Chronic Obstructive Pulmonary Disease (COPD) Market to 2019 Highly-Priced New Combination Products Forecast to Capture Significant Market Share and Drive Growth

Home , Abediterol, Ipratropium bromide, Tulobuterol

GBI Research Report Guidance

GBI Research Report Guidance  The second chapter provides an introduction to the COPD indication, including symptoms, etiology, pathophysiology, diagnosis methods, determining severity and treatment algorithms.  The third chapter provides an overview of the COPD marketed landscape, including product profiles for leading brands.  The fourth chapter analyzes the COPD pipeline, detailing, among other parameters, drug distribution by phase, molecule type and mechanism of action. The COPD clinical trial landscape is then analyzed, with a particular emphasis on failure rates across phases as well as the trends in clinical trial size and duration and by mechanism of action.  The COPD market forecast to 2019 is displayed in chapter five, covering treatment usage patterns, annual cost of treatment and finally, a market size forecast for the seven major global markets.  A strategic consolidation analysis is completed in chapter six, including major co-development and licensing deals.

Executive Summary

Executive Summary The global COPD market is New Market Entrants Forecast to Drive COPD Market Growth estimated to be currently worth $XX billion, and The global COPD market is estimated to be currently worth $XX billion, and forecast to reach $XX billion by forecast to reach $XX billion 2019. Much of this growth will be fueled by a high number of new, more efficacious and convenient by 2019 products entering the market and commanding greater value when compared to already-marketed therapies. These products will subsequently capture significant market share, making up approximately XX% of the market by 2019.

COPD Market, Global, Market Size ($m), 2012–2019

Projected Figures: CAGR 2012-2019: XX% Minimum: CAGR 2012-2019: XX% Maximum: CAGR 2012-2019: XX% ) bn ($ Market size Market

2012 2013 2014 2015 2016 2017 2018 2019 Low Variance Medium Variance High Variance Projected

The projected figure is taken to be the most likely scenario, with a high probability of minor variance from that point. Higher variance outcomes are those believed to be plausible but less likely Source: GBI Research

The drugs driving this growth include once-daily Long-Acting Beta Agonists/Long Acting Muscarinic Antagonist (LABA/LAMA) fixed dose combinations such as QVA-XX, the umeclidinium bromide/vilanterol and olodaterol/tiotropium combinations. As well as being once-daily medications, these drugs have been shown to be more efficacious than currently available treatments, including the market leader Spiriva (tiotropium). The uptake of these drugs, and the likelihood of them being more expensive than marketed therapies, will drive market growth. Despite recent patent expirations, including that of Advair Diskus (salmeterol/fluticasone propionate), a market leader, generic erosion in the COPD market may not be as pronounced as that observed in other indications. This is largely down to the difficulty in replicating a fixed-dose combination therapy and its associated device. Indeed, since its US patent expired in 2010, Advair Diskus has faced little generic competition.

Table of Contents

1 Table of Contents 1 Table of Contents ...... 5 1.1 List of Tables ...... 7 1.2 List of Figures...... 8 2 Introduction...... 9 2.1 Disease Introduction ...... 9 2.2 Symptoms ...... 9 2.3 Etiology ...... 9 2.4 Pathophysiology ...... 10 2.5 Diagnosis ...... 10 2.6 Assessment of Disease Severity ...... 11 2.7 Treatment ...... 11 2.7.1 Treatment Algorithm...... 13 3 Marketed Products ...... 14 3.1 Product Profile ...... 15 3.1.1 Spiriva – Boehringer Ingelheim Pharmaceuticals, Pfizer Inc...... 15 3.1.2 Advair Diskus – GlaxoSmithKline ...... 15 3.1.3 Symbicort – AstraZeneca (Co-promotion with Astellas Pharma Inc) ...... 16 3.1.4 Combivent– Boehringer Ingelheim ...... 17 3.1.5 Foradil – Novartis (Co-marketed by Novartis and Schering Corporation) ...... 17 3.1.6 Arcapta/Onbrez Breezhaler – Novartis ...... 18 3.1.7 Daliresp – Nycomed ...... 19 3.1.8 Seebri Breezhaler – Novartis ...... 20 3.1.9 Striverdi Respimat – Boehringer Ingelheim ...... 20 3.1.10 Relvar/Breo – GlaxoSmithKline/Theravance ...... 21 3.1.11 Heat Map – Marketed Products Overview ...... 22 4 COPD Pipeline ...... 23 4.1 Overview ...... 24 4.2 Mechanisms of Action in the Pipeline ...... 26 4.3 Clinical Trials ...... 28 4.3.1 Failure Rate ...... 28 4.3.2 Clinical Trial Duration ...... 34 4.3.3 Clinical Trial Size...... 36 4.4 Promising Pipeline Molecules ...... 39 4.4.1 Umeclidinium Bromide – GlaxoSmithKline ...... 39 4.4.2 Umeclidinium Bromide + Vilanterol – GlaxoSmithKline/Theravance ...... 39 4.4.3 Vilanterol Trifenatate – GlaxoSmithKline/Theravance...... 40 4.4.4 Olodaterol + tiotropium – Boehringer Ingelheim...... 40 4.4.5 TD-4208 – Theravance...... 41 4.4.6 QVA-149 – Novartis ...... 41 4.4.7 Andolast (CR 2039) – Rottapharm | Madaus ...... 42 4.5 Heat Map of Safety and Efficacy for Pipeline and Marketed Products ...... 43 5 Market Forecast to 2019 ...... 49 5.1 Geographical Markets ...... 49 5.1.1 Global Market ...... 51 5.1.2 United States ...... 53 5.1.3 Top Five Countries of Europe ...... 56 5.1.4 Japan ...... 60 5.2 Drivers and Barriers for the COPD Market ...... 62 5.2.1 Drivers ...... 62 5.2.2 Barriers ...... 63

Table of Contents

6 Strategic Consolidations ...... 64 6.1 Major Co-development Deals ...... 64 6.1.1 Galapagos Enters into Strategic Alliance with Roche ...... 65 6.1.2 Five Prime Therapeutics Enters into Co-development Agreement with GlaxoSmithKline ...... 65 6.1.3 Forest Labs Enters into Co-development Agreement with Nycomed ...... 65 6.2 Major Licensing Deals ...... 66 6.2.1 Orexo Enters into Licensing Agreement with Ortho-McNeil-Janssen and Janssen Pharmaceutica ...... 69 6.2.2 Mundipharma Enters into Licensing Agreement with SkyePharma ...... 70 6.2.3 Evotec Enters into Licensing Agreement with Zhejiang Conba Pharma for EVT 401 ...... 70 6.2.4 Halozyme Therapeutics Enters into Licensing Agreement with Intrexon ...... 70 7 Appendix ...... 71 7.1 All Pipeline Drugs by Phase ...... 71 7.1.1 Discovery ...... 71 7.1.2 Pre-clinical ...... 72 7.1.3 Phase I ...... 75 7.1.4 Phase II ...... 76 7.1.5 Phase III ...... 77 7.1.6 Filed ...... 77 7.1.7 Undisclosed...... 78 7.1.8 Market Forecasts to 2019 ...... 78 7.1.9 The United States ...... 78 7.1.10 The UK ...... 79 7.1.11 France ...... 79 7.1.12 Germany ...... 79 7.1.13 Italy ...... 80 7.1.14 Spain ...... 80 7.1.15 Japan ...... 80 7.2 Market Definition ...... 81 7.3 Abbreviations ...... 81 7.4 References ...... 82 7.4.1 References for Pipeline Heat Map ...... 87 7.4.2 References for Marketed Products Heat Map ...... 88 7.5 Methodology ...... 88 7.6 Coverage ...... 89 7.7 Secondary Research ...... 89 7.8 Therapeutic Landscape ...... 89 7.9 Epidemiology-Based Forecasting ...... 90 7.10 Market Size by Geography ...... 91 7.11 Geographical Landscape ...... 92 7.12 Pipeline Analysis ...... 92 7.13 Competitive Landscape ...... 92 7.13.1 Expert Panel Validation ...... 92 7.14 Contact Us ...... 92 7.15 Disclaimer...... 92

Table of Contents

1.1 List of Tables Table 1: COPD Market, Introduction, Disease Severity, 2012 ...... 11 Table 2: COPD Market, Introduction, Treatment Algorithm, 2012 ...... 13 Table 3: COPD Market, Global, Pipeline, Discovery, 2013 ...... 71 Table 4: COPD Market, Global, Pipeline, Pre-clinical, 2013 ...... 72 Table 5: COPD Market, Global, Pipeline, Phase I, 2013 ...... 75 Table 6: COPD Market, Global, Pipeline, Phase II, 2013 ...... 76 Table 7: COPD Market, Global, Pipeline, Phase III, 2013 ...... 77 Table 8: COPD Market, Global, Pipeline, Filed, 2013 ...... 77 Table 9: COPD Market, Global, Pipeline, Undisclosed, 2013 ...... 78 Table 10: COPD, Global, Market Forecast, 2012–2019 ...... 78 Table 11: COPD, US, Market Forecast, 2012–2019 ...... 78 Table 12: COPD, UK, Market Forecast, 2012–2019 ...... 79 Table 13: COPD, France, Market Forecast, 2012–2019 ...... 79 Table 14: COPD, Germany, Market Forecast, 2012–2019 ...... 79 Table 15: COPD, Italy, Market Forecast, 2012–2019 ...... 80 Table 16: COPD, Spain, Market Forecast, 2012–2019 ...... 80 Table 17: COPD, Japan, Market Forecast, 2012–2019 ...... 80

Table of Contents

1.2 List of Figures Figure 1: COPD Market, Global, Marketed Products, Heat Map, 2012 ...... 22 Figure 2: COPD Market, Global, Pipeline, 2012 ...... 25 Figure 3: COPD Market, Global, Pipeline by Mechanism of Action, 2012 ...... 26 Figure 4: COPD Market, Global, Clinical Trials, Failure Rate, 2012 ...... 29 Figure 5: COPD Market, Global, Clinical Trials, Failure Rates by ...... 31 Figure 6: COPD Market, Global, Pipeline, Failure Rates by Mechanism of Action, Heat Map, 2012 ...... 32 Figure 7: COPD Market, Global, Pipeline, Clinical Trial Duration, 2012...... 34 Figure 8: COPD Market, Global, Pipeline, Clinical Trial Duration by Mechanism, 2012 ...... 35 Figure 9: COPD Market, Global, Pipeline, Clinical Trial Size, 2012 ...... 36 Figure 10: COPD Market, Global, Pipeline, Clinical Trial Size by Mechanism of Action, 2012 ...... 37 Figure 11: COPD Market, Global, Pipeline, Number of Clinical Trials per Drug, 2012 ...... 38 Figure 12: COPD Market, Global, Pipeline, Efficacy Heat Map, 2012 ...... 44 Figure 13: COPD Market, Global, Pipeline, Safety Heat Map, 2012 ...... 45 Figure 14: COPD Market, Global, Marketed Products, Heat Map, 2012 ...... 46 Figure 15: COPD Market, Global, Pipeline, Competitor Grid, 2012 ...... 48 Figure 16: COPD Market, Global, Treatment Patterns, 2012–2019 ...... 51 Figure 17: COPD Market, Global, Market Size ($m) 2012–2019...... 52 Figure 18: COPD Market, the US, Treatment Usage Patterns, Annual Cost of Treatment ($), 2012–2019 ...53 Figure 19: COPD Market, US, Market Size ($m), 2012–2019 ...... 54 Figure 20: COPD Market, Top Five EU Countries, Treatment Usage Patterns, 2012–2019 ...... 56 Figure 21: COPD Market, Top Five EU Countries, Annual Cost of Treatment, 2012–2019 ...... 57 Figure 22: COPD Market, Top Five EU Countries, Market Size ($m), 2012–2019 ...... 59 Figure 23: COPD Market, Japan, Treatment Usage Patterns, Annual Cost of Treatment ($), 2012–2019 .....60 Figure 24: COPD Market, Japan, Market Size ($m), 2012–2019 ...... 61 Figure 25: COPD Market, Global, Co-development Deals, 2006–2012 ...... 64 Figure 26: COPD Market, Global, Number and Aggregate Value of Co-development Deals by Year, 2006– 2013 ...... 65 Figure 27: COPD Market, Global, Licensing Deals, 2006–2012...... 66 Figure 28: COPD Market, Global, Number and Aggregate Value of Licensing Deals by Year, 2006–2012.....66 Figure 29: COPD Market, Global, Licensing Deals, 2006–2012...... 67 Figure 30: COPD Market, Global, Licensing Deals by Phase and Molecule Type and Aggregate Deal Value, 2006–2012 ...... 68 Figure 31: COPD Market, Global, Licensing Deals by Mechanism of Action, 2006–2012 ...... 69 Figure 32: COPD Market, Global, GBI Research Market Sizing Model ...... 91

Introduction

2 Introduction Chronic obstructive pulmonary disease (COPD), 2.1 Disease Introduction the fifth leading cause of death in the world, is a Chronic Obstructive Pulmonary Disease (COPD), the fifth-leading cause of death in the world (WHO, 2013a), progressive disorder is a progressive disorder associated with chronic inflammation of the airways and lungs. Persistent associated with chronic breathing difficulties, coupled with repeated exacerbations of COPD symptoms, make the disease one of inflammation of the airways the leading causes of morbidity and mortality worldwide. and lungs The disease is characterized by structural changes that result in a narrowing of the small airways, ultimately causing airflow limitation. Both parenchymal destruction, termed emphysema, and small airways disease, referred to as chronic bronchitis, contribute towards these changes in varying degrees in each patient (GOLD, 2011). COPD is linked to cumulative exposure to risk factors, primarily tobacco smoke, but also environmental pollutants. Although an inflammatory response in the airways and lungs is normal following exposure to such particles, it is more pronounced in COPD patients, and is thought to result in the structural abnormalities that cause the disease. As well as being heavily linked to smoking, the prevalence of COPD increases markedly with age. The results of COPD prevalence studies vary drastically depending on the methodology used, however, it is apparent that those aged over XX are most at risk. 2.2 Symptoms COPD symptoms may include the following:  Chronic dyspnea  Chronic cough  Chronic sputum production Chronic cough and sputum production may present prior to airflow obstruction by a number of years (GOLD, 2011). Chronic cough is often the first symptom to appear, and may develop from being intermittent to persistent, and present throughout the day on a daily basis (GOLD, 2011). Coughing is often followed by sputum production, which is persistent over a long period of time. Chronic dyspnea, that is, difficulty breathing, which is described as progressive, persistent and gets worse with exercise, is another key symptom of COPD. 2.3 Etiology Smoking is believed to be the primary causative factor associated with COPD. Not only is COPD prevalence significantly higher in smokers, the decline in lung function is more pronounced and symptoms are more severe compared to non-smokers (Kohansal et al., 2009). Passive smoking may also contribute to the deterioration of lung function. However, it is important to note that a number of other risk factors are associated with the development of COPD. Studies have demonstrated that a genetic factor can increase the risk of developing COPD. One example includes a hereditary deficiency in alpha-XX antitrypsin, an inhibitor of serine proteases (Stoller and Aboussouan, 2005), and is considered to be a genetic risk factor for COPD. Such findings provide evidence for a gene-environment interaction resulting in susceptibility to the disorder. Age is also cited as a risk factor for COPD. It is a widely held belief that COPD prevalence increases substantially with age; however, this may well be the result of a cumulative exposure to risk factors over a number of years. Healthy aging may itself not result in COPD, and therefore, might not be a risk factor. Poverty has also been linked to increased risk of COPD (Prescott et al., 1999). This could be due to a combination of risk factors associated with poor living standards, such as nutrition, education and air pollutants. However, it is unclear which components contribute the most.

COPD Pipeline

4.2 Mechanisms of Action in the Pipeline The development of once- daily bronchodilators, Many of the mechanisms used by drugs developed for COPD are well-established. As shown in Figure 3 whether combination below, there is a strong presence of bronchodilators in the pipeline, which also consists of LABA/ICS therapies or mono-therapies, combinations. looks set to expand market value Figure 3: COPD Market, Global, Pipeline by Mechanism of Action, 2012

All Stages of Development A

B Mechanism by Phase of Development

Discovery Pre-clinical Phase I Phase II Phase III Filed LABA LABA/ICS LAMA LABA/LAMA PDE Inhibitors LABA/LAMA/ICS p38 MAP Kinase Inhibitor Chemokine receptor antagonist Interleukin receptor antagonist Other Undisclosed

Source: GBI Research Proprietary Database, Products, Pipeline Products

The use of bronchodilators in the form of LAMA and LABA is well established in the pharmacological management of COPD. Such medication is administered during acute episodes, or on a regular basis to reduce symptoms, improve exercise tolerance and reduce the frequency of exacerbations. (GOLD, 2011). Despite recent patent expirations, namely salmeterol and formoterol, the development of once-daily bronchodilators, whether combination therapies or mono-therapies, looks set to expand market value. Some pipeline products have performed favorably against currently available, once-daily, medication. For instance, when compared to the tiotropium, the only other once-daily LAMA being marketed, glycopyrronium (in Phase III in US) has performed favorably, with a quicker onset of action and similar safety profile. LAMA monotherapies play a significant role in the COPD treatment algorithm, therefore any new, once- daily LAMA will likely have a pronounced effect upon the treatment choice. The development of ultra-LABA is gaining prominence. The longer half-life of compounds such as olodaterol and the umeclidinium bromide/vilanterol trifenatate combination are hoped to achieve the once-daily medication aim, therefore improving patient outcomes.

Market Forecast to 2019

5.1.1 Global Market Despite a slight decrease in prevalence population over Figure 16 below shows a forecast for the treatment patterns in COPD across the seven major markets. the forecasted period, the Despite a slight decrease in prevalence population over the forecast period, the treatment population is treatment population is predicted to gradually increase. predicted to gradually increase Figure 16: COPD Market, Global, Treatment Patterns, 2012–2019 Patients (thousands)Patients

2012 2013 2014 2015 2016 2017 2018 2019

Prevalence Population Diagnosed Population Treatment Population

Source: GBI Research

Published COPD prevalence data varies greatly, depending on the age-range of the subjects studied, the definition of COPD used and the method of diagnosis. This is extensively discussed in the meta-analysis and systematic reviews conducted by Halbert et al. (2006) as well as Raherison and Girodet (2009). The diversity of definitions used for the diagnosis of COPD range from diagnosis made by a doctor, symptom questionnaires and spirometric data. Furthermore, there is conflicting data regarding the pattern of prevalence across time-frames and geographies. Some studies have found no change in prevalence rates over the past XX years (Vasankari et al., 2010), whereas other findings differ. Data published by the Centers for Disease Control and Prevention (CDC) suggests the US prevalence of COPD was relatively stable from 1998 to 2009 (CDC, 2011a), although a moderate decrease from XX% to XX% was recorded over this period. The prevalence population data displayed above reflects these findings. The COPD prevalence rate will remain relatively stable over the forecast period, with a slight decrease in the numbers affected. The graph also includes the diagnosed population rate, which is markedly lower than the total prevalence. This is coherent with the widely held belief that COPD is under-diagnosed in common general practice due to inadequate diagnostic methods and the lack of knowledge patients have about the disease (Hill et al., 2010; Pena et al., 2000). As a result, individuals at an early stage of the disease are often unaware of their disease or deem it unnecessary to seek medical attention. However, attempts have been made to universally standardize the diagnosis of COPD, including the establishment of the GOLD program, which standardized the diagnosis of COPD based on symptoms, exposure to risk factors and spirometry data. In addition, awareness campaigns such as those organized by the National Heart, Lung, and Blood Institute (NIH), contribute towards patients identifying symptoms earlier and seeking treatment (NIH, 2012a). These factors will result in an increase in the diagnosed population over the forecast period, as shown in the graph above.

Appendix

7 Appendix 7.1 All Pipeline Drugs by Phase 7.1.1 Discovery

Table 3: COPD Market, Global, Pipeline, Discovery, 2013 Product name Company Stage of development AT-1005 Alba Therapeutics Corporation BT Compound Inhalation Microbion Corp C-301 Corridor Pharmaceuticals Inc. Cell Migration Inhibitors SelectX Pharmaceuticals, Inc. COPD VAST Program Alchemia Limited dapsone Nostrum Pharmaceuticals, LLC Drug For Chronic Inflammatory Diseases vida therapeutics inc. Drug For COPD Torrent Pharmaceuticals Limited Drug Targeting GPCR Axikin Pharmaceuticals, Inc. Human Rhinovirus Program Theraclone Sciences, Inc. LISA Respiratorius AB N-6000 Series N30 Pharmaceuticals N-9000 Series N30 Pharmaceuticals Narrow Spectrum Kinase Inhibitors Janssen Biotech, Inc. Neutrophil Elastases Inhibitors Chiesi Farmaceutici SpA Selective Phosphodiesterase-4 Inhibitors University of Strathclyde STNM-03 Stelic Institute & Co. Vaccine For Moraxella catarrhalis Ancora Pharmaceuticals Inc.

Source: GBI Research Proprietary Database, Products, Pipeline Products

Appendix

7.1.2 Pre-clinical

Table 4: COPD Market, Global, Pipeline, Pre-clinical, 2013 Stage of Product name Company Development (aclidinium bromide + Inhaled Corticosteroid) Almirall, S.A. (glycopyrrolate + formoterol fumarate + inhaled Pearl Therapeutics, Inc. corticosteroid) (PT-002 + PT-009) Pearl Therapeutics, Inc. ADC-3277 Pulmagen Therapeutics LLP ADC-8316 Pulmagen Therapeutics LLP AFX-300 Series Aphoenix, Inc. AIM-102 AIM Therapeutics Inc. AMA-0247 Amakem NV AZD-1419 Dynavax Technologies Corporation AZD-9708 AstraZeneca PLC BTT-1023 Biotie Therapies Corp. C-201 Corridor Pharmaceuticals Inc. CG-459 Clarassance, Inc. CK-2018571 Cytokinetics, Incorporated CK-2019165 Cytokinetics, Incorporated cobiprostone Sucampo Pharmaceuticals, Inc. COPD PI Medivir AB DA-3201 Dong-A Pharmaceutical Co., Ltd. Drug For Chronic Bronchitis NanoBio Corporation Drug For Chronic Obstructive Pulmonary Disease Spring Bank Pharmaceuticals, Inc. Drug For Chronic Obstructive Pulmonary Disease Ache Laboratorios Farmaceuticos S/A Drug For COPD Bioneer Corporation Drug for Emphysema Northern Therapeutics, Inc. Drug Targeting 7-Transmembrane GPCR Axikin Pharmaceuticals, Inc. Dual Activity Molecule Muscarinic Antagonist And Beta- Chiesi Farmaceutici SpA 2 Agonist Elafin Proteo, Inc. FP-003 Foresee Pharmaceuticals, LLC HPP-737 TransTech Pharma, Inc. hPTX-2 Promedior, Inc. IC-1202 iCeutica, Inc. Interleukin-6 Disulfide Rich Peptides Antagonist Protagonist Therapeutics Inc. Program IPH-33 Program Innate Pharma SA Prous Institute for Biomedical JRP-878 Research S.A. KB-003 KaloBios Pharmaceuticals, Inc. LAS-186368 Almirall, S.A. LAS-190792 Almirall, S.A.

Appendix

Long Acting Corticosteroids Chiesi Farmaceutici SpA MDT-011 MicroDose Therapeutx, Inc. MSM-042 MSM Protein Technologies, Inc. Myosin Inhibitor Cytokinetics, Incorporated nadolol Invion Limited Neu-105 Neurim Pharmaceuticals Ltd Neu-164 Neurim Pharmaceuticals Ltd New Generation Program REVOTAR Biopharmaceuticals AG Non-Antibiotic Macrolide Program for COPD Cempra, Inc. Novel Bronchodilator For COPD Pulmatrix, Inc. OX-2477 Orexo AB OX-AAF Orexo AB p-38 Inhibitor Chiesi Farmaceutici SpA PD-3766 P2D Bioscience PIN-201104 Peptinnovate Limited PNQ-103 Advinus Therapeutics Ltd. POL-6014 Polyphor Ltd. PRM-151 Promedior, Inc. PUR-0200 Pulmatrix, Inc. PXS TPI-1100 Pharmaxis Limited PXS-2200 Pharmaxis Limited PXS-4728 Pharmaxis Limited PYM-60001 Phytopharm Plc R-65 Asterand, Inc RBx-343E48F0 Ranbaxy Laboratories Limited RCD-007 Respiratorius AB Recombinant A1PI Grifols, S.A. RESP-1000 Respiratorius AB RESP-2000 Respiratorius AB Retinoic Acid Receptor Agonists Georgetown University rhAAT rEVO Biologics RV-1088 Johnson & Johnson SB-021 sterna biologicals Gmbh & Co KG Selective PI3K-Delta/Gamma Dual Inhibitors Rhizen Pharmaceuticals SA SM-101 SuppreMol GmbH SPC-702 Seoul Pharma Co., Ltd. SR-1001 Visionary Pharmaceuticals, Inc. Sylexins Visionary Pharmaceuticals, Inc. T-0901317 Visionary Pharmaceuticals, Inc. THRX-200495 Theravance, Inc. TRN-157 Theron Pharmaceuticals Inc. VA-118020 Vantia Therapeutics VPI-0003 Visionary Pharmaceuticals, Inc.

Appendix

VPI-0022 Visionary Pharmaceuticals, Inc. VPI-0028 Visionary Pharmaceuticals, Inc. VPI-0033 Visionary Pharmaceuticals, Inc. VPI-0035 Visionary Pharmaceuticals, Inc. VPI-0036 Visionary Pharmaceuticals, Inc. VPI-0037 Visionary Pharmaceuticals, Inc. VPI-0038 Visionary Pharmaceuticals, Inc. VPI-0039 Visionary Pharmaceuticals, Inc. VPI-0040 Visionary Pharmaceuticals, Inc. VPI-0041 Visionary Pharmaceuticals, Inc. VPR-66 Visionary Pharmaceuticals, Inc. VR-496 Vectura Group plc YH_Chem4 Yuhan Corporation

Source: GBI Research Proprietary Database, Products, Pipeline Products

Appendix

7.1.3 Phase I

Table 5: COPD Market, Global, Pipeline, Phase I, 2013 Stage of Product name Company Development AM-211 Panmira Pharmaceuticals, LLC. AM-461 Panmira Pharmaceuticals, LLC. AZD-7594 AstraZeneca PLC AZD-7624 AstraZeneca PLC bedoradrine sulfate Kissei Pharmaceutical Co., Ltd. CHF-6001 Chiesi Farmaceutici SpA danirixin GlaxoSmithKline plc dexpirronium Meda AB EP-102 Sunovion Pharmaceuticals Inc. fluticasone furoate + umeclidinium GlaxoSmithKline plc fluticasone furoate + umeclidinium + vilanterol GlaxoSmithKline plc trifenatate GS-5737 Gilead Sciences, Inc. GSK-2256294 GlaxoSmithKline plc GSK-2269557 GlaxoSmithKline plc Inhalational Phosphodiesterases IV Inhibitors Chiesi Farmaceutici SpA interferon beta Synairgen plc Long Acting Muscarinic Antagonists Chiesi Farmaceutici SpA MEDI-2338 MedImmune, LLC MEDI-7814 MedImmune, LLC mequitazine Laboratoires Pierre Fabre SA OCID-2987 Orchid Chemicals & Pharmaceuticals Ltd OligoG For COPD AlgiPharma AS OPK-0018 OPKO Health, Inc. PA-401 ProtAffin Biotechnologie AG PF-3715455 Pfizer Inc. PUR-118 Pulmatrix, Inc. ronomilast Biotie Therapies Corp. RV-1729 Johnson & Johnson suvorexant Merck & Co., Inc. UR-13870 Palau Pharma, S.A. YPL-001 Yungjin Pharm Ind. Co., Ltd. Source: GBI Research Proprietary Database, Products, Pipeline Products

Appendix

7.1.4 Phase II

Table 6: COPD Market, Global, Pipeline, Phase II, 2013 Stage of Product name Company Development (abediterol + Inhaled Corticosteroids) Almirall, S.A. (fluticasone + salmeterol) Teva Pharmaceutical Industries Limited (glycopyrrolate + formoterol) Pearl Therapeutics, Inc. (indacaterol maleate + mometasone furoate) Novartis AG AAT Inhaled Kamada Ltd. abediterol Almirall, S.A. ADC-4022 Pulmagen Therapeutics LLP albuterol Amphastar Pharmaceuticals, Inc. AMG-108 Amgen Inc. APC-1000 Adamis Pharmaceuticals Corporation APC-2000 Adamis Pharmaceuticals Corporation AQX-1125 Aquinox Pharmaceuticals Inc. ASM-024 Asmacure Ltee aspirin Medical University of Vienna AZD-2115 AstraZeneca PLC AZD-5069 AstraZeneca PLC AZD-5423 AstraZeneca PLC BCT-197 Novartis AG bedoradrine sulfate Kissei Pharmaceutical Co., Ltd. benralizumab Kyowa Hakko Kirin Co., Ltd. bimosiamose disodium REVOTAR Biopharmaceuticals AG BIO-11006 BioMarck Pharmaceuticals, Ltd. canakinumab Novartis AG Drug For Respiratory Disease Beech Tree Labs, Inc. erdosteine Edmond Pharma Srl formoterol fumarate Pearl Therapeutics, Inc. FX-125-L Boehringer Ingelheim GmbH glycopyrrolate Pearl Therapeutics, Inc. Glycopyrrolate Chiesi Farmaceutici SpA glycopyrrolate Dainippon Sumitomo Pharma Co., Ltd. glycopyrrolate + [(beclomethasone dipropionate + Chiesi Farmaceutici SpA formoterol fumarate)] GPD-1116 ASKA Pharmaceutical Co., Ltd. GSK-961081 GlaxoSmithKline plc HI-164OV Bioxyne Limited. IK-7002 Ikaria Inc. Iodinated Activated Charcoal PharmaLundensis AB losmapimod GlaxoSmithKline plc lovastatin National Jewish Health

Appendix

Lysine Acetylsalicylate Medestea Research & Production S.p.A. PH-797804 Pfizer Inc. RBx-10017609 Ranbaxy Laboratories Limited remestemcel-L Osiris Therapeutics, Inc. revamilast Glenmark Pharmaceuticals Ltd. RPL-554 Verona Pharma Plc RV-568 Johnson & Johnson Stempeucel-COPD Stempeutics Research Private Limited TD-4208 Theravance, Inc. tetomilast Otsuka Holdings Co., Ltd. Source: GBI Research Proprietary Database, Products, Pipeline Products

7.1.5 Phase III

Table 7: COPD Market, Global, Pipeline, Phase III, 2013 Product name Company Stage of Development (aclidinium bromide + formoterol fumarate) Almirall, S.A. (fluticasone propionate + formoterol) Ache Laboratorios Farmaceuticos S/A (fluticasone propionate + salmeterol) Orion Oyj (glycopyrronium bromide + indacaterol maleate) Novartis AG (olodaterol + tiotropium bromide) Boehringer Ingelheim GmbH andolast Rottapharm|Madaus erdosteine Edmond Pharma Srl glycopyrrolate Novartis AG olodaterol Boehringer Ingelheim GmbH tulobuterol Sparsha Pharma International Pvt. Ltd. umeclidinium bromide GlaxoSmithKline plc vilanterol trifenatate GlaxoSmithKline plc YHD-001 Yuhan Corporation

Source: GBI Research Proprietary Database, Products, Pipeline Products

7.1.6 Filed

Table 8: COPD Market, Global, Pipeline, Filed, 2013 Product name Company Stage of Development (budesonide + formoterol) Teva Pharmaceutical Industries Limited (glycopyrronium bromide + indacaterol maleate) Novartis AG (umeclidinium bromide + vilanterol) GlaxoSmithKline plc umeclidinium bromide GlaxoSmithKline plc

Source: GBI Research Proprietary Database, Products, Pipeline Products

Appendix

7.1.7 Undisclosed

Table 9: COPD Market, Global, Pipeline, Undisclosed, 2013 Product name Company Stage of Development 2nd Generation HDAC Inhibitor Errant Gene Therapeutics, LLC aclidinium bromide Almirall, S.A. Drug For COPD Galapagos NV EP-103 Sunovion Pharmaceuticals Inc. mannitol Pharmaxis Limited QBKPN SSI Qu Biologics Inc. Recombinant Coversin Varleigh Immuno-Pharmaceuticals Ltd Short Acting APL-1 Apellis Pharmaceuticals, Inc. ZP-003 Zambon Company S.p.A. ZP-014 Zambon Company S.p.A.

Source: GBI Research Proprietary Database, Products, Pipeline Products

7.1.8 Market Forecasts to 2019

Table 10: COPD, Global, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

7.1.9 The United States

Table 11: COPD, US, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum ACOT ($) Projected ACOT ($) Minimum ACOT ($) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

Appendix

7.1.10 The UK

Table 12: COPD, UK, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum ACOT ($) Projected ACOT ($) Minimum ACOT ($) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

7.1.11 France

Table 13: COPD, France, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum ACOT ($) Projected ACOT ($) Minimum ACOT ($) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

7.1.12 Germany

Table 14: COPD, Germany, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum ACOT ($) Projected ACOT ($) Minimum ACOT ($) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

Appendix

7.1.13 Italy

Table 15: COPD, Italy, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum ACOT ($) Projected ACOT ($) Minimum ACOT ($) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

7.1.14 Spain

Table 16: COPD, Spain, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum ACOT ($) Projected ACOT ($) Minimum ACOT ($) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

7.1.15 Japan

Table 17: COPD, Japan, Market Forecast, 2012–2019 Year 2012 2013 2014 2015 2016 2017 2018 2019 CAGR (%) Prevalence Population (Millions) Treatment Population (Millions) Maximum ACOT ($) Projected ACOT ($) Minimum ACOT ($) Maximum Revenue ($m) Projected Revenue ($m) Minimum Revenue ($m)

Source: GBI Research

Appendix

7.2 Market Definition  The global COPD market includes the top seven markets of the US, the UK, Germany, France, Spain, Italy and Japan.  The top five European countries include the UK, Germany, France, Spain and Italy  Prevalence Population: The prevalence population is the estimated number of people at any given point of time who are affected by COPD 7.3 Abbreviations ACh – Acetylcholine ACOT – Annual cost of treatment AEs – Adverse events BLVR – Bronchoscopic lung volume reduction CAGR – Compound annual growth rate cAMP - cyclic-3,5-adenosine monophosphate CAT – COPD Assessment Test CDC - Centers for disease control and prevention COPD – Chronic obstructive pulmonary disease DPI – Dry powder inhaler EIB - Exercise Induced Bronchospasm

FEV1 – Forced expiratory volume in one second FF/VI - Vilanterol trifenatate/fluticasone furoate FPT - Five Prime Therapeutics FVC – Forced vital capacity GLOW - GLycopyrronium bromide in COPD airWays GOLD – Global initiative for chronic obstructive lung disease GR – Glucocorticoid receptor ICS – Inhaled corticosteroids IgE – Immunoglobulin IL – interleukin LABA – Long acting beta agonist LAMA – Long acting muscarinic antagonist LVRS – Lung volume reduction surgery mAChR – Muscarinic Acetylcholine receptor MDI – Metered dose inhaler ml - milliliters mMRC - Modified British Medical Research Council NIH - National Heart, Lung, and Blood Institute PBMCs – peripheral blood mononuclear cells PDE-4 – Phosphodiesterase -4 PEFR – Peak expiratory flow rate

Appendix

RSV - respiratory syncytial virus SABA – Short acting beta agonist SAMA – Short acting muscarinic antagonist SFC – salmeterol/fluticasone propionate µg – micrograms UMEC/VI – umeclidinium bromide and vilanterol VI - Vilanterol 7.4 References  Aalbers, R et al. (2012). Dose-finding study for tiotropium and olodaterol when administered in combination via the Respimat inhaler in patients with COPD. European Respiratory Society Annual Congress, Vienna, Austria. Poster #P2882.  Adams, CP and Brantner, VV (2010). Spending on new drug development. Health Economics; 19: 130– 141.  Arrowsmith, J (2012a). Phase II failures: 2008–2010. Nature Reviews Drug Discovery; 10:1.  Arrowsmith, J (2012b). Phase III and submission failures: 2007–2010. Nature Reviews Drug Discovery; 10:1.  Balint, B et al. (2010). Onset of action of indacaterol in patients with COPD: comparison with salbutamol and salmeterol-fluticasone. International Journal of Chronic Obstructive Pulmonary Disease; 5: 311–318.  Barr, RG et al. (2005). Inhaled tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews; 11:7:CD002876.  Barnes, PJ et al. (2003). Chronic obstructive pulmonary disease: molecular and cellular mechanisms. European Respiratory Journal; 22: 672–88.  Barnes, PJ (2005). New approaches to COPD. European Respiratory Review; 14:94, 2–11.  Baye, J (2012). Roflumilast (Daliresp) a novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. Pharmacy and Therapeutics; 37; 3.  Beeh, KM et al. (2012). Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. International Journal of Chronic Obstructive Pulmonary Disorder. 7: 503– 513.  Berggren, R et al. (2012). Outlook for the next 5 years in drug innovation. Nature Reviews Drug Discovery; 11: 435–436.  Boehringer Ingelheim (2012a). New data show significant improvements in lung function using combination of tiotropium and olodaterol in COPD patients. Available at: http://www.boehringer- ingelheim.com/news/news_releases/press_releases/2012/03_september_2012_copd.html. [Accessed on April 8, 2013].  Boehringer Ingelheim (2012b). Combivent (ipratropium bromide and albuterol sulfate). Prescribing information. Available at: http://bidocs.boehringer- ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information /PIs/Combivent+IA/combivent.pdf.  Boehringer Ingelheim (2013). FDA Advisory Committee recommends approval for Boehringer Ingelheim’s olodaterol for maintenance treatment of COPD. Available at: http://www.boehringer- ingelheim.com/news/news_releases/press_releases/2013/30_january_2013_olodaterol.html. [Accessed on April 9, 2013].  Bouyssou, T et al. (2010). Pharmacologic characterization of olodaterol, a novel inhaled β2- adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. The Journal of Pharmacology and Experimental Therapeutics; 334: 53–62.

Appendix

 Buhl, R et al. (2011). Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. European Respiratory Journal; 38 (4): 797–803  Buhl, R and Banerji, D (2012). Profile of glycopyrronium for once-daily treatment of moderate-to- severe COPD. International Journal of COPD; 7: 729–741.  Campbell, M et al. (2005). Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respiratory Medicine; 99 (12): 1511–1520.  Casaburi, R et al. (2002). A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. European Respiratory Journal; 19: 217–224  Casanova, C et al. (2007). The 6-min walking distance: long-term follow up in patients with COPD. European Respiratory Journal; 29: 535–540  Calverley, P et al. (2003). Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet; 361:449–456.  Calverley, P et al. (2007). Effect of 1-year treatment with Roflumilast in severe chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine; 176: 154–161.  Calverley, P et al. (2009). Roflumilast in symptomatic chronic obstructive pulmonary disease: Two randomised clinical trials. Lancet; 374 (9691):685–694.

 Cazzola, M et al. (2010). The scientific rationale for combining long-acting β2 agonists and muscarinic antagonists in COPD. Pulmonary Pharmacology and Therapeutics; 23 (4): 257–267.  Centers for Disease Control and Prevention (2011a). Chronic Obstructive Pulmonary Disease Among Adults Aged 18 and Over in the United States, 1998–2009. Available at: http://www.cdc.gov/nchs/data/databriefs/db63.htm. [Accessed on February 15, 2013].  Centers for Disease Control and Prevention (2011b). Smoking & tobacco use. Available at: http://www.cdc.gov/tobacco/data_statistics/tables/index.htm. [Accessed on February 25, 2013].  Chee, A and Sin, DD (2008). Treatment of mild chronic obstructive pulmonary disease. International Journal of Chronic Obstructive Pulmonary Disease; 3 (4): 563–573.  Condemi, JJ (2001). Comparison of the efficacy of formoterol and salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. Clinical Therapeutics; 23 (9): 1529–1541.  Dahl, R et al. (2000). Inhaled Formoterol Dry Powder Versus Ipratropium Bromide in Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine; 164: 778– 784  Dahl, R et al. (2010). Efficacy of a new once-daily long-acting inhaled b2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax; 65: 473–479.  Decramer, M et al. (2013). Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respiratory Physiology & Neurobiology; 185: 393–399.  Disse, et al. (1999). Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sciences; 64: 457–464.  Donohue, et al. (2010). Once-daily Bronchodilators for chronic obstructive pulmonary disease. Indacaterol versus tiotropium. American Journal of Respiratory and Critical Care Medicine; 182: 155– 162.  D’Urzo, A et al. (2011). Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respiratory Research; 12: 156.  Fabbri, L M et al. (2009). Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomized clinical trials. Lancet; 374: 695–703.  Fukuchi, et al. (2004). COPD in Japan: the Nippon COPD epidemiology study. Respirology; 9: 458–465.

Appendix

 Gamble, E et al. (2003). Anti-inflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine; 168: 976–982.  Grootendorst, DC et al. (2007). Reduction in sputum neutrophil and eosinophil numbers by the PDE-4 inhibitor roflumilast in patients with COPD. Thorax; 62: 1081–1087.  GOLD (2011). Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Available from: http://www.goldcopd.com. [Accessed on July 11, 2012.]  Gross, N et al. (2007). Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients. Respiratory Medicine; 102: 189–197  GlaxoSmithKline (2011). Annual Report for Shareholders. 2011. Available from: http://www.gsk.com/content/dam/gsk/globals/documents/pdf/GSK-Annual-Report-2011.pdf. Accessed on May 5, 2013.  Halbert, RJ et al. (2006). Global burden of COPD: systemic review and meta-analysis. European Respiratory Journal; 28: 523–532.  Hanania, NA et al. (2012). The efficacy and safety of the novel long-acting β2 agonist vilanterol in COPD patients: a randomized placebo-controlled trial. Chest Journal; [epub ahead of print].

 Highland KB et al. (2003). Long-term effects of inhaled corticosteroids on FEV1 in patients with COPD. Annals of Internal Medicine; 17;138(12):969-73.  Hill, K et al. (2010). Prevalence and under-diagnosis of chronic obstructive pulmonary disease among patients at risk in primary care. Canadian Medical Association Journal; 182 (7): 673–678.  James, GD et al. (2011). Longitudinal changes in the rate and mean age of incidence and prevalence of COPD in the UK, 2000–2009. Thorax ;66.  Jenkins, CR et al. (2009). Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respiratory Research; 10: 59.  Kardos, P et al. (2007) Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine; 175 (2): 144–149.  Kempsford, R et al. (2012). Vilanterol trifenatate, a novel inhaled long-acting β2 adrenoceptor agonist, is well-tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD. Pulmonary Pharmacology and Therapeutics Journal; 26 (2): 256–264.  Kerwin, E et al. (2012). Efficacy and safety of NVA237 versus placebo and tiotropium i patients with moderate-to-severe COPD over 52 weeks: The GLOW2 study. European Respiratory Journal. [Epub ahead of print.]  Kohansal, R et al. (2009). The natural history of chronic airflow obstructive revisited: an analysis of the Framingham offspring cohort. American Journal of Respiratory and Critical Care Medicine; 180: 3–10.  Koumis, T and Samuel, S (2005). Tiotropium bromide: a new long-acting bronchodilator for the treatment of chronic obstructive pulmonary disease. Clinical Therapeutics; 27 (4):377–392.  Legnani, D (2009). Acute bacterial exacerbation of chronic obstructive pulmonary disease and biofilm. Le Infezioni in Medicina; 17 (2): 10–19.  Lomas, DA et al. (2012). An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. Journal of Clinical Pharmacology; 52 (3): 416–424.  Mahler, DA et al. (2002). Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine; 166 (8):1048–1091.  Mahler, DA et al. (2013). Superior lung function with once-daily QVA149 translates into improvements in patient-reported breathlessness compared with placebo and tiotropium in COPD patients: the BLAZE study. American Thoracic Society. Abstract 45308.

Appendix

 Malerba, M et al. (2009). Andolast acts at different cellular levels to inhibit immunoglobulin E synthesis. International Journal of Immunopathology and Pharmacology; 22 (1): 85–94.  Maltais, F (2010). Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients. European Respiratory Society. Abstract #5557.  National Institutes of Health (2012a). November is National COPD Awareness Month. Available at: http://www.nhlbi.nih.gov/health/public/lung/copd/event-listing/awareness-month/materials- resources.htm. [Accessed on March 3, 2013].  National Institutes of Health (2012b). Take the First Step to Breathing Better. Learn More About COPD. Available at: http://www.nhlbi.nih.gov/health/public/lung/copd/index.htm. [Accessed on March 25, 2013].  Park, HY (2012). Inhaled corticosteroids for chronic obstructive pulmonary disease. British Medical Journal; 345:e6843.  Pena, VS et al. (2000). Geographical variations in prevalence and under-diagnosis of COPD. Chest Journal; 118: 981–989.  Prescott, E et al. (1999). Socioeconomic status, lung function and admission to hospital for COPD: results from the Copenhagen City Heart Study. European Respiratory Journal; 13: 1109–1114.  Rabe, KF et al. (2005). Roflumilast — an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: A randomised controlled trial. Lancet; 366 (9485): 563–571.  Raherison, C and Girodet, PO (2009). Epidemiology of COPD. European Respiratory Review; 18: 114, 213–221.  Revill, SM et al. (1999). The endurance shuttle walk: a new field test for the assessment of endurance capacity in chronic obstructive pulmonary disease. Thorax; 54: 213–222.  Rodrigo, GJ and Neffen, H (2012). Comparison of indacaterol with tiotropium or twice-daily long-acting β -agonists for stable COPD: a systematic review. Chest; 142 (5):1104–1110.  Rudolf, M and Tashkin, D (2012). Bronchodilators- future role in the management of chronic obstructive pulmonary disease. European Respiratory Disease; 8(2):108–115  Scherer, FM (2011). R&D costs and productivity in biopharmaceuticals. Harvard Kennedy School. Mossavar-Rahmani Center for Business and Government.  Sin, DD et al. (2009). Budesonide and the risk of pneumonia: a meta-analysis of individual patient data. Lancet; 374 (9691):712–719.  Soriano, JB et al. (2000). Recent trends in physician diagnosed COPD in women and men in the UK. Thorax; 55: 789–794.  Spencer, S et al. (2011). Inhaled corticosteroids versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systemic Reviews; (10): CD007033.  Stebbins, et al. (2010). Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke- Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung. Journal of Pharmacology and Experimental Therapeutics; 332: 764–775.  Stoller, JK and Aboussouan, LS (2005). Alpha 1-antitrypsin deficiency. Lancet; 365:2225–2236.  Stoller, JK et al. (2010). Oxygen therapy for patients with COPD: current evidence and the long-term oxygen treatment trial. Chest; 138: 179–187.  Szafranski, W et al. (2003) Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. European Respiratory Journal; 21: 74–81.  Theravance (2012). GSK and Theravance Announce Positive Results From Four Pivotal Phase III Studies for Once-Daily LAMA/LABA (UMEC/VI) in COPD. Available from: http://investor.theravance.com/releasedetail.cfm?releaseid=688175. [Accessed on April 8, 2013].

Appendix

 UKMi (2012). New Drugs Online Report for fluticasone furoate + vilanterol trifenatate. Available at: http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4877. [Accessed on April 8, 2013].  Vasankari, TM et al. (2010). No increase in the prevalence of COPD in two decades. European Respiratory Journal; 36: 766–773.  Vogelmeier, CF et al. (2011). Tiotropium versus salmeterol for the prevention of exacerbations of COPD. The New England Journal of Medicine; 364: 1093–1103.  Vogelmeier, CF et al. (2012). Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol—fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. The Lancet Respiratory Medicine; 1 (1): 51–60.  van der Molen, T and Cazzola, M (2012). Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes. Primary Care Respiratory Journal; 21 (1): 101–108.  van Noord, JA et al. (2000). A randomized controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax; 55: 289–294.  van Noord, JA et al. (2009). Four weeks once-daily treatment with BI 1744 CL, a novel long-acting β2- agonist, is effective in COPD patients. American Journal of Respiratory and Critical Care Medicine; 179: A6183.  van Noord, JA et al. (2010). QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease. Thorax; 65 (12):1086–1091.  van Noord, JA et al. (2011). 24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD. Pulm Pharmacol Ther; 24(6): 666–672.  Vincken, W et al. (2002) Improved health outcomes in patients with COPD during 1 year’s treatment with tiotropium. European Respiratory Journal; 19: 209–16.  Welte, T et al. (2009). Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine; 180 (8): 741–750.  Whalen, J (2010). “Advair poses generic hurdle”, The Wall Street Journal, November 22, 2010. Available at: http://online.wsj.com/article/SB10001424052748703628204575618332675513808.html. [Accessed on April 25, 2013].  World Health Organization (2013a). Chronic respiratory diseases. Burden of COPD. Available at: http://www.who.int/respiratory/copd/burden/en/index.html. [Accessed on March 27, 2013].  World Health Organization (2013b). Health topics. Ageing. Available at: http://www.who.int/topics/ageing/en/. [Accessed on April 9, 2013].  Yang, IA et al. (2012). Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews; 11: 7: CD002991.

Appendix

7.4.1 References for Pipeline Heat Map  Novartis Pharmaceuticals, Study to Assess the Efficacy, Safety and Tolerability of Once-daily QVA149 in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD), NCT01202188. http://clinicaltrials.gov/show/NCT01202188 [Accessed on April 12, 2013].  Hanania, NA et al. (2010). Dose-related efficacy of vilanterol trifenatate (VI) in COPD. European Respiratory Society; Abstract #1227.  Hanania, NA et al. (2010). Safety of vilanterol trifenatate (VI) in a COPD dose-ranging study. European Respiratory Society; Abstract #1185.  Kelleher, DL et al. (2012). Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Umeclidinium and Vilanterol Alone and in Combination: A Randomized Crossover Trial. PLOS ONE 7 (12).  Feldman, G et al. (2012). Safety and Tolerability of the GSK573719/Vilanterol Combination in Patients with COPD. American Journal of Respiratory and Critical Care Medicine; 185: A2938.  GlaxoSmithKline, A 24-week Evaluation of GSK573719/Vilanterol (62.5/25µg) and Components in COPD (DB2113373), NCT01313650 http://www.clinicaltrials.gov/ct2/show/NCT01313650?term=2010&lup_s=09%2F04%2F2012&lup_d=3 0 [Accessed on April 12, 2013].  Doherty, DE et al. (2012). Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on Chronic Obstructive Pulmonary Disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD. International Journal of Chronic Obstruct Pulmonary Disease; 7: 57–71.  Sunovion Respiratory Development Inc, Study to Investigate the Dose Response, Safety and Efficacy of Nebulized EP-101 in Patients With Chronic Obstructive Pulmonary Disease (COPD): GOLDEN-1 Study, NCT01426009. http://clinicaltrials.gov/ct2/show/NCT01426009 [Accessed on April 12, 2013].  GlaxoSmithKline, A 4-week Dose-Ranging, Dose-Interval, Efficacy, Safety and Tolerability Study of GSK961081 in Subjects with Chronic Obstructive Pulmonary Disease (COPD), NCT01319019. http://clinicaltrials.gov/show/NCT01319019 [Accessed on April 12, 2013].  GlaxoSmithKline, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Losmapimod Tablets Administered Twice Daily Compared with Placebo for 24 Weeks in Adult Subjects with COPD, NCT01218126. http://clinicaltrials.gov/ct2/show/NCT01218126 [Accessed on April 12, 2013].  Theravance (2011), via Market Wired. “Theravance Announces Positive Results From a Phase 2a Study of Its LAMA Candidate, TD-4208, for the Treatment of COPD”, Market Wired, November 14, 2011. Available from: http://www.marketwire.com/press-release/theravance-announces-positive-results- from-phase-2a-study-its-lama-candidate-td-4208-nasdaq-thrx-1586645.htm. [Accessed on April 12, 2013].  Aalbers, R et al. (2012). Dose-finding study for tiotropium and olodaterol when administered in combination via the Respimat inhaler in patients with COPD. European Respiratory Society Annual Congress; Abstract #P2882.  Church, A et al. (2012). An Analysis of the Dose Response of Umeclidinium (GSK573719) Administered Once or Twice Daily in Patients with COPD. Chest; Abstract #672A.

Appendix

7.4.2 References for Marketed Products Heat Map  van Noord, JA et al. (2000) A randomized controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax; 55: 289–294.  Freeman, D et al. (2007). Efficacy and safety of tiotropium in COPD patients in primary care – the SPiRiva Usual CarE (SPRUCE) study. Respiratory Research; 8: 45.  Vincken, W et al. (2002) Improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. European Respiratory Journal; 19: 209–216.  Kardos, P et al. (2007) Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine; 175 (2):144–149.  Calverley, P et al. (2003). Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet; 361:449–456.  Zheng, J et al. (2007). The efficacy and safety of combination salmeterol (50µg)/fluticasone propionate (500µg) inhalation twice daily via accuhaler in Chinese patients with COPD. Chest Journal; 132 (6): 1756–1763.  Jenkins, CR et al. (2009). Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respiratory Research; 10: 59.  Dahl, R et al. (2010). Efficacy of a new once-daily long-acting inhaled b2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax; 65: 473–479.  Cope, S et al. (2012). Efficacy of indacaterol 75µg versus fixed-dose combinations of formoterol- budesonide or salmeterol-fluticasone for COPD: a network meta-analysis. International Journal of Chronic Obstructive Pulmonary Disease; 7: 415–20.  Rabe, KF et al. (2005). Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: A randomised controlled trial. Lancet; 366 (9485): 563–571.  Calverley P et al. (2007). Effect of 1-year treatment with Roflumilast in severe chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine; 176: 154–161.  Lee, SD et al. (2011). Roflumilast in Asian patients with COPD: A randomized placebo-controlled trial. Respirology; 16 (8): 1249–1257.  GlaxoSmithKline, Efficacy and Safety Study of Fluticasone Furoate (FF)/GW642444 Inhalation Powder and the Individual Components in Subjects With Chronic Obstructive Pulmonary Disease (COPD), NCT01054885 http://clinicaltrials.gov/ct2/show/NCT01054885 [Accessed on April 12, 2013]. 7.5 Methodology GBI Research’s dedicated research and analysis teams consist of experienced professionals with marketing, market research and consulting backgrounds in the pharmaceutical industry as well as advanced statistical expertise. GBI Research adheres to the codes of practice of the Market Research Society (www.mrs.org.uk) and the Strategic and Competitive Intelligence Professionals (www.scip.org). All GBI Research databases are continuously updated and revised.

Appendix

7.6 Coverage The objective of updating GBI Research coverage is to ensure that it represents the most up-to-date vision of the industry possible. Changes to the industry taxonomy are built on the basis of extensive research of company, association and competitor sources. Company coverage is based on three key factors: market capitalization, revenues and media attention/innovation/market potential.  An exhaustive search of 56 member exchanges is conducted and companies are prioritized on the basis of their market capitalization.  The estimated revenues of all major companies, including private and governmental, are gathered and used to prioritize coverage.  Companies which are making the news, or which are of particular interest due to their innovative approach, are prioritized. GBI Research aims to cover all major news events and deals in the pharmaceutical industry, updated on a daily basis. The coverage is further streamlined and strengthened with additional inputs from GBI Research’s expert panel (see below). 7.7 Secondary Research The research process begins with exhaustive secondary research on internal and external sources being carried out to source qualitative and quantitative information relating to each market. The secondary research sources that are typically referred to include, but are not limited to:  Company websites, annual reports, financial reports, broker reports, investor presentations and US Securities and Exchanges Commission (SEC) filings  Industry trade journals, scientific journals and other technical literature  Internal and external proprietary databases  Relevant patent and regulatory databases  National government documents, statistical databases and market reports;  Procedure registries  News articles, press releases and web-casts specific to the companies operating in the market 7.8 Therapeutic Landscape  Revenues for each indication, geography-wise is arrived at by utilizing the GBI Research market forecasting model. The global revenue for each indication is the sum value of revenues of all seven regions.  The annual cost of therapy for each indication is arrived at by considering the cost of the drugs, dosage of the drugs and the duration of the therapy.  The generic share of the market for each indication is obtained by calculating the prescription share for generic drugs and the respective cost of treatment.  The treatment usage pattern which includes quantitative data on the diseased population, treatment- seeking population, diagnosed population and treated population for an indication, is arrived at by referring to various sources as mentioned below. GBI Research uses the epidemiology-based treatment flow model to forecast market size for therapeutic indications.

Appendix

7.9 Epidemiology-Based Forecasting The forecasting model used at GBI Research makes use of epidemiology data gathered from research publications and primary interviews with physicians to represent the treatment flow patterns for individual diseases and therapies. The market for any disease segment is directly proportional to the volume of units sold and the price per unit. Sales = Volume of Units sold X Price per Unit The volume of units sold is calculated on the average dosage regimen for that disease, duration of treatment and number of patients who are prescribed drug treatment (prescription population). Prescription population is calculated as the percentage of population diagnosed with a disease (diagnosis population). The diagnosis population is the population diagnosed with a disease expressed as a percentage of the population that is seeking treatment (the treatment-seeking population). The prevalence of a disease (diseased population) is the percentage of the total population that suffer from a disease/condition. Data on treatment-seeking rates and diagnosis and prescription rates, if unavailable from research publications, are gathered from interviews with physicians and are used to estimate the patient volumes for the disease under consideration. Therapy uptake and compliance data are fitted in the forecasting model to account for patient switching and compliance behavior. To account for differences in patient affordability of drugs across various geographies, macroeconomic data such as inflation and GDP and healthcare indicators such as healthcare spending, insurance coverage and average income per individual are used. The annual cost of treatment is calculated using product purchase frequency and the average price of the therapy. Product purchase frequency is calculated from the dosage data available for the therapies and drug prices are gathered from public sources. The source for the price of drugs are RxUSA, ZenRx, the UK Prescription Cost Analysis, the British National Formulary and data from the Japan Pharmaceutical Information Center (JAPIC). The epidemiology-based forecasting model uses a bottom-up methodology and it makes use of estimations in the absence of data from research publications. Such estimations may result in a final market value which is different from the actual value. To correct this ‘gap’ the forecasting model uses ‘triangulation’ with the help of base year sales data (from company annual reports, internal and external databases) and sales estimations. Analogous Forecasting Methodology Analogous forecasting methodology is used to account for the introduction of new products, patent expiries of branded products and subsequent introduction of generics. Historic data for new product launches and generics penetration are used to arrive at robust forecasts. Increase or decrease of prevalence rates, treatment seeking rate, diagnosis rate and prescription rate are fitted into the forecasting model to estimate market growth rate. The proprietary model enables GBI Research to account for the impact of individual drivers and restraints in the growth of the market. The year of impact and the extent of impact are quantified in the forecasting model to provide close-to-accurate data sets.

Appendix

7.10 Market Size by Geography The treatment usage pattern and annual cost of treatment in each country has been factored in while deriving the individual country market size. Forecasting Model for Therapeutic Areas

Figure 32: COPD Market, Global, GBI Research Market Sizing Model

GBI Research Market Sizing Model

D isease Population General Population 743,535,048 Qualifying condition 1 (Age/Sex/Occupation etc) Qualifying condition 2 (Age/Sex/Occupation etc) Prevalence tissue valve disease 0 .2 % 1 ,78 4 ,4 8 4 Qualifying condition (com plication, severity) DISEASED POPULATION 1 ,78 4 ,4 8 4

Treatment Flow Patterns Treatm ent Seeking Rate (Symptoms/Dis Awareness) 8 9% 1 ,58 8 ,1 9 1 Diagnosis Rate (Clinical and D iagn ostic Tests) 7 5% 1 ,19 1 ,1 4 3 Prescription Rate (Physician Perceptio n, Treatment Effectiv e ness) Tissue Valve 7 0% 83 3 ,8 0 0 Other Treatments for Valve (Surg/M ed/N one) - Fulfillm en t A vailab ilit y NA W illingness to Use (Patient Perceptions) NA Ready to U se (S urgery eligibility, R euse etc) NA Affo rd ability at Price HE as % of GDP spend A verage Incom e (per individual) Patient Out-of-pocket Budget (Annual) Budget allocation to one-time surgery Budget allocation to other health needs Average Payor Coverage P atient Liability Target Price (@20% pat liab) ASP for Cost of Therapy TOTAL PATIENT VOLUMES Pro duct Purchase Frequency 1 TOTAL UNIT VOLUMES

Pricing per Un it $ 1 8 ,0 00 In flation P rice D ec rease due to com petition

Market Value Source: GBI Research

The above figure represents a typical forecasting model followed in GBI Research. As discussed previously, the model is built on the treatment flow patterns. The model starts with the general population, then the diseased population as a percentage of the general population, and then follows the treatment-seeking population as a percentage of the diseased population and the diagnosed population as a percentage of the treatment-seeking population. Finally, the total volume of units sold is calculated by multiplying the treated population by the average dosage per year per patient.

Appendix

7.11 Geographical Landscape GBI Research analyzes only seven major geographies: the US, the top five countries in Europe (the UK, Germany, France, Spain, Italy) and Japan. The total market size for each country is provided which is the sum value of the market sizes of all the indications for that particular country. 7.12 Pipeline Analysis This section provides a list of molecules at various stages in the pipeline for various indications. The list is sourced from internal database and validated for the accuracy of phase and mechanism of action at ClinicalTrials.gov and company websites. The section also includes a list of promising molecules which is narrowed down based on the results of the clinical trials at various stages and the novelty of mechanism of action. The latest press releases issued by the company and news reports are also the source of information for the status of the molecule in the pipeline. 7.13 Competitive Landscape Profiles of leading players are provided. An analysis of strengths, weaknesses, opportunities and threats of each company with is also listed. GBI Research aims to cover all major M&As (Mergers and Acquisitions), licensing deals and co-development deals related to the market. This section is sourced from the companies’ websites, company annual reports and internal databases. 7.13.1 Expert Panel Validation GBI Research uses a panel of experts to cross-verify its databases and forecasts. GBI Research expert panel comprises marketing managers, product specialists, international sales managers from pharmaceutical companies, academics from research universities and key opinion leaders from hospitals. Historic data and forecasts are relayed to GBI Research’s expert panel for feedback and are adjusted in accordance with their feedback.

7.15 Disclaimer All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GBI Research.