CONTENTS
LIST OF TABLES
METHODOLOGY
EXECUTIVE SUMMARY
ABBREVIATIONS
CHAPTER 1 THE CONDITION, ITS DIAGNOSIS AND MANAGEMENT
1.1 What is asthma?
1.2 Cause and effect of asthma
1.2.1 Causes of asthma
1.2.1.1 Extrinsic asthma
1.2.1.2 Intrinsic asthma
1.2.2 The effect of asthma
1.3 Diagnosis
1.4 Treatment guidelines
1.5 Worldwide epidemiology
1.5.1 Prevalence
1.5.2 Mortality
1.6 Cost of asthma treatment

CHAPTER 2 CURRENT AND EMERGING MEDICINES
2.1 Current trends
2.2 Old generation versus new generation medicines
2.2.1 Increasing use of long-acting ß2-agonists
2.2.2 Fluticasone instead of other inhaled corticosteroids
2.2.3 Anti-leucotrienes
2.3 Implications of the new medicines on the market
2.4 Descriptions of the current and emerging medicines
2.4.1 Bronchodilators
2.4.1.1 b2-agonists
2.4.1.2 Antimuscarinics
2.4.1.3 Methyl xanthines
2.4.1.4 Compound preparations
2.4.2 Anti-inflammatory medicines
2.4.2.1 Corticosteroids
2.4.2.2 Cromogens and related therapies
2.4.3 Anti-leucotrienes
2.4.3.1 Inhibitors of leucotriene synthesis
2.4.3.2 Leucotriene receptor antagonists
2.4.4 Others
2.4.4.1 Amlexanox
2.4.4.2 Emedastine difumarate
2.4.4.3 Epinastine
2.4.4.4 Seratrodast
2.4.4.5 Suplatast tosilate
2.4.4.6 Tranilast

CHAPTER 3 MEDICINES IN DEVELOPMENT
3.1 Research trends
3.2 A review of products in R&D
3.2.1 Bronchodilators
3.2.1.1 ß2-agonists
3.2.1.2 Antimuscarinics
3.2.1.3 Phosphodiesterase IV inhibitors
3.2.2 Anti-inflammatory medicines
3.2.2.1 Corticosteroids
3.2.2.2 Cromogens and related therapies
3.2.3 Compound preparations
3.2.3.1 Eformoterol + budesonide
3.2.3.2 Salmeterol + fluticasone
3.2.4 Anti-leucotrienes
3.2.4.1 Inhibitors of leucotriene synthesis or release
3.2.4.2 Leucotriene receptor antagonists
3.2.5 Modulators of other products of arachidonic acid metabolism
3.2.5.1 Bay-u-3405
3.2.5.2 Domitroban calcium hydrate
3.2.5.3 E-6700
3.2.5.4 HSR-284
3.2.5.5 Imitrodast sodium
3.2.5.6 SC-109
3.2.5.7 Others
3.2.6 Inhibitors of platelet-activating factor
3.2.6.1 Apafant
3.2.6.2 E-6123
3.2.6.3 Foropafant
3.2.6.4 KW-4679
3.2.6.5 TRA-575 derivatives
3.2.7 Modulators of histamine synthesis, release or action
3.2.7.1 Inhibitors of histamine synthesis or release
3.2.7.2 Histamine agonists
3.2.8 Tachykinin antagonists
3.2.8.1 FK-888
3.2.8.2 Icatibant
3.2.8.3 MEN 10627 and other Menarini tachykinin antagonists
3.2.8.4 Neuronorms
3.2.8.5 NPC-17731
3.2.8.6 Saredutant
3.2.8.7 SR-48968
3.2.8.8 SR-144190
3.2.8.9 TAC-363
3.2.8.10 ZD-7944
3.2.8.11 Others
3.2.9 Modulators of cell adhesion molecules
3.2.9.1 BIO-1211
3.2.9.2 TBC-772
3.2.9.3 TBC-1269
3.2.9.4 VLA-4 antagonists
3.2.9.5 Others
3.2.10 Tryptase inhibitors
3.2.10.1 APC-366
3.2.10.2 Bay-35-8535
3.2.10.3 Others
3.2.11 Potassium channel openers
3.2.11.1 BIIX 1
3.2.11.2 LM-3339
3.2.11.3 PM-56D9
3.2.11.4 Others
3.2.12 Agents with other and/or multiple sites of action
3.2.12.1 AAF1
3.2.12.2 Andolast
3.2.12.3 ARL-67974
3.2.12.4 Bamaquimast
3.2.12.5 BTS-71-321
3.2.12.6 CD40 antagonists
3.2.12.7 CDP-835 (SCH-55700)
3.2.12.8 D-7193
3.2.12.9 Dextro-mequitamium iodide
3.2.12.10 Eosinophil receptor inhibitors (mAb 7B11)
3.2.12.11 EpiGenRx
3.2.12.12 F-1322
3.2.12.13 IL-4 receptor
3.2.12.14 IPL-576
3.2.12.15 Israpafant
3.2.12.16 KA-398
3.2.12.17 KY-234
3.2.12.18 L0066
3.2.12.19 LAS-32688
3.2.12.20 P31
3.2.12.21 PACAP(1-27) analogue
3.2.12.22 PF-904
3.2.12.23 Phytomedicines
3.2.12.24 rhuMab-E25
3.2.12.25 RPR-23618
3.2.12.26 SR-129
3.2.12.27 ST-126
3.2.12.28 TO-194
3.2.12.29 Vantox
3.2.12.30 YM-57158
3.2.12.31 Others
3.2.13 Antiallergy vaccine
3.3 Comments on the potential of these products
3.4 Predictions for the direction of future research

CHAPTER 4 MARKET DATA
4.1 Total market
4.2 Market size by geographical region
4.3 Current and predicted sales of major medicines
4.4 Market share of major products and companies
4.5 Future trends

CHAPTER 5 COMPANY PROFILES
5.1 Abbott Laboratories
5.2 Asta Medica AG
5.3 Astra AB
5.4 Boehringer Ingelheim
5.5 Glaxo Wellcome
5.6 Merck & Co Inc
5.7 Merck KGaA
5.8 Novartis
5.9 Rhone-Poulenc Rorer Inc
5.10 Sanofi
5.11 Schering-Plough Corporation
5.12 SmithKline Beecham
5.13 Warner-Lambert Co
5.14 Zeneca
DIRECTORY
REFERENCES

LIST OF TABLES
Table 1.1 Some important 'trigger factors' for asthma

Table 1.2 The association of key diagnostic symptoms with asthma
Table 1.3 Classification of asthma severity: UK perspective using Peak Expiratory Flow Rates
Table 1.4 Classification of asthma severity: US perspective using FEV1, Forced Vital Capacity, and blood gas analyses
Table 1.5 Some criteria which might be used to distinguish asthma from chronic bronchitis and emphysema
Table 1.6 US guidelines for the management of asthma
Table 1.7 ISAAC - 12-month prevalences of self-reported asthma symptoms from written questionnaires
Table 1.8 Asthma mortality around the world in people aged 5-34 years
Table 1.9 Some changes in the prescribing of asthma medicines in primary care in England 1980-1996
Table 1.10 Daily costs of asthma treatment in five major markets and predicted increases by 2005
Table 2.1 Current treatment of asthma I. Bronchodilators
Table 2.2 Current treatment of asthma II. Anti-inflammatory medicines
Table 2.3 An overview of the inhaler formulations available for the various asthma medicines
Table 2.4 Currently available anti-leucotrienes
Table 2.5 Other agents used in asthma management
Table 2.6 Principal anti-leucotrienes and some of their established effects
Table 3.1 Summary of the major development-stage products reviewed above
Table 4.1 Asthma medicines with the largest worldwide sales
Table 4.2 Historic and forecast sales ($ million) of the major classes of asthma medicines in the US, 1991-2000
Table 4.3 The number of prescriptions dispensed for respiratory medicines and their cost in England in 1995 and 1996
Table 4.4 Estimated peak sales for bronchodilators used in asthma management
Table 4.5 Estimated peak sales for methyl xanthines and other phosphodiesterase type IV inhibitors used in asthma management
Table 4.6 Estimated peak sales for corticosteroids used in asthma management
Table 4.7 Estimated peak sales for cromogens and related compounds used in asthma management
Table 4.8 Estimated peak sales for the anti-leucotrienes used in asthma management
Table 4.9 Estimated peak sales for other inhibitors of the products of arachidonic acid metabolism used in asthma management
Table 4.10 Estimated peak sales for inhibitors of platelet-activating factor used in asthma management
Table 4.11 Estimated peak sales for various other products likely to be used in asthma management
Table 4.12 Likely changes in the relative importance of different therapeutic approaches to the management of asthma 1997-2007
Table 4.13 Pharmaceutical companies best placed to exploit the growing market for asthma medicines
Table 5.1 Abbott's financial figures ($ million) for 1992-1997
Table 5.2 Abbott's sales ($ million in 1995) by geographical region and company division
Table 5.3 Asta Medica's financial figures (DM million) for 1992-1996
Table 5.4 Asta Medica's sales (DM million in 1996) by geographical region
Table 5.5 Astra's financial figures (SKr million) for 1992-1997
Table 5.6 Astra's sales (SKr million in 1997) by geographical region and company division
Table 5.7 Boehringer Ingelheim's financial figures (DM million) for 1992-1997
Table 5.8 Boehringer Ingelheim's sales (DM million in 1996) by geographical region and business segment
Table 5.9 Boehringer Ingelheim's sales by product area (in DM million in 1996) and actual (1997) and predicted (1998) (both in DM million) sales of the company's leading respiratory products
Table 5.10 Glaxo Wellcome's financial figures (£ million) for 1992-1998
Table 5.11 Glaxo Wellcome's sales (£ million in 1997) by geographical region and therapeutic category
Table 5.12 Merck & Co's financial figures ($ million) for 1992-1998
Table 5.13 Merck & Co's sales ($ million) by geographical region (in 1997) and business segment (1996)
Table 5.14 Merck & Co's sales ($ million) by product area (in 1997) and of the company's leading products (1996)
Table 5.15 Merck KGaA's financial figures (DM million) for 1992-1997
Table 5.16 Merck KGaA's sales (DM million in 1996) by geographical region and business segment
Table 5.17 Novartis's financial figures (SwFr billion) for 1995-1998
Table 5.18 Novartis's sales (both in SwFr billion) by geographical region (in 1997) and company division (6 months of 1998)
Table 5.19 Rhone-Poulenc Rorer's financial figures ($ million) for 1992-1997
Table 5.20 Rhone-Poulenc Rorer's sales by geographical region and therapeutic category (both in $ million in 1996)
Table 5.21 Sanofi's financial figures (Fr million) for 1992-1997
Table 5.22 Sanofi's sales by geographical region (in Fr million in 1996) and business segment (in Fr million in 1995)
Table 5.23 Sanofi's sales by therapeutic area and of its leading products (both in Fr million in 1996)
Table 5.24 Schering-Plough's financial figures ($ million) for 1992-1997
Table 5.25 Schering-Plough's sales by geographical region and business segment (both in $ million in 1997)
Table 5.26 Schering-Plough's sales ($ million in 1997) by therapeutic category and of its leading products
Table 5.27 SmithKline Beecham's financial figures (£ million) for 1992-1998
Table 5.28 SmithKline Beecham's sales by geographical region (in £ million in 1995) and by business sector (in £ million in 1996)
Table 5.29 SmithKline Beecham's product and therapeutic category sales (both in £ million in 1996)
Table 5.30 Warner-Lambert's financial figures ($ million) for 1992-1997
Table 5.31 Warner-Lambert's pharmaceutical sales by geographical region and total sales by company division (both in $ million in 1996)
Table 5.32 Zeneca's financial figures (in £ million) for 1992-1997
Table 5.33 Zeneca's sales by geographical region and by company division (both in £ million in 1996)
Table 5.34 Zeneca's sales by therapeutic category and of the company's leading products (both in £ million in 1996)
Table D.1 Pharmaceutical companies with their major current and development-stage products for asthma

METHODOLOGY
Objectives
This report is intended to provide an up-to-date review of the development status of medicines likely to be used in the management of patients with asthma. The references have been selected because they not only provide details of such medicines, but also some contemporary information about recent developments in understanding the complex interplay between cells, cytokines, and proteins which underpin the development of asthma and which are the targets of therapy. Focusing on the medicines, it is therefore assumed that readers of this report have background knowledge of current concepts of asthma pathology and of how it might realistically be modified.

Methodology and sources of information
The author of this report is in day-to-day contact with asthma patients, their physicians, and with representatives of pharmaceutical companies marketing medicines used in asthma management. Such contacts were the primary source of information for this review. The author also routinely reviews the major UK and international pharmaceutical and medical literature. Such reviews provided the secondary sources of information.

Computer searches were undertaken of the PJB databases. These provided an overview of the medicines in development and of the companies working in the area of asthma, other respiratory diseases, and allergies. From these searches, the companies and organisations listed in the Directory were contacted. The Directory table provides a realistic assessment of the companies involved in such research and of the products on which they are actively working.

Given the large amount of material obtained from the above sources, it was deemed impractical to use material from such online databases as BIOSIS, Excerpta Medica, Index Medicus, Medline, and the Science Citation Index, which a cursory review indicated contained an extensive amount of information on asthma. Except to search for specific papers mentioned in passing in documents acquired from the above sources, no information from the online databases is included in this review unless it was provided by some of the companies or organisations contacted. Similarly, superficial searches of the World Wide Web revealed thousands of 'hits' for asthma of which the following addresses can be considered as directories for more detailed searches:

Asthma - Doctor's Guide to the Internet at: www.pslgroup.com/ASTHMA.HTM

UPHS Health Care: Asthma - What is Asthma? at: www.med.upenn.edu/~health/hi_fils/topics/asthma/ast_what.html

The web site of the American College of Allergy, Asthma & Immunology at: www.allergy.mcg.edu/

Facts About Asthma at: www.lungusa.org/learn/asthma/astasthma.html

Teach Your Patients About Asthma: A Clinician's Guide at: www.meddean.luc.edu/lumen/MedEd/medicine/Allergy/Asthma/asthtoc.html

AMA Physician Select Reference Library: Asthma at: www.ama-assn.org/aps/asthma/asthma.htm

National Asthma Campaign (UK) at: www.asthma.org.uk www.omni.ac.uk of OMNI - Organised Medical Networked Information - which claims to be 'UK's gateway to high quality biomedical resources on the Internet' and which provides high quality medical information specifically developed for the medical and pharmaceutical professions (Kiley 1997, 1998).

Otherwise unreferenced material in this report has been extracted from various PJB databases.

Scope/boundaries
The primary focus of this report is on medicines in development for asthma (Chapter 3). To provide the background information essential to appreciate the potential advantages of these development-stage medicines, Chapter 1 provides a brief overview of various issues broadly related to the pathology and epidemiology of asthma, and Chapter 2 gives indications of current therapies. Chapters 4 and 5 focus on various issues related to the marketing of both current, emerging, and development-stage medicines. Except where they specifically impinge on these issues, topics such as replacement of CFCs in metered dose inhalers; improvements in inhaler technology (and general advances in drug delivery to the respiratory tract); and treatment guidelines (except a brief contextual summary in Section 1.4) are generally beyond the scope of this report. Similarly, no discussion is included of antihistamines except for those products specifically approved, or under development, for the treatment of asthma.

EXECUTIVE SUMMARY
This document reviews the current and future medical management of patients with asthma. As such, the primary focus is on medicines and, except where they specifically impinge on them, significant and major topics such as replacement of chlorofluorocarbons (CFCs) in metered dose inhalers; improvements in inhaler technology (and general advances in drug delivery to the respiratory tract); and treatment guidelines (except a brief contextual summary in Section 1.4) are not discussed.

Chapter 1 sets the scene by providing a definition of asthma and continues by outlining its possible causes and its consequences to patients and their families. Despite difficulties in producing a precise definition, diagnosis is relatively straightforward, and national guidelines in the UK and US provide a framework for effective control of the disorder even if current therapies neither control asthma in perhaps 10% of patients with severe disease, nor correct the underlying inflammatory processes. Asthma is common and associated with considerable social and financial costs.

Chapter 2 provides something in the way of status reports for currently available medicines used in asthma management - both those which are widely available, and those which are emerging - have so-far been launched in relatively few markets. Products are traditionally subdivided into the bronchodilators (dominated by the ß2-agonists such as salbutamol) and the anti-inflammatories (the inhaled corticosteroids and cromogens). A section is devoted to a discussion of the anti-leucotrienes - a major new class of orally-active asthma medicines set to have a significant impact on the market. The properties of several of these agents which have been launched around the world are reviewed as are issues such as the anti-inflammatory potential of the methyl xanthines; the relative advantages of fluticasone over other inhaled corticosteroids; and the role of long-acting ß2-agonists. It seems accepted that the anti-leucotrienes - led by montelukast - will significantly influence the market most probably by reducing demand for the cromogens. The chapter concludes with more detailed descriptions of all the current and emerging medicines.

Chapter 3 moves the discussion into the future by reviewing a range of asthma medicines which are in various stages in development. While there remains considerable interest in the traditional approaches of bronchodilators and anti-inflammatories, it is clear the emphasis is beginning to change towards medicines targeted at specific sites within the immunological system. The anti-leucotrienes are currently the focus of this attention but other inflammatory mediators - other metabolites of arachidonic acid, cell adhesion molecules, and platelet-activating factor - are being actively evaluated. In the longer term, antisense oligonucleotides offer the potential of specific control of asthma susceptibility genes.

Chapter 4 shifts the emphasis of the report from pharmacology and medicine to finance and business. Thus, predicted sales of current, emerging, and development-stage therapies are highlighted. There is a consensus that the market, driven by forces outlined in some detail, will shift more and more towards anti-inflammatory medicines - to earlier intervention with corticosteroids in the short term, growing use of anti-leucotrienes in the short-medium term, and, increasing use of various specific anti-inflammatory agents in the long term. The 'losers' in this transition are likely to be the bronchodilators whose market will decrease as anti-inflammatory control becomes more effective. The multinational companies most likely to exploit this change are identified and, in Chapter 5, are profiled in more detail: they represent less than 10% of the companies contacted for background information for this report. It is the alliances these multinationals have formed, and are forming, with smaller high tech companies that is likely to underpin their success rather more than the traditional approaches to medicine development.

In the Directory can be found a listing of the companies and organisations contacted during the preparation of this report. A summary table, compiled from information provided by the companies and from various PJB databases, provides a list of the principal pharmaceutical companies in asthma medicines, of their leading products, and of their important characteristics.

Asthma: New treatment horizons and market challenges

Transformation of the asthma product market is underway, with new orally active anti-leucotrienes challenging traditional inhaled therapies. These premium-priced drugs are predicted to claim as much as 20% of the market by 2005.

This new, fully updated, report focuses on the future of asthma medicines. It provides you with an overview of exactly how new developments will affect both current and emerging products. Asthma: New treatment horizons and market challenges assesses: traditional inhaled approaches such as bronchodilators and anti-inflammatories; medicines targeting the immunological system, including anti-leucotrienes; and future developments offering control of asthma susceptibility genes.

This report includes sales predictions, details of product placement, profiles of major companies currently involved in asthma treatment and descriptions of current and emerging medicines. It is an invaluable source of competitor information for all pharmaceutical decision makers interested in the asthma market.

PUBLISHED: AUGUST 1998
REF: BS970E
PAGES: 175
PRICE: £370/$780/¥89,000

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