines for COPD, eg, the American College of Chest Physicians and Canadian Thoracic Society guidelines, 21 and the Spanish COPD Guidelines, GesEPOC (initiative of the Spanish Society for Pulmonology and Thoracic Surgery). 22 Longacting bronchodilators are a mainstay of treatment across treatment guidelines; however, recommendations for dual LAMA/LABA combinations vary across Europe. 23 When diagnosed, COPD is often undertreated, and studies have reported that 30 70% of diagnosed patients receive no treatment; 24,25 if received, treatments are often suboptimal. 25 The COPD Foundation Guide for Diagnosis and Management of COPD was designed to address this need, and can assist primary care providers in recognizing undiagnosed COPD. It provides clear, practical recommendations for the management of COPD to optimize therapy (Table 1). 25 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has produced a set of diagnosis and treatment recommendations for COPD management. 6 These recommendations are a useful tool to guide treatment selection (Figure 1). The GOLD strategy has put forward a model to inform treatment initiation and escalation in the management of COPD based on the patient s severity of airflow limitation (mild, moderate, severe, or very severe [spirometric grade 1 4]) and other characteristics (GOLD A D), determined by COPD symptom severity and exacerbation risk (Figure 1). Either a short- or a long-acting bronchodilator monotherapy is recommended as initial therapy for GOLD A patients. 6 Long-acting bronchodilators are generally recommended as initial treatment for GOLD B (LAMA or LABA monotherapy), GOLD C (LAMA monotherapy), and GOLD D (LAMA/LABA Page 7 Page 7 of 34

dual bronchodilator therapy), and as an option for treatment escalation in GOLD B and C patients whose COPD is not adequately controlled with recommended initial therapies, although exceptions do apply. For example, GOLD B patients may be initiated on LAMA/LABA dual bronchodilator therapy if they present with severe symptoms, while therapy for GOLD D patients may incorporate an inhaled corticosteroid (i.e. triple therapy) or be changed to inhaled corticosteroid/laba combination therapy if there is a history and/or findings suggestive of asthma/copd overlap. 4 Treatment selection also depends on medication availability, patient response (in terms of symptom relief and side effects), and patient preference. 6 Although the GOLD strategy and the COPD Foundation Guidelines are broadly similar, their approaches to disease characterization and categorization of severity of airflow limitation differ. In addition, the COPD Foundation Guidelines do not distinguish between use of LAMA or LABA monotherapy, and LAMA/LABA combinations as a first-line recommendation for patients with moderate-to-severe airflow obstruction and regular symptoms at high risk of exacerbation. 25 Scientific Basis for Combining Two Bronchodilators There is increasing evidence and a robust rationale for the use of dual bronchodilator therapy in COPD management. The mechanism of action of LAMAs and LABAs are different and complementary, resulting in greater bronchodilation when used in combination, and reducing the risk of receptor-specific side effects when compared with using increased doses of monobronchodilator. 26 LAMAs and LABAs induce airway smooth muscle relaxation; LAMAs by inhibiting the M3 receptor, and LABAs by activating 2 -adrenoreceptors. 27 Patients may vary in their responsiveness (reversibility) to anticholinergics and β 2 -agonists over time, and can be responsive to Page 8 Page 8 of 34

each medication class at different times and to different extents. 28 This varied responsiveness could be addressed by providing a LAMA and LABA in combination. Studies in patients with COPD treated with the currently approved LAMA/LABA combinations have indicated that dual bronchodilation can result in clinical benefits, such as improvements in lung function (FEV 1 ), exercise capacity, dyspnea and other relevant spirometry measurements, and in some cases reduce exacerbation frequency, compared with treatment with placebo or monocomponents. 26 Improvements in FEV 1 reported in key Phase III clinical trials of the LAMA/LABA combinations that are currently approved by the US Food and Drug Administration umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, and glycopyrronium (or glycopyrrolate)/indacaterol are outlined in Table 2. Compared with their monocomponents and placebo treatment, the four approved LAMA/LABA combinations have demonstrated improvements in lung function in patients with COPD, with treatment resulting in significant increases in FEV 1 in their respective Phase III trials. 29-44 Umeclidinium/vilanterol, glycopyrronium/indacaterol, and tiotropium/olodaterol have also shown significant improvements in lung function compared with the inhaled corticosteroid/laba fluticasone propionate/salmeterol in patients with moderate to severe COPD with infrequent exacerbations. 33,40-42 The four dual bronchodilators have consistently shown quality of life benefits compared with placebo or monocomponents, as demonstrated by trials assessing St. George s Respiratory Questionnaire (SGRQ) scores, which are calculated based on symptom scores, and activity and impact scores. For example, umeclidinium/vilanterol demonstrated significant improvements in SGRQ scores versus placebo, its monocomponents, 29 and tiotropium. 32 Tiotropium/olodaterol Page 9 Page 9 of 34

maintenance therapy, which has been investigated in patients with moderate to severe COPD in the TOviTO Phase III program, provided clinically meaningful and statistically significant improvements in SGRQ scores and dyspnea compared with monocomponents in a 52-week study in patients with moderate to very severe COPD. 34 Data from the PINNACLE trials showed improvements in the change from baseline in SGRQ total score over 24 weeks with glycopyrrolate/formoterol fumarate versus placebo and its monocomponents. Results from PINNACLE-1 showed statistically significant improvements in SGRQ total score at Week 24 with glycopyrrolate/formoterol fumarate versus placebo and glycopyrrolate alone, and patients receiving the fixed-dose combination were more likely to exceed the threshold for clinically-significant SGRQ improvement than those receiving placebo or glycopyrrolate only. 43 Numerical trends towards SGRQ score improvement were also reported in PINNACLE-2 and PINNACLE-3 with glycopyrrolate/formoterol fumarate versus placebo and glycopyrrolate alone. 43,44 Statistically significant improvements in SGRQ total score, as well as Transition Dyspnea Index (TDI) total score, has also been reported with glycopyrrolate/indacaterol (15.6/27.5 μg) compared with placebo and its monocomponents as part the EXPEDITION US Phase III clinical development program. 35 Use of rescue medication is consistently reduced in patients receiving dual bronchodilator therapy compared with those receiving monocomponents or a placebo. 29-44 Select studies have also assessed additional outcomes that investigate rescue medication use and symptoms scores in greater detail. For example, treatment with glycopyrrolate/formoterol fumarate significantly reduced night-time rescue medication use in both the PINNACLE-1 and PINNACLE-2 trials, and improved mean total symptom scores (e-diary data) compared with placebo and Page 10 Page 10 of 34

glycopyrrolate alone. 43 Day-time rescue medication use was also significantly reduced with glycopyrrolate/formoterol fumarate compared with placebo in the PINNACLE-1 trial, and both placebo and glycopyrrolate alone in the PINNACLE-2 trial. 44 Similar benefits were reported for glycopyrrolate/indacaterol as part of its clinical development program. For example, the FLIGHT 1 and 2 studies reported that symptom score endpoints and CAT scores were significantly improved compared with those reported in patients receiving indacaterol monotherapy. 35 Results of the SHINE study, part of the glycopyrronium/indacaterol clinical trial program conducted in countries outside of the US (where the combination is approved at a once-daily dosage of 50/110 g), reported that some symptoms scores were improved compared with placebo, including nights without night-time awakenings and days without daytime symptoms. The percentage of days that patients could perform their usual daily activities was significantly higher in the glycopyrronium/indacaterol group compared with placebo, and all active comparators over the treatment period. 38 A key concern for physicians and patients with COPD is exacerbation risk. The FLAME study assessed effects on exacerbation rate with a LAMA/LABA combination versus inhaled corticosteroid/laba, a treatment traditionally used for preventing exacerbations in COPD. This double-blind, non-inferiority and superiority study randomized 3362 patients with COPD with a history of 1 exacerbation during the previous year to receive glycopyrronium/indacaterol administered once daily (dosage not approved in the US) or fluticasone propionate/salmeterol twice daily. 42 The fixeddose combination of glycopyrronium/indacaterol once daily demonstrated an 11% decrease in exacerbation rate, as well as a longer time to first exacerbation, Page 11 Page 11 of 34

compared with the fluticasone propionate/salmeterol twice daily. The FLAME study also reported that the effect of glycopyrronium/indacaterol versus fluticasone propionate/salmeterol on rate of COPD exacerbations was independent of whether a patient s baseline blood eosinophil percentage was either <2% or 2%. 42 However, it should be noted that patients with a blood eosinophil count of >600/mm 3 were excluded from the study, as well as patients with allergic rhinitis who were using a H 1 antagonist or intra-nasal corticosteroids intermittently. 42 As eosinophil counts are a proposed biomarker of inhaled corticosteroid response, further studies are required to compare LAMA/LABA combination therapy with inhaled corticosteroid/laba in patients with higher eosinophil counts, where the effects of inhaled corticosteroids are likely to be more pronounced. 45,46 When evaluating the findings of the FLAME study, it is important to acknowledge the study s limitations. During the study s four-week run-in phase (during which patients were treated with inhaled tiotropium at a dose of 18 μg once daily), 32% of patients discontinued therapy; 42 this may have introduced a selection bias by reducing the number of participants who respond poorly to LAMA therapy, or indeed those who do poorly when taken off inhaled corticosteroids. In addition, the case report forms used during the run-in period of the study did not include an option for exacerbation as a reason for discontinuation; 42 therefore, the reported number of patients entering the run-in period, and discontinuing because of an exacerbation (3.6%) may be inaccurate. Caution is therefore warranted when assessing the generalizability of these data. The four approved LAMA/LABA combinations have demonstrated safety profiles that are consistent with their monocomponents, and sustained on a long-term basis. In the clinical development program for umeclidinium/vilanterol, no new safety issues Page 12 Page 12 of 34

were observed with the combination versus umeclidinium and vilanterol alone, with only a low incidence of adverse events associated with anticholinergic treatment, such as dry mouth. 29-31 Tiotropium/olodaterol was found to have a similar safety profile to its monocomponents; 47 the results of TOnado 1 and 2 found no evidence of any increased safety risk for the tiotropium/olodaterol combination compared to the monotherapy groups. 48 Similarly, PINNACLE-3, the long-term safety extension study for glycopyrrolate/formoterol, showed that the incidence of adverse events, such as nasopharyngitis, cough, and upper respiratory tract infection, were comparable for patients treated with glycopyrrolate/formoterol fumarate versus its monocomponents. 44 The fixed combination of glycopyrrolate/indacaterol (15.6/27.5 μg) administered twice-daily also had a comparable safety and tolerability profile to indacaterol alone that was maintained over 52 weeks. 36 When umeclidinium/vilanterol, glycopyrronium/indacaterol, and tiotropium/olodaterol were compared with a LABA and inhaled corticosteroid, the incidence of adverse events was similar between treatment groups. 33,40-42,49,50 Head-to-head trials comparing different LAMA and LABA combinations are lacking. In their absence, a meta-analysis was carried out by Calzetta et al to compare the safety and efficacy of different dual bronchodilators. 13 All LAMA/LABAs investigated in the meta-analysis improved FEV 1 and patients TDI and SGRQ scores. 13 Other Treatment Considerations: Adopting a Patient-Centric Approach to Personalize Care Physicians need to consider several factors including patient comorbidities when selecting treatment for patients with COPD. For example, selecting a dosing regimen that aligns with a patient s preference, be it once or twice daily, supports treatment adherence, and so facilitates optimized care. For patient discussions, it is useful to Page 13 Page 13 of 34

note that in the US, the fixed-dose LAMA/LABA combinations tiotropium/olodaterol and umeclidinium/vilanterol are administered once daily, 51,52 while glycopyrronium/indacaterol and glycopyrrolate/formoterol are administered twice daily. 53,54 Whether or not twice daily dosing regimens confer any additional outcomes benefit compared with once daily regimens has yet to be established, and is a topic that warrants further investigation. Acute exacerbations can be extremely distressing for patients, are a burden on health care resources, and negatively affect quality of life. 55 The GOLD 2017 strategy suggests a LAMA/LABA combination as initial therapy for patients with a history of 2 exacerbations or 1 hospitalization and high symptom burden (i.e, GOLD D), and for treatment escalation from LAMA monotherapy in patients with lower symptom burden but persistent exacerbations (i.e, GOLD C), except in those with an asthma history or asthma characteristics. 4 LAMA/LABA combinations may provide an alternative treatment option for patients already on inhaled corticosteroid treatment, as an alternative to inhaled corticosteroid/laba when initiating therapy, or for patients for whom inhaled corticosteroids are inappropriate. 42,50 Systemic manifestations and comorbidities of COPD contribute to different clinical phenotypes, and create the need for an individualized approach as part of integrated disease management. 7,9 Prevention of exacerbations may require interventions beyond the lungs, such as treatment of gastroesophageal reflux disease, reduction of cardiovascular risk, and management of dyspnea and anxiety. 7 Barriers to optimal COPD management include poor treatment adherence and incorrect inhaler use. A prospective observational study objectively quantified adherence to inhaled corticosteroid/laba therapy in patients with COPD, and Page 14 Page 14 of 34

reported that only 7% of patients had an adherence rate >80%. 56 Poor lung function and comorbidities were predictive of poor inhaler technique in some patients, whereas poor adherence was associated with poor lung function, age, and cognitive status. 56 Therefore, assessing inhaler device suitability is an important component of COPD management. Glycopyrronium/indacaterol and umeclidinium/vilanterol are both delivered using a dry powder inhaler; tiotropium/olodaterol is delivered using a Soft Mist TM inhaler; andglycopyrronium/formoterol is delivered using a pressurized metered-dose inhaler. 57,58 Recommendations for device selection in current guidelines are limited. As device suitability depends on several factors (eg, inhalation technique, coordination, inspiratory flow; Table 3), an algorithm has been developed to help identify the most suitable inhaler type for a given patient (Figure 2). A device should be chosen after careful evaluation of the patient's clinical condition, as well as patient preference. To optimize patient device matching, physicians should consider patient characteristics (severity, fluctuation in airflow obstruction, etc.), class of medication indicated, and where in the lung the drug delivery would be most effective for that patient type. 59,60 Tools such as the In-Check DIAL G16 (Clement Clarke International Ltd, Harlow, UK) and the Vitalograph AIM (Aerosol Inhalation Monitor; Vitalograph, Buckingham, UK) can also be useful in assessment of device suitability. Page 15 Page 15 of 34

Rationale for Early Intervention in COPD Current data suggest that treatment at early stages of COPD is beneficial. 61 Most of this evidence comes from the TORCH and UPLIFT studies, 62,63 which showed that decline in pulmonary function occurs at a faster rate in the early stages. 61 Physical inactivity may also drive COPD progression and many of its comorbidities. 64 Exacerbations are associated with accelerated lung function decline in patients with established COPD, particularly those with mild disease, 65 hence the need for early intervention. Earlier intervention with more intensive bronchodilator treatment has been associated with a slower decline in lung function and fewer exacerbations in some patients. 66,67 An initial treatment strategy to reduce exacerbation risk in COPD is to maximize bronchodilation. For patients who continue to experience exacerbations despite maximal bronchodilation, treatment according to their phenotype is recommended. In many cases this approach will require a more specialized setting (Figure 3). 68 Page 16 Page 16 of 34

Conclusions The mechanisms of action of LAMAs and LABAs are different and complementary, and combining a LAMA and LABA in a single, fixed-dose inhaler can support maximal bronchodilation in patients with COPD. Use of LAMA/LABA dual therapy in patients with COPD has demonstrated greater bronchodilation, improvements in lung function, symptom reduction, and overall improvement in quality of life compared with monotherapy. Treatment recommendations, which may vary by country, can guide health care providers on the appropriate use of LAMA/LABA treatments and other therapies, and help them to avoid common problems of misdiagnosis and overor under-treatment in patients with COPD. Several fixed-dose combination LAMA/LABAs within a single inhaler have now been developed, with specific devices available for use with the different LAMA/LABA treatments. It is important that health care providers have a comprehensive understanding of the variety of different agents and their device options, and awareness of patient preferences and characteristics that should be considered to optimize personalized care for patients with COPD. Acknowledgments Medical writing support was provided by Hannah Burke, BSc, of Core (London, UK) and editorial support was provided by Maryam Vahdat, PGDip, of Core (London, UK), which were funded by AstraZeneca LP (Wilmington, DE, USA), in accordance with Good Publication Practice guidelines (Battisti WP, Wager E, Baltzer L, Bridges D, Cairns A, Carswell CI, et al. Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3. Ann Intern Med. 2015;163:461 464. doi: 10.7326/M15-0288). Page 17 Page 17 of 34

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68. Miravitlles M, Anzueto A. A new two-step algorithm for the treatment of COPD. Eur Respir J. 2017;49:1602200. Page 22 Page 22 of 34

Figure 1 GOLD Treatment Recommendations for Patients According to Disease Severity and Risk (Reprinted with permission of the American Thoracic Society. Copyright 2017 American Thoracic Society) 4 [NOTE: 2-column fitting image] FEV 1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist. Page 23 Page 23 of 34

Figure 2 Algorithm for choosing an inhaler device according to the patient s inspiratory flow and ability to coordinate inhaler actuation and inspiration (Adapted with permission from Dekhuijzen et al., 2013) 58 [NOTE: 2-column fitting image] Page 24 Page 24 of 34

Figure 3 Therapeutic recommendations based on exacerbation phenotype (Reproduced with permission from Miravitlles et al., 2017). 67 There is a strong case for maximizing bronchodilation to reduce exacerbation risk in patients with COPD. For those who persist with exacerbations despite this, treatment according to their phenotype is recommended. [NOTE: 2-column fitting image] ICS = inhaled corticosteroid; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; mmrc = modified Medical Research Council. Page 25 Page 25 of 34

Table 1 COPD Foundation Guidelines for COPD Treatment (Reproduced with permission from The COPD Foundation [Rennard et al., 2013]) 24 Short-Acting Bronchodilator LAMA or LABA or LAMA plus LABA ICS/LABA Roflumilast Oxygen Exercise/ Pulmonary Rehabilitation Lung Volume Reduction Surgery Azithromycin Spirometry Grade SG1 Mild First line as needed Possibly second line SG2/3 Moderate/Severe First line as needed First line Second line Second line Regular symptoms First line as needed First line Second line First line Exacerbation risk high First line* First line* Second line Second line Oxygenation Severe hypoxemia Episodic hypoxemia Emphysema First line Possibly second line Second line in selected cases Chronic bronchitis Second line Comorbidities Evaluate and treat identified comorbid conditions as part of first-line therapy ICS = inhaled corticosteroid; LABA = long-acting β 2 -agonist; LAMA = long-acting muscarinic antagonist; SG = spirometric grade. *LAMA, ICS/LABA, LAMA plus LABA, or LAMA plus ICS/LABA all potential options depending upon frequency of exacerbations and severity of COPD. Indicated if chronic bronchitis, high exacerbation risk, and spirometry grades 2/3 all present. Off-label use. SG1 Mild obstruction: post bronchodilator FEV 1 /FVC ratio <0.7, FEV 1 60% predicted; SG2 Moderate obstruction: post bronchodilator FEV 1 /FVC ratio <0.7, 30% FEV 1 60% predicted; SG3 Severe obstruction: post bronchodilator FEV 1 /FVC ratio <0.7, FEV 1 <30% predicted. Page 26 Page 26 of 34

Table 2 Effects of LAMA/LABA on Lung Function: Findings from Key Phase III LAMA/LABA Double-blind, Randomized Trials in Moderate to Very Severe COPD Study Study Duration Study Design Umeclidinium/vilanterol (Anoro Ellipta) DPI (Donohue et 24 weeks mmrc 2 al., 2013) 28 FEV 1 <70% predicted (Celli et al., 2014) 29 24 weeks mmrc 2 FEV 1 <70% predicted Excludes patients who have been hospitalized due to COPD within 12 weeks of screening (Decramer et 24 weeks mmrc 2 al., 2014) 30 Excludes patients who have been hospitalized due to COPD within 12 weeks prior to Visit 1 Patient Number Treatment Groups (Once Daily Dosing Unless Otherwise Stated) 1532 UMEC/VI 62.5/25 g UMEC 62.5 g VI 25 g Placebo 1493 UMEC/VI 125/25 g UMEC 125 g VI 25 g Placebo 843 UMEC/VI 125/25 g TIO 18 g VI 25 g UMEC/VI 62.5/25 g TIO 18 g VI 25 g Trough FEV 1 (Pre-dose trough FEV 1 on Day 169 23 24 hours after dosing on Day 168, unless specified) +52 ml vs UMEC 62.5 μg +95 ml vs VI 25 μg +167 ml vs placebo +79 ml vs UMEC 125 g +114 ml vs VI 25 g +238 ml vs placebo +88 ml vs TIO 18 g +88 ml vs VI 25 g +90 ml vs TIO 18 g +90 ml vs VI 25 g 869 UMEC/VI 125/25 g TIO 18 g UMEC 125 g UMEC/VI 62.5/25 g TIO 18 g UMEC 125 g +74 ml vs TIO 18 g +37 ml vs UMEC 125 g +60 ml vs TIO +22 ml vs UMEC 125 g Page 27 Page 27 of 34

(Maleki-Yazdi et al., 2014) 31 24 weeks FEV 1 <70% predicted Excludes patients who have been hospitalized due to COPD within 12 weeks prior to Visit 1 (Donohue et 12 weeks 30% FEV 1 70% predicted al., 2015) 32 mmrc 2 Excludes patients with documented history of 1 COPD exacerbation in the 12 months prior to first visit that required oral corticosteroids, antibiotics, or hospitalization Tiotropium/olodaterol (Stiolto Respimat) Soft Mist inhaler TOnado 1 (Buhl et al., 2015) 33 52 weeks (endpoint at 24 weeks) 905 UMEC/VI 62.5/25 g TIO 18 g 634 638 UMEC/VI 62.5/25 g FP/SAL 250/50 g twice daily UMEC/VI 62.5/25 g FP/SAL 250/50 g twice daily FEV 1 <80% predicted 2624 TIO/OLO 5/5 g TIO 5 g OLO 5 g TIO/OLO 2.5/5 g +112 ml vs TIO 18 g +82 ml vs FP/SAL 250/50 g +98 ml vs FP/SAL 250/50 g (Trough FEV 1 on Day 85) +71 ml vs TIO 5 g +82 ml vs OLO 5 g +21 ml vs TIO/OLO 2.5/5 g TOnado 2 (Buhl et al., 2015) 33 52 weeks (endpoint at 24 weeks) TIO/OLO 2.5/5 g TIO 2.5 g OLO 5 g TIO 5 g FEV 1 <80% predicted 2539 TIO/OLO 5/5 g TIO 5 g OLO 5 g TIO/OLO 2.5/5 g +29 ml vs TIO 2.5 g +58 ml vs OLO 5 g +46 ml vs TIO 5 g (Trough FEV 1 response on Day 170) +50 ml vs TIO 5 g +88 ml vs OLO 5 g +21mL vs TIO/OLO 2.5/5 g Page 28 Page 28 of 34

TIO/OLO 2.5/5 g TIO 2.5 g OLO 5 g TIO 5 g Glycopyrrolate/formoterol (Bevespi Aerosphere ) Co-Suspension Delivery Technology fixed-dose MDI PINNACLE-1 (Martinez et al., 2017) 42 PINNACLE-2 (Martinez et al., 2017) 42 24 weeks FEV 1 <80% predicted Patients with FEV 1 <30% predicted must have post-bronchodilator FEV 1 750 ml Excludes patients hospitalized due to poorly controlled COPD within 3 months prior to screening or during screening 24 weeks FEV 1 <80% predicted Patients with FEV 1 <30% predicted must have post-bronchodilator FEV 1 750 ml Excludes patients hospitalized due to poorly controlled COPD within 3 months prior to screening or during screening 2103 GFF 18/9.6 μg twice daily GLY 18 μg twice daily FF 9.6 μg twice daily Open-label TIO inhalation powder 18 μg Placebo twice daily 1615 GFF 18/9.6 μg twice daily GLY 18 μg twice daily FF 9.6 μg twice daily Placebo twice daily +62 ml vs TIO 2.5 g +67 ml vs OLO 5 g +29 ml vs TIO 5 g (Trough FEV 1 response on Day 170) +59 ml vs GLY +64 ml vs FF +21 ml vs TIO +150 ml vs placebo (Change from baseline in morning pre-dose trough FEV 1 at Week 24) +54 ml vs GLY +56 ml vs FF +103 ml vs placebo (Change from baseline in morning pre-dose trough FEV 1 at Week 24) PINNACLE-3 28-week Extension study of PINNACLE 1 & 2 893 GFF 18/9.6 μg twice daily (Hanania et al., 2017) 43 safety extension GLY 18 μg twice daily FF 9.6 μg twice daily Open-label TIO inhalation powder 18 μg once daily +57 ml vs GLY +65 ml vs FF +25 ml vs TIO (Change from baseline in morning pre-dose trough FEV 1 at Week 52) Glycopyrrolate/indacaterol (Utibron Neohaler [United States]) or Glycopyrronium/indacaterol (Ultibro Breezhaler [Europe]) DPI FLIGHT 1 (Mahler et al., 2015) 34 12-week 30% FEV 1 <80% predicted Excludes patients with COPD exacerbation that required oral corticosteroids, 1042 GP/IND 15.6/27.5 g twice daily GP 15.6 g twice daily + 100 ml vs GP 15.6 g Page 29 Page 29 of 34

FLIGHT 2 (Mahler et al., 2015) 34 FLIGHT 3 (Ferguson et al., 2016) 35 12-week 52-week antibiotics, or hospitalization in the 6 weeks prior to screening or between screening and randomization 30% FEV 1 <80% predicted Excludes patients with COPD exacerbation that required oral corticosteroids, antibiotics, or hospitalization in the 6 weeks prior to screening or between screening and randomization 30% FEV 1 <80% predicted Excludes patients with COPD exacerbation that required oral corticosteroids, antibiotics, or hospitalization in the 6 weeks prior to screening or between screening and randomization IND 27.5 g twice daily Placebo 1001 GP/IND 15.6/27.5 g twice daily GP 15.6 g twice daily IND 27.5 g twice daily Placebo 615 GP/IND 15.6/27.5 g twice daily IND 75 g once daily GP/IND 31.2/27.5 g twice daily IND 75 g once daily twice daily + 78 ml vs IND 27.5 g twice daily +213 ml vs placebo (Pre-dose trough FEV 1 [mean of FEV 1 at 15 and 45 minutes premorning dose] at Week 12) + 85 ml vs GP 15.6 g twice daily + 93 ml vs IND 27.5 g twice daily + 220 ml vs placebo (Pre-dose trough FEV 1 [mean of FEV 1 at 15 and 45 minutes premorning dose] at Week 12) + 80 ml vs IND 75 g once daily + 79 ml vs IND 75 g once daily (Pre-dose trough FEV 1 [mean of FEV 1 values at 15 and 45 minutes pre-dose] at Week 52) ENLIGHTEN (Dahl et al., 2013) 36 52 weeks 30% FEV 1 <80% predicted Excludes patients with COPD exacerbation that required either oral corticosteroids, antibiotics, and/or hospitalization in the 6 339 GLY/IND 50/110g Placebo +189 ml vs placebo (Pre-dose trough FEV 1 [mean of FEV 1 values at 15 and 45 minutes pre-morning dose] at Week 52) Page 30 Page 30 of 34