Scrip's Complete Guide to Cardiovascular Diseases


Therapeutic


NEW
Providing in-depth information on all the major cardiovascular disease (CVD) areas of hypertension, coronary heart disease, arrhythmia, congestive heart failure and stroke, this extensive report includes:


* R&D information for over 200 drugs currently in development
* Market potential estimates for new and emerging therapies
* Current market figures and sales forecasts to 2002
* Profiles of 19 major players in the CVD treatment market


Scrip's Complete Guide to Cardiovascular Diseases provides you with a comprehensive overview of the CVD market. Volume 1 of the report details the most advanced clinical understanding of CVD. By providing you with the latest market data, and commentary on trends and influences that will shape the CVD drug market, this report allows you to gain a complete understanding of both current and future market status.


Volumes 2-5 cover each disease area separately. Each includes an introduction to the disease area and the latest understanding of the disease process, an in-depth evaluation of drugs on the market and their performance, opportunities for new products and a detailed analysis of products in clinical development. Each volume also has up-to-date trial data and tabulated information on compounds in development, from preclinical to registered.


PUBLISHED: November 1999
REF: BS1030E
PAGES: 500+
PRICE: Complete six-volume set �990/$1,995/�238,000


CONTENTS
LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
METHODOLOGY
ABBREVIATIONS
CLINICAL TRIAL ACRONYMS


CHAPTER 1 INTRODUCTION
1.1 Cardiovascular diseases
1.2 Classification of cardiovascular diseases
1.2.1 Heart diseases
1.2.1.1 Coronary heart disease
1.2.1.2 Angina pectoris
1.2.1.3 Acute coronary syndromes
1.2.1.4 Congestive heart failure
1.2.1.5 Arrhythmias
1.2.2 Hypertension
1.2.3 Stroke
1.2.4 Arterial diseases
1.2.4.1 Atherosclerosis
1.3 Cardiovascular diseases and their risk factors
1.4 Treatment of cardiovascular diseases
1.4.1 Treatment of hypertension
1.4.2 Treatment of angina
1.4.3 Treatment of coronary heart disease
1.4.3.1 Primary prevention
1.4.3.2 Treatment of acute ischaemic events
1.4.3.3 Secondary prevention
1.4.4 Treatment of congestive heart failure
1.4.5 Treatment of arrhythmias
1.4.6 Treatment of stroke


CHAPTER 2 MARKET INFORMATION AND EPIDEMIOLOGY
2.1 Introduction
2.2 Market value
2.2.1 World pharmaceutical sales
2.2.2 Sales of cardiovascular products by geographical region
2.3 Market growth
2.4 Market structure
2.5 Major products by drug class and therapeutic area
2.5.1 Treatments for hypertension
2.5.1.1 Beta-blockers
2.5.1.2 Angiotensin converting enzyme inhibitors
2.5.1.3 Calcium channel blockers
2.5.1.4 Angiotensin II receptor antagonists
2.5.1.5 Other antihypertensives
2.5.2 Treatments for atherosclerosis/coronary heart disease
2.5.2.1 HMG-CoA reductase inhibitors
2.5.3 Treatments for angina
2.5.4 Treatments for acute coronary syndromes
2.5.4.1 Thrombolytics
2.5.4.2 Antiplatelets
2.5.4.3 Antithrombotics
2.5.5 Treatments for arrhythmia
2.5.6 Treatments for congestive heart failure
2.5.7 Treatments for stroke
2.6 Market influences
2.7 Epidemiology
2.7.1 Global prevalence of cardiovascular disease
2.7.2 Hypertension
2.7.3 Coronary heart disease
2.7.4 Arrhythmias
2.7.5 Congestive heart failure
2.7.6 Stroke


CHAPTER 3 COMPANY PROFILES
3.1 AstraZeneca
3.1.1 Agreements re cardiovascular therapy
3.1.2 Financial highlights
3.1.3 Cardiovascular drugs marketed and in development
3.2 Bayer
3.2.1 Cardiovascular therapy agreements
3.2.2 Financial highlights
3.2.3 Cardiovascular drugs marketed and in development
3.3 Boehringer Ingelheim
3.3.1 Cardiovascular therapy agreements
3.3.2 Financial highlights
3.3.3 Cardiovascular drugs marketed and in development
3.4 Bristol-Myers Squibb
3.4.1 Cardiovascular therapy agreements
3.4.2 Financial highlights
3.4.3 Cardiovascular drugs marketed and in development
3.5 Eli Lilly
3.5.1 Cardiovascular diseases agreements
3.5.2 Financial highlights
3.5.3 Cardiovascular drugs marketed and in development
3.6 Glaxo Wellcome
3.6.1 Cardiovascular therapy agreements
3.6.2 Financial highlights
3.6.3 Cardiovascular drugs marketed and in development
3.7 Hoechst Marion Roussel
3.7.1 Cardiovascular therapy agreements
3.7.2 Financial highlights
3.7.3 Cardiovascular drugs marketed and in development
3.8 Knoll
3.8.1 Cardiovascular therapy agreements
3.8.2 Financial highlights
3.8.3 Cardiovascular drugs marketed and in development
3.9 Merck & Co
3.9.1 Cardiovascular therapy agreements
3.9.2 Financial highlights
3.9.3 Cardiovascular drugs marketed and in development

3.10 Novartis
3.10.1 Cardiovascular therapy agreements
3.10.2 Financial highlights
3.10.3 Cardiovascular drugs marketed and in development
3.11 Pfizer
3.11.1 Cardiovascular therapy agreements
3.11.2 Financial highlights
3.11.3 Cardiovascular drugs marketed and in development
3.12 Rh�ne-Poulenc Rorer
3.12.1 Cardiovascular therapy agreements
3.12.2 Financial highlights
3.12.3 Cardiovascular drugs marketed and in development
3.13 Roche
3.13.1 Cardiovascular therapy agreements
3.13.2 Financial highlights
3.13.3 Cardiovascular drugs marketed and in development
3.14 Sanofi-Synth�labo
3.14.1 Agreements re cardiovascular therapy
3.14.2 Financial highlights
3.14.3 Cardiovascular drugs marketed and in development
3.15 Schering-Plough
3.15.1 Cardiovascular therapy agreements
3.15.2 Financial highlights
3.15.3 Cardiovascular drugs marketed and in development
3.16 Searle
3.16.1 Cardiovascular therapy agreements
3.16.2 Financial highlights
3.16.3 Cardiovascular drugs marketed and in development
3.17 Servier
3.17.1 Cardiovascular therapy agreements
3.17.2 Financial highlights
3.17.3 Cardiovascular drugs marketed and in development
3.18 Solvay
3.18.1 Cardiovascular therapy agreements
3.18.2 Financial highlights
3.18.3 Cardiovascular drugs marketed and in development


CHAPTER 4 REGULATORY INFORMATION
4.1 Introduction
4.2 Guidance for clinical investigations of lipid-lowering drugs
4.2.1 Efficacy evaluation of lipid-lowering drugs
4.2.2 Safety evaluation of lipid-lowering drugs
4.3 Guidance for clinical investigations of antihypertensive drugs
4.3.1 Efficacy evaluation of antihypertensive drugs
4.3.2 Safety evaluation of antihypertensive drugs
4.4 Guidance for clinical investigations of antianginal drugs
4.4.1 Efficacy evaluation of antianginal drugs
4.4.2 Safety evaluation of antianginal drugs
4.5 Guidance for clinical investigations of drugs for the treatment of acute coronary syndromes
4.5.1 Efficacy evaluation of drugs for the treatment of acute coronary syndromes
4.5.2 Safety evaluation of drugs for the treatment of acute coronary syndromes
4.6 Guidance for clinical investigations of antiarrhythmic drugs
4.6.1 Efficacy evaluation of antiarrhythmic drugs
4.6.2 Safety evaluation of antiarrhythmic drugs

4.7 Guidance for clinical investigations of heart failure drugs
4.7.1 Efficacy evaluation of heart failure drugs
4.7.2 Safety evaluation of heart failure drugs
4.8 Guidance for clinical investigations of drugs for the treatment of ischaemic stroke


REFERENCES
APPENDIX I COMPANY DIRECTORY
APPENDIX II CARDIOVASCULAR CONFERENCE CALENDAR


LIST OF TABLES
Table M.1 Average exchange rates against the US$, 1996-1998
Table 1.1 Risk factors associated with coronary heart disease
Table 1.2 Risk factors associated with stroke
Table 1.4 Risk factors associated with cardiovascular disease
Table 1.5 Antihypertensive drugs currently on the market
Table 1.6 Antianginal drugs currently on the market
Table 1.7 Drugs for the primary prevention of coronary artery disease/coronary heart disease
Table 1.8 Drugs for the treatment of acute ischaemic events
Table 1.9 Drugs for the secondary prevention of acute ischaemic events
Table 1.10 Drugs for the treatment of congestive heart failure
Table 1.11 Antiarrhythmic drugs classified by their mode of action
Table 1.12 Drugs for the treatment of stroke
Table 1.13 Drugs for the secondary prevention of stroke
Table 2.1 Top 10 major therapeutic categories, 1998
Table 2.2 Top 10 pharmaceutical categories in the leading three markets, 1998-1999
Table 2.3 Growth of cardiovascular product sales in the top 12 markets, 1997-1998
Table 2.4 Sales of major cardiovascular products by therapeutic category, 1997-1998
Table 2.5 Sales of the leading beta-blockers, 1998
Table 2.6 Sales of the leading ACE inhibitors, 1998
Table 2.7 Sales of the leading calcium channel antagonists, 1998
Table 2.8 Sales of the leading angiotensin II antagonists, 1998
Table 2.9 Sales of statins, 1998
Table 2.10 Sales of the leading antiplatelet agents, 1998
Table 2.11 Trends in the control of hypertension in the US, 1976-1994
Table 2.12 The prevalence of hypertension in selected countries around the world
Table 2.13 Mortality per year due to congestive heart failure in the US and Europe
Table 3.1 Astra and Zeneca financial results, 1996-1998
Table 3.2 Astra and Zeneca sales by therapeutic category, 1997-1998
Table 3.3 Bayer's financial results, 1996-1998
Table 3.4 Bayer's sales by region, 1996-1998
Table 3.5 Boehringer Ingelheim's financial results, 1996-1998
Table 3.6 Bristol-Myers Squibb's financial results, 1996-1998
Table 3.7 Bristol-Myers Squibb's sales by region, 1996-1998
Table 3.8 Bristol-Myers Squibb's sales by therapeutic category, 1996-1998
Table 3.9 Eli Lilly's financial results, 1996-1998
Table 3.10 Glaxo Wellcome's financial results, 1996-1998
Table 3.11 Hoechst Marion Roussel's financial results, 1996-1998
Table 3.12 Hoechst Marion Roussel's pharmaceutical sales by region, 1996-1998
Table 3.13 Hoechst Marion Roussel's 10 leading products, 1996-1998
Table 3.14 Knoll's financial results, 1996-1998
Table 3.15 Merck & Co's financial results, 1996-1998
Table 3.16 Merck & Co's pharmaceutical sales by region, 1996-1998
Table 3.17 Merck & Co's sales by therapeutic category, 1996-1998
Table 3.18 Merck & Co's leading products, 1998
Table 3.19 Novartis' financial results, 1996-1998
Table 3.20 Novartis' pharmaceutical sales by region, 1996-1998
Table 3.21 Pfizer's financial results, 1996-1998
Table 3.22 Pfizer's sales by therapeutic category, 1996-1998
Table 3.23 Pfizer's leading products, 1998
Table 3.24 Rh�ne-Poulenc Rorer's financial results, 1996-1998
Table 3.25 Roche's financial results, 1996-1998
Table 3.26 Roche's group sales by region, 1996-1998
Table 3.27 Sanofi and Synth�labo financial results, 1996-1998
Table 3.28 Sanofi and Synth�labo pharmaceutical sales by region, 1997-1998
Table 3.29 Sanofi and Synth�labo sales by therapeutic category, 1997-1998
Table 3.30 Schering-Plough's financial results, 1996-1998
Table 3.31 Searle's financial results, 1996-1998
Table 3.32 Servier's financial results, 1995-1997
Table 3.33 Solvay's financial results, 1996-1998


LIST OF FIGURES
Figure 1.1 Worldwide causes of death, 1997
Figure 1.2 Main causes of death in the developed and developing world in 1997
Figure 2.1 Ethical pharmaceutical sales for the top 10 markets, 1998
Figure 2.2 Growth in the cardiovascular market by geographical region, 1997-1998
Figure 2.3 Leading companies in the cardiovascular market, 1998
Figure 2.4 Projected sales of antihypertensive products, 1997-2002
Figure 2.5 Projected sales of the calcium channel antagonists, 1996-2002
Figure 2.6 Projected sales of angiotensin II antagonists, 1997-2002
Figure 2.7 Projected sales of statins, 1997-2002
Figure 2.8 Market share of the leading statins in the US and Japan, 1998
Figure 2.9 Projected sales of the branded nitrates, 1997-2002
Figure 2.10 Projected sales of thrombolytic agents, 1997-2002
Figure 2.11 Projected sales of antiplatelet agents, 1997-2002
Figure 2.12 Projected sales of antithrombotic agents, 1997-2002
Figure 2.13 Projected sales of antiarrhythmic agents, 1997-2002
Figure 2.14 Projected sales of congestive heart failure agents, 1997-2002
Figure 2.15 Percentage of deaths due to coronary heart disease and strokes in WHO Member States, 1998
Figure 2.16 Estimated DALYs due to cardiovascular disease in middle and low-income countries, 1998



This volume, CVD Market Overview, is part of a series forming Scrip's Complete Guide to Cardiovascular Diseases. The other volumes in this series are:


EXECUTIVE SUMMARY
The cardiovascular market is by far the largest therapeutic sector in the pharmaceutical industry, reflecting the enormity of the disease area and its impact on healthcare. The exceptional growth of cardiovascular drugs and the blockbuster potential of new agents in this category further illustrate the importance of this therapy sector.


Cardiovascular disease (CVD) is an immense emotional and economic burden worldwide. It is the leading killer in industrialised countries and the consequences of CVD are beginning to be felt in the developing countries. Nearly 30% of all deaths worldwide were due to CVD in 1997 - accounting for over 15 million deaths. Forty-six percent of all deaths in the developed world were attributed to CVD in 1997, which amounts to over 5 million fatalities. In the developing world, nearly 10 million deaths (24%) were due to CVD. These alarming figures demonstrate the scale of CVD and its associated problems. The problem is set to expand as 20th century lifestyles leads to an increase in CVD risk factors. Obesity, diabetes and an ageing population will all have a knock-on effect on health and in particular on cardiovascular-related conditions.


CVDs encompass a range of circulatory and heart disorders including hypertension, coronary heart disease (CHD), arrhythmias, congestive heart failure (CHF) and stroke. This report will give a complete overview of the CVD market, which was valued at $36.9 billion in 1998 and is still rising. Volume 1 will introduce the general aspects of CVD and provide the latest market data with comments on the trends and influences that will shape the future of the CVD market. The CVD market has consistently been the premier therapeutic category in terms of sales; the commercial value of this sector being demonstrated by the blockbuster status of many CVD agents. The introductory volume will also profile the leading companies involved in the CVD market.


The remaining volumes in this report will highlight the major therapeutic subcategories within CVD. Each volume will introduce the individual diseases, emphasising the treatment trends of each condition and the medical options available on the market with an in-depth analysis of the performance of key products. In addition, the individual disease volumes will highlight the direction of current research. The reports will give a comprehensive review of innovations in therapy, new drugs in development and potential blockbusters.


Antihypertensives make up the largest single therapeutic class within the CVD category. Volume 2 reviews the status of this market, which is valued at over $22 billion with a projected growth of 24% by 2002. Hypertension affects 700 million people, with 20% of the adult population thought to suffer from high blood pressure. Agents from this therapy class are consistently strong performers, however, the problems of patent expiry and generic competition threaten to affect this lucrative market.

Traditional first-line agents, like beta-blockers, have relied on line extensions and additional indications to maintain their market share. Even these strategies have not been completely successful and sales of branded products have slowly declined. Calcium channel antagonists and angiotensin converting enzyme (ACE) inhibitors are the strongest performers in the antihypertensive category. These two classes of drugs have a combined market value of $15.2 billion. Nevertheless, the imminent patent expiration of the two leading ACE inhibitors, AstraZeneca's Zestril (lisinopril) and Merck & Co's Vasotec (enalapril) may adversely affect the market.


The leading calcium channel antagonists are less effected by patent issues and have shown impressive growth over recent years. Although calcium channel antagonists are not recommended as first-line drugs, they have increased in popularity. The newer dihydropyridine calcium channel blockers in particular have become widely used. This has been partly due to an increased marketing emphasis and the positive results from clinical trials demonstrating the beneficial effects of the agents. The recently published HOT study indicated that blood pressure reduction with the dihydropyridine, felodipine, significantly reduced cardiovascular risks. The angiotensin II antagonists are relative newcomers to the antihypertensive field but have quickly gained market acceptance. Angiotensin II antagonists offer improvements in safety profile and equivalent efficacy and their success is illustrated by Merck & Co's Cozaar (losartan), the first agent from this class to break the $1 billion sales barrier.


To improve their chances of succeeding in the extremely competitive antihypertensive market, new innovations will have to improve on the safety profile and efficacy of the established agents. The dual neutral endopeptidase/ACE inhibitors look the most promising. These agents appear to have a good safety profile and have demonstrated favourable efficacy in their trials compared with ACE inhibitors alone.


Innovative products and new product launches have all contributed to the success of the market for atherosclerosis/CHD - it is one of the fastest growing segments in the industry. Volume 3 discusses the latest developments in the treatment and understanding of the disease. CHD is the highest single cause of mortality in the world and its consequences are felt throughout the spectrum of CVDs, leading directly to CHF, arrhythmia and stroke.


The phenomenal growth of the statins reflects the real need for effective management of CHD. These agents have the potential to stop further heart attacks and even prevent the occurrence of a first heart attack in high-risk patients. Thus, statins have been both a medical and commercial success. In the near future, statins are predicted to become the world's leading drugs in terms of sales, surpassing the high-selling antiulcer agents.


In the treatment of acute ischaemic attacks, such as unstable angina, non-Q-wave myocardial infarction (MI) and acute MI (AMI), novel therapeutic agents have been introduced that promise to save more lives. Traditionally, the emergency treatment of unstable angina and non-Q-wave MI involves the use of antithrombotics (aspirin and heparin) whilst the treatment of AMI favoured the use of thrombolytics (streptokinase).


Low molecular weight heparins, direct thrombin inhibitors and glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonists show promise over the standard treatment options of aspirin and heparin. A number of clinical trials have shown that these agents have a comparable or better efficacy to aspirin or heparin but the cost effectiveness of the latter agents will mean that the new drugs will have to demonstrate significantly improved benefits to succeed.


Second-generation thrombolytics such as the tissue plasminogen activators, alteplase and reteplase, offer significant advantages over the older thrombolytic, streptokinase. Alteplase and reteplase do not have the immune response associated with streptokinase; in addition, the second-generation thrombolytics increase the chance of a positive outcome.


R&D in CHD-related therapy is constantly evolving as investigators attempt to improve on the current therapeutic modalities. Research has started to focus on the combined use of thrombolytics with antiplatelet drugs; preliminary trials using such combinations indicate that this may be the way forward in the acute treatment of heart attacks. The future for oral
GPIIb/IIIa receptor antagonists does not bode well and poor clinical trial results have resulted in a number of companies discontinuing development of these agents. Antithrombotic drugs in development have also faced problems, mainly because they have not shown a large increase in benefit over heparin.


Although new therapeutic approaches using immunotherapy and gene therapy are still a long way off from the market, these agents have shown some promising results in preclinical and early clinical trials and hold exciting possibilities.


Volume 4 covers the treatment of arrhythmia, a disease affecting over 4.3 million people in the US. Atrial fibrillation is the most common type of arrhythmia and its prevalence is rising due to the increasing number of post-MI survivors. The antiarrhythmic market has been beset by problems in recent times. Class I antiarrhythmic drugs were the first-line agents in antiarrhythmic therapy, but recent trials highlighted the proarrhythmic properties of these agents, which can actually increase mortality. The pharmacological management of arrhythmia is also under intense pressure from the increasing popularity of implantable devices. Only beta-blockers currently appear to have a consistent benefit on mortality in certain forms of arrhythmia but Class III agents such as amiodarone have proved beneficial, especially in guided therapy, and this may be the future direction for antiarrhythmic drugs.


The development of agents specifically for patients with atrial fibrillation/flutter is still an active research area, especially as these patients are not ideal candidates for implantable cardioverter defibrillator treatment. Antiarrhythmic drug development has largely focused on Class III agents. Drugs of this class appear to have a better safety profile compared with the Class I antiarrhythmics. New approaches are also under investigation in an attempt to provide safer and more effective alternatives to the present options.


Heart failure is a progressive disease that, once initiated, usually advances to a life-threatening state and, in many cases, death. The current understanding of the processes involved in the development of CHF and the resultant shift in treatment strategies is the focus of Volume 5. Worldwide, 2 million new cases are diagnosed each year and it is one of the leading causes of hospitalisation in people aged over 65 years.


The medical management of CHF is based on two main criteria. The first is short-term treatment to alleviate the symptoms of the disease and the second goal is a long-term strategy to stop or slow down disease progression. Traditional drugs in CHF include diuretics, coronary vasodilators and cardiostimulants, which aid the functioning of the heart. However, in recent years the focus has moved on to the neurohormonal influences in CHF and in particular the role they play in the structural changes of the heart. Consequently, ACE inhibitors and beta-blockers have come to the fore in the management of CHF. The importance of these drugs in the treatment of heart failure is directly related to new understanding of the role that the renin-angiotensin system and sympathetic nervous system play in the progression of heart failure. However, the optimum therapeutic options are still not being used to their full potential and ACE inhibitors and beta-blockers are still underprescribed for CHF.


The emerging role of the angiotensin II antagonists in the management of CHF is also analysed. Clinical trials with these agents have provided promising results and they appear to be comparable to the ACE inhibitors.


The benefits of beta-blockade in the treatment of CHF were being further evaluated in the BEST trial with Intercardia's Bextra (bucindolol) but the results from this Phase III trial were disappointing and the trial was terminated early on the recommendation of an independent review board. However, Bristol-Myers Squibb's vasopeptidase, Vanlev (omapatrilat), which has beta-blocking properties, is looking promising. The potential of endothelin antagonists to prevent cardiac remodelling in CHF is an exciting prospect but the development of these agents may have been set back by the troubles encountered by the leading product in development, Actelion's bosentan. Scios' Natrecor (nesiritide), a recombinant form of brain natriuretic peptide, if successful will be the first new agent approved for the treatment of acute heart failure in many years. However, it has failed to gain approval in the US after receiving an initial approval recommendation by the Food and Drug Administration regulatory review panel.


The consequences of a stroke can be devastating - apart from the large number of fatalities associated with strokes, the disease is the leading cause of adult disability in the world with up to 30 million people left disabled each year. Volume 6 provides an analysis of the therapeutic options available to treat this crippling disease, including drugs currently on the market and those in development.


The medical treatment of ischaemic stroke has largely been inadequate and there is still a tremendous unmet need for an effective therapeutic option. The thrombolytic alteplase, used with some success in the treatment of heart attacks, has provided an improved option but its narrow treatment window means that a large proportion of patients are still not accommodated for. New agents in development may have the potential to extend the limited treatment window well beyond the current 3 hours. Such agents include Abbott's Prolyse (prourokinase) and Knoll's Viprinex (ancrod).


Preventative treatment in stroke still revolves around the traditional medicines of warfarin and aspirin. Agents in development that play a role in protecting against a first stroke or a recurrent attack have not shown much improvement over the established options, as such, there may be little justification in using them.


The biggest disappointment in stroke therapy has been the failure to develop an effective neuroprotector to shield the brain from injury during a cerebrovascular attack. The majority of neuroprotective agents developed thus far have proved inconclusive and some may even be detrimental to the patient. Nevertheless, there are some promising agents in development and although the failures still outweigh the successes, a number of investigational drugs may yet offer a better alternative to the current choices.

© PJB Publications Ltd. 2000
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