COPD (chronic obstructive pulmonary disease) is attracting increasing interest from the pharmaceutical industry, as new therapies begin to show promise for treating the underlying causes of the disease.
This publication focuses on novel targets and therapies for the treatment of COPD. It assesses the diagnostic and treatment markets for the disease. It also discusses the clinical and market impact that the new and emerging products will have on the current treatment market.
In addition, the report covers hot topics, such as the benefits of corticosteroids for the treatment of COPD, as well as the race to the market of novel treatments, including Glaxo Wellcome's Flixotide, and Astra Zeneca's Pulmicort.
PUBLISHED: December 2000
REF: BS1085E
PAGES: 130+
Price: £495/$1,040/¥119,000
CONTENTS
LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
ABBREVIATIONS
CHAPTER 1 THE CONDITION, ITS DIAGNOSIS AND MANAGEMENT
1.1 Definitions of chronic obstructive pulmonary disease
1.2 Causes of chronic obstructive pulmonary disease
1.3 Prevalence
1.4 The economic burden
1.5 Clinical assessment of chronic obstructive pulmonary disease
1.5.1 Diagnosis of chronic obstructive pulmonary disease
1.5.2 Disease exacerbations
1.5.3 Pulmonary hypertension secondary to chronic obstructive pulmonary disease
1.6 The distinctions between chronic obstructive pulmonary disease and asthma
1.7 Disease mechanisms
1.7.1 Principal inflammatory cell axes
1.8 Management of chronic obstructive pulmonary disease
1.8.1 International treatment guidelines
1.8.1.1 Non-pharmacological guidelines
1.8.1.2 Pharmacological guidelines
1.8.2 Compliance with disease management guidelines
1.8.3 Pharmacological treatments
1.9 Summary comments
1.10 Exchange rates
CHAPTER 2 EXISTING AND EMERGING DRUG THERAPIES
2.1 Pharmacological treatment
2.1.1 Cessation of smoking
2.1.1.1 Nicotine replacement therapy
2.1.1.2 Non-nicotine drugs
2.1.1.3 Combination therapy
2.1.2 Bronchodilator drugs
2.1.2.1 Anticholinergic drugs
2.1.2.2 ß2 agonists
2.1.2.3 Methylxanthine derivatives
2.1.3 Anti-inflammatory therapy
2.1.3.1 Corticosteroids
2.1.3.2 Bronchodilator/corticosteroid combination therapy
2.1.4 Mucolytics
2.2 Non-pharmacological treatment
2.2.1 Supplemental oxygen therapy
2.2.2 Lung surgery
2.2.3 Pulmonary rehabilitation
2.3 Summary of relative costs and effectiveness of chronic COPD treatment
CHAPTER 3 DRUGS IN DEVELOPMENT
3.1 The range of treatment
3.2 Smoking cessation
3.2.1 Safe cigarettes
3.2.1.1 Eclipse
3.2.1.2 1555U88
3.3 Bronchodilators
3.3.1 Anticholinergics
3.3.1.1 Tiotropium bromide
3.3.1.2 Glycopyrronium bromide
3.3.1.3 Revatropate (UK 112166)
3.3.1.4 Darifenacin
3.3.1.5 J 106366
3.3.1.6 J 104129
3.3.2 Novel ß2 agonists
3.3.2.1 AR-C68397AA (Viozan)
3.4 Emerging anti-inflammatory therapy
3.4.1 Inhaled corticosteroids
3.4.1.1 GW-215864 and GW-250495
3.4.2 Phosphodiesterase 4 inhibitors
3.4.2.1 Ariflo (cilomilast)
3.4.2.2 D-4418 (Sch-351591)
3.4.2.3 D-4396
3.4.2.4 BAY-19-8004
3.4.2.5 Roflumilast
3.4.2.6 YM-976
3.4.3 NF-kB inhibitors
3.4.3.1 IPL-576092
3.4.4 Adhesion molecule antagonists
3.4.4.1 CGP 69669A
3.4.4.2 TBC 1269
3.4.4.3 PP 6179
3.4.5 IL-10
3.4.5.1 IL-10 (tenovil)
3.4.6 p38 mitogen-activated protein kinase inhibitors
3.4.6.1 SB-235699
3.4.6.2 SB-220025
3.4.6.3 VX-745
3.4.6.4 RPR 200765A
3.4.6.5 L-167307
3.4.7 Chloride channel blockers
3.4.7.1 BAY 14160
3.5 Antagonists/inhibitors of inflammatory mediators
3.5.1 LTB4 inhibitors
3.5.1.1 BIIL-284/BIIL-260
3.5.1.2 SC-53228
3.5.1.3 CP-105696
3.5.1.4 SB-201146
3.5.1.5 LY-293111
3.5.2 5-LO inhibitors
3.5.2.1 Zileuton
3.5.2.2 ZD-4407
3.5.2.3 CMI-977 (LDP-977)
3.5.2.4 CMI-568
3.5.3 Thromboxane A2 receptor antagonists
3.5.3.1 Seratrodast
3.5.3.2 BAY-U-3405 (ramatroban)
3.5.3.3 OKY-046
3.5.3.4 Prostanoid inhibitors
3.5.4 Endothelin antagonists
3.5.4.1 SB-217242
3.5.4.2 TBC 11251 (sitaxsentan)
3.5.5 Purine agonists/antagonists
3.5.5.1 GW-328267
3.6 Antioxidants
3.6.1 BXT-51072
3.6.1.1 Ebselen
3.7 Cytokine/chemokine inhibitors
3.7.1 IL-8 receptor antagonists
3.7.1.1 SB-225002 and SB-332235
3.7.2 TNFalpha inhibitors
3.7.2.1 Infliximab and etanercept
3.8 Protease inhibitors
3.8.1 Neutrophil elastase inhibitors
3.8.1.1 ZD-8321
3.8.1.2 ZD-0892
3.8.1.3 Sivelestat (ONO-5046)
3.8.1.4 ONO-6818
3.8.1.5 EPI-HNE-4
3.8.1.6 FR 134043
3.8.1.7 FR 901277
3.8.1.8 GW-311616
3.8.1.9 L 680833
3.8.1.10 DMP 777
3.8.1.11 MR 889 (midesteine)
3.8.1.12 LEX-032
3.8.2 Endogenous inhibitors of HNE
3.8.2.1 alpha1-antitrypsin
3.8.2.2 Neolastin and Dermolastin
3.8.2.3 alpha1-protease inhibitor
3.8.2.4 SLPI
3.8.3 MMP inhibitors
3.8.3.1 CDP-845
3.8.3.2 CH-715
3.8.3.3 BAY-15-7496
3.8.3.4 MMP inhibitors (DuPont)
3.8.3.5 MMP-9 inhibitors (Pfizer)
3.8.3.6 PNU-171829
3.8.3.7 Tanomastat
3.9 Mucoregulators
3.9.1 Tachykinin receptor antagonists
3.9.1.1 CP-99994
3.9.1.2 FK-224
3.9.1.3 FK-888
3.9.1.4 SR 140333 (nolpitantium besilate)
3.9.1.5 SR 48968
3.9.1.6 BIIF-1149
3.9.1.7 NKP-608
3.9.1.8 S 19752
3.9.1.9 Talnetant (SB-223412)
3.9.1.10 PP 6384
3.9.1.11 DNK-333A
3.9.1.12 PP 6436
3.9.1.13 PP 6108
3.9.2 Tachykinin release inhibitors
3.9.2.1 KCO 912
3.9.2.2 BIIX-1
3.9.3 Mucolytics
3.9.3.1 HP-3
3.9.3.2 CPR 7011
3.9.4 MUC gene suppressors
3.9.5 Mucociliary clearance
3.9.5.1 INS 365
3.10 Antibiotic/antiviral therapy
3.10.1 AG 7088
3.10.2 NE-1530
3.11 Summary of products in development for COPD
3.12 Future trends of COPD research
3.12.1 Smoking cessation
3.12.2 Bronchodilators
3.12.3 Mucolytics
3.12.4 Inflammatory cell chemotaxis
3.12.5 Antioxidants
3.12.5.1 Transcription factors
CHAPTER 4 DISEASE DIAGNOSIS AND RESPIRATORY DEVICES � OPPORTUNITIES FOR DIAGNOSTICS AND DRUG DELIVERY DEVICES
4.1 Disease diagnosis � the GOLD standard
4.2 Lung function measurement
4.2.1 Spirometers
4.2.2 Peak flow meters
4.2.3 High resolution computed tomography
4.2.4 Lung volume measurements
4.3 Gas transfer and blood gases
4.4 Emerging biomarkers of disease progression
4.4.1 Exhaled breath
4.4.1.1 Carbon monoxide
4.4.1.2 Nitric oxide
4.4.1.3 Ethane
4.4.2 Exhaled condensate
4.4.2.1 Nitrotyrosine
4.4.2.2 8-isoprostane
4.4.3 Acoustic monitoring
4.5 Drug delivery devices
4.5.1 Inhalers
4.5.1.1 Background
4.5.1.2 Types of inhaler and current issues
4.5.1.3 Respimat
4.5.1.4 Sheffield Pharmaceuticals
4.5.1.5 Accuhaler
4.5.1.6 Easi-Breathe
4.5.1.7 Clickhaler
4.5.1.8 Pulvinal
4.5.1.9 Spiros
4.5.1.10 Easyhaler
4.6 Delivery of nitric oxide for treatment of pulmonary hypertension
CHAPTER 5 COMPANY PROFILES
5.1 American Home Products
5.2 AstraZeneca
5.3 Aventis
5.4 Bayer
5.5 Boehringer Ingelheim
5.6 Byk Gulden
5.7 Celltech Chiroscience
5.8 Glaxo Wellcome
5.9 Inspire Pharmaceuticals
5.10 IVAX (holding Baker Norton)
5.11 3M Pharmaceuticals
5.12 Milkhaus
5.13 Millenium Pharmaceuticals
5.14 Novartis
5.15 Ono Pharmaceuticals
5.16 SmithKline Beecham
5.17 Sheffield Pharmaceuticals
5.18 Vitalograph Limited
5.19 Summary
CHAPTER 6 MARKET ASSESSMENT
6.1 Market overview
6.2 Epidemiology and current statistics
6.2.1 The growing and ageing population
6.2.2 The smoking population
6.2.3 The global incidence and prevalence of COPD
6.2.4 Morbidity
6.2.5 Future prospects for the incidence of COPD
6.2.6 The cost of illness
6.3 World pharmaceutical sales
6.4 Market value for respiratory products
6.4.1 Smoking cessation therapies
6.4.2 Market by respiratory drug classes
6.4.2.1 Anticholinergics
6.4.2.2 ß2 agonists
6.4.2.3 Methylxanthines
6.4.2.4 Corticosteroids
6.4.2.5 Combination therapies
6.4.2.6 Other
6.5 Respiratory device and diagnostic products
6.5.1 Drug delivery devices
6.6 New drugs
6.6.1 Bronchodilators
6.6.2 PDE4 inhibitors
6.6.3 Cell migration inhibition
6.6.4 Mucolytics
6.6.5 Mediator antagonists
6.6.6 Enzyme inhibitors
6.7 Concluding remarks
REFERENCES
list of tables
Table 1.1 Current cost of COPD to the UK NHS
Table 1.2 Classification of COPD severity in the US, Europe and UK, 1995�1997
Table 1.3 Distribution of COPD patient treatment by the acute respiratory assessment service
Table 2.1 Combined use of nicotine patch and gum in smoking cessation
Table 2.2 Combined use of nicotine patch and bupropion in smoking cessation
Table 2.3 Classification of major drugs used to treat COPD
Table 2.4 Comparative costs of chronic COPD treatment
Table 3.1 Sputum levels of IL-10 in healthy subjects compared with asthmatics and COPD patients
Table 3.2 Summarised lists of drugs in preregistration and Phase III development and for COPD, 2000
Table 3.3 Summary of drugs in Phase II development for COPD, 2000
Table 3.4 Summary of drugs in Phase I development for COPD, 2000
Table 3.5 Summary of drugs in preclinical development, 2000
Table 5.1 AHP's financial figures, 1995�1999 ($ million)
Table 5.2 AstraZeneca pharmacutical financial figures, 1998�1999 ($ million)
Table 5.3 Aventis' financial figures, 1998�1999 (Euromillion)
Table 5.4 Bayer's financial figures, 1995�1999 (Euro million)
Table 5.5 Boehringer Ingelheim's financial figures, 1995�1999 (Euro million)
Table 5.6 Byk Gulden's financial figures, 1998�1999 (Euro million)
Table 5.7 Celltech Chiroscience's financial figures, 1998�1999 (£ million)
Table 5.8 Glaxo Wellcome's financial figures, 1995�1999 (£ million)
Table 5.9 IVAX' financial figures, 1995�1999 ($ million)
Table 5.10 3M's financial figures, 1995�1999 ($ million)
Table 5.11 Millenium Pharmaceuticals' financial figures, 1995�1999 ($ thousand)
Table 5.12 Novartis' financial figures, 1996�1999 (SwFr million)
Table 5.13 Ono Pharmaceuticals' financial figures, 1996�1999 (¥ billion)
Table 5.14 SmithKline Beecham's financial figures, 1996�1999 (£ million)
Table 5.15 Sheffield Pharmaceuticals' financial figures, 1995�1999 ($ million)
Table 5.16 Vitalograph Ltd's financial figures, 1995�1999 ($ millions)
Table 5.17 Summary status of selected company development pipelines, 2000
Table 6.1 Life expectancy trends in selected regions, 1986�1996
Table 6.2 Summarised world incidence, prevalence and mortality data for COPD in 1990, with projections to 2020
Table 6.3 World purchases of all drugs from retail pharmacies according to therapeutic category
Table 6.4 Analysis of the asthma/COPD market sector to illustrate market leaders and 5-year trends
Table 6.5 Representative world sales of short-acting ß2 agonists, 1998�2002
Table 6.6 US and exUS performance of Serevent (salmeterol) with post-launch Easi-Breathe predictive impact, 1998-2000 ($ million)
Table 6.7 Inhaled corticosteroid market leaders, 1998�20002 ($ million)
Table 6.8 Comparative growth of Berodual and Combivent, 1998�2002
Table 6.9 World sales of LT antagonists, 1998�2002
Table 6.10 Predicted markets for respiratory therapeutic and diagnostic equipment, 2003 ($ million)
Table 6.11 Market forecasts for recent and upcoming delivery devices
Table 6.12 Estimated peak sales of molecules in development for the treatment of COPD
List of figures
Figure 1.1 Effect of smoking upon annual decline in lung function
Figure 1.2 The interrelationships between asthma and COPD
Figure 1.3 Mechanisms by which cigarette smoke can induce COPD
Figure 1.4 UK general practice awareness of COPD guidelines
Figure 1.5 Effects of supportive therapies on smoking cessation
Figure 2.1 Effect of smoking cessation upon FEV1
Figure 3.1 Chemical structure of tiotropium bromide
Figure 6.1 Annual cigarette consumption and smoking-related deaths by WHO region
Figure 6.2 Comparison of numbers of deaths with disease class in the UK, 1970�1998
Figure 6.3 Major global causes of death, 1997
Figure 6.4 Deaths globally attributed to COPD, 1985�1995
Figure 6.5 Regional mortality attributed to respiratory disease (thousands)
Figure 6.6 World purchases of all drugs from retail pharmacies
Figure 6.7 Potential growth of the global respiratory market if current rates are maintained to 2007
EXECUTIVE SUMMARY
Chronic obstructive pulmonary disease (COPD) encompasses chronic bronchitis, emphysema and related conditions in which pulmonary obstructive airflow is the dominant feature. It is a major killer worldwide and, almost entirely due to its dependence upon trends in tobacco smoking, is set to rise from the fourth and fifth largest causes of disease mortality in the US and Europe, respectively, to the third most prevalent cause, worldwide, by 2020. Despite its senior position in world mortality tables, however, it has been relatively ignored by medical research, always overshadowed by research into asthma, for which treatment has proved a more practical proposition.
It is now evident, however, that COPD is about to challenge its subordinate role. This report seeks to update the reader on current understanding of the disease, its diagnosis and treatment. It emphasises the positives and negatives of the latter and seeks to identify new initiatives which may lead to reduced risks and/or improved prognosis for patients who become afflicted with this apparently irreversible disease.
Chapter 1 is an introduction to COPD, its definition and diagnosis, prevalence and almost unerring association with tobacco consumption. The disease is distinct from asthma but there are notable areas of overlap and patient symptoms are often complicated by co-existence of the two conditions. The similarities and differences are compared at both the symptomatic and pathological levels. Disease prevalence and the associated economic burden are discussed. There have been few reports describing pharmacoeconomic data but those that exist have been used to put real figures on both parameters; both emphasise the enormous numbers involved. A section on disease mechanisms describes the possible links between the active ingredients of cigarette smoke, inflammatory cell recruitment, mediator release and end organ damage. Finally, the above contributions are drawn together to describe international treatment guidelines, compliance issues and the light in which drug treatment is currently regarded.
In Chapter 2 emphasis is placed on smoking cessation programmes because they are the most cost effective and are the only treatments to date, to have shown an ability to slow the insidious progression of the disease. The area is also an exciting one in which nicotine replacement therapies (NRTs), so long the mainstay of support programmes, are being augmented by the new drug, bupropion hydrochloride, and an increasing awareness of the importance of counselling and pschycological support. These initiatives are gaining wide acceptance and funding; bupropion was recently made reimbursable by the UK National Health Service (NHS) and NRT is set to follow suit in 2001.
Chapter 2 also reviews current drug treatment which is dominated by bronchodilators and corticosteroids. The bronchodilators are represented by two groups; the cholinergic receptor antagonists and ß2 agonists. While both offer symptomatic relief, the anticholinergic (antimuscarinic) drugs often appear slightly more efficacious, although ß2 agonists can have advantage when rapid onsets are required. Long-acting ß2 agonists are also being used and, while beset with some cost issues, may have unexpected advantage compared with the short-acting equivalents. If the slight supremacy of antimuscarinic agents in COPD suggests some differences between COPD and asthma, the relative activities of corticosteroids in each disease reinforce the opinion. Although steroids are highly efficacious anti-inflammatory drugs in the treatment of asthma, four very large and long-term trials with the market leaders have shown but marginal effects in COPD. They continue to be widely prescribed but as cost/benefit ratios start to be better communicated, there may be a downturn in their use and an alternative is desperately sought.
This chapter also looks at non-pharmacological treatment, supplemental oxygen, lung surgery and pulmonary rehabilitation. Long-term oxygen therapy has been shown to extend the life expectation of COPD patients but at high economic costs; the bill to the US healthcare offices currently stands at $35/week/patient and the annual UK NHS costs are estimated at £156 million ($223 million). Lung surgery has recently enjoyed increased operational success but the long-term benefits have yet to be validated and, again, costs are very high at $12,000/patient. In contrast, rehabilitation programmes are highly cost effective and gaining wider acceptance.
Chapter 3 describes a wide variety of potential drugs currently in the development pipelines of a number of pharmaceutical companies. They range from imminent launches of improved antimuscarinic drugs exemplified by tiotropium bromide (Boehringer Ingelheim) to innovative approaches to modulation of cell migration patterns by interleukin-8 antagonism or promotion of mucus clearance by stimulation of 2PY receptors.
Each section of this chapter is introduced by description of the biology which underpins the approach with commentary on potential advantages or disadvantages. The potential impact of Type 4 phosphodiesterase inhibitors is described in some detail because, not only does this approach present genuine opportunity for disease modification, but also has a candidate, Ariflo (cilomilast), in Phase III development which may soon be able to test the theories.
The chapter reviews all approaches and candidates which have been in press over the last 10 years. This has been possible through detailed appraisal of the records of the pharmaceutical industry maintained at PJB Publications, discussion with opinion leaders and attendance of two key conferences on COPD � Clinical Aspects and Modern Management of Chronic Obstructive Pulmonary Disease 17�18 July 2000, London, IBC Global Conferences Ltd; and COPD, New Developments and Therapeutic Opportunities, 26�28 September 2000, Imperial College of Medicine, London, Barnes and Pride. There is a focus on emerging anti-inflammatory therapy (cells and mediators) antioxidants, cytokines and chemokines, and mucoregulators. Antibiotics are not reviewed in depth partly because, to do them justice is beyond the scope of this report and partly because while micro-organisms may precipitate the disease and disease exacerbations, their modification does not appear to alter its overall course.
Chapter 4 addresses two issues key to the success of COPD treatment; diagnosis and drug delivery. The subjects are combined because they are both heavily dependent upon clinical equipment and their markets have historically been evaluated alongside each other. The key diagnostic parameter of COPD is declining FEV1 (forced expiratory volume in 1 second); there are other measures of lung function but to all opinion leaders FEV1 is the gold standard. Thus, there is a review of spirometry and its move to portable units increasingly linked to microcomputers. There are new initiatives, however, which are exposing and validating non-invasive opportunities for early disease diagnosis. In particular, disease markers in sputum and breath condensate may offer sophisticated analysis of pro-inflammatory markers derived from oxidants and the arachidonic acid cascade.
Inhalation delivery has been successfully applied to the treatment of asthma and an increasingly sophisticated selection of inhalation devices has been developed alongside to improve pulmonary delivery. Unfortunately, asthmatic patients are typically unlike COPD patients in some important respects; although compromised, asthmatic lung function is better than that of the COPD patient and the patient population is, on average, younger. Given a free hand, inhalation is not the ideal delivery route for the COPD patient but, if the drugs demand it, there is a need for a new inhaler technology to be developed that will specifically meet the COPD patient's needs. Recent product launches are reviewed which may offer these technological advances.
Scrip Reports publish a Pharmaceutical Companies Fact File which contains contact details, company highlights, financial records and product pipelines of well over 1,100 companies in, or associated with, the pharmaceutical industry. It is a daunting task to extract a suitable sample to describe the respiratory sector but Chapter 5 seeks to do so with 18 examples. These include the giants such as Glaxo Wellcome and SmithKline Beecham but also included are new companies with innovative ideas such as Inspire Pharmaceuticals and Milkhaus. There is also a sample of equipment and inhaler manufacturers. Those readers requiring a further information are referred to Scrip's Pharmaceutical Companies Factfile.
Chapter 6 seeks to bring together all the elements previously presented to predict and analyse future needs and market trends. There is more detailed description of global mortality with World Health Organisation figures of total disease, smoking populations and COPD downward spirals. Adding to the Chapter 5 data, new figures on the cost of illness are presented.
When a disease such as COPD is (has been) so confused with asthma, it is difficult to assess one market independent of the other. Indeed, this may never be possible because the diseases are so frequently linked and accurate diagnosis falls a poor second to successful patient treatment whatever the cause. Thus, efforts have been made to differentiate between asthma and COPD markets but in all cases the total respiratory sales are also included and are likely to have the greater value.
A variety of sources was drafted for the financial figures which ranged from company annual reports to small articles gleaned from the scientific and national press. The author is particularly indebted to figures made available by IMS Health and Lehman Brothers.
There are some final concluding remarks which state that the recognition of COPD as a collection of diseases distinct from asthma is increasing. Treatment regimens designed for asthmatics are not ideally placed to treat chronic bronchitis and emphysema. However, the historical perception that the latter conditions are irreversible has favoured a focus on the asthmatic patient and there is a paucity of treatment available in COPD. The status of the disease may be set to change, however. High prevalence, astronomical healthcare costs and depressing tobacco consumption trends predict a major presence for the disease but new initiatives, both pharmacological and non-pharmacological, may be set to provide benefit and favourably alter disease outcomes.
© PJB Publications Ltd. 2001
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