Superstatins – Implications for the lipid-lowering market
Therapeutic
The imminent arrival of AstraZeneca's "superstatin" Crestor is expected to change the competitive landscape of the statins market.
With new US guidelines advocating the aggressive treatment of blood cholesterol levels, the potential of statins in primary prevention of coronary heart disease (CHD) is enormous.
Scrip's Superstatins – Implications for the lipid-lowering market analyses the huge success of recently marketed statins and discusses the potential the market has – given that only one-third of those at risk of CHD are reported to be receiving cholesterol-lowering drugs.
The focus of this topical report on this commercially rewarding market is on:
Published: July 2001
Pages: 125
Ref: BS1139E
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CONTENTS
LIST OF TABLES
LIST OF FIGURES
EXECUTIVE SUMMARY
SCOPE AND METHODOLOGY
S.1 Objectives
S.2 Scope
S.3 Methodology
ABBREVIATIONS AND GLOSSARY
CLINICAL TRIAL ACRONYMS
CHAPTER 1 AN INTRODUCTION TO CORONARY HEART DISEASE
1.1 Definition of coronary heart disease
1.2 Epidemiology of CHD
1.2.1 Prevalence and incidence of CHD
1.2.2 Incidence and prevalence of CHD in specific populations
1.2.2.1 Familial hyperlipidaemia
1.2.2.2 The elderly
1.2.2.3 Males versus females
1.2.2.4 Ethnic groups
1.2.2.5 Socio-economic background
1.2.3 Morbidity associated with CHD
1.2.4 Mortality from CHD
1.2.4.1 Trends in CHD mortality
1.2.5 Economic implications of CHD
1.2.6 Risk factors for atherosclerosis and CHD
1.2.6.1 Dyslipidaemia
1.2.6.2 Smoking
1.2.6.3 Hypertension
1.2.6.4 Others
1.3 Strategies for the prevention of CHD
1.3.1 Aim of CHD prevention
1.3.2 Lifestyle modification
1.3.3 Dietary therapy
1.3.4 Drug therapy
CHAPTER 2 CHOLESTEROL, LIPOPROTEINS AND BLOOD LIPIDS AND THEIR ROLE IN ATHEROSCLEROSIS
2.1 Introduction
2.2 What are cholesterol, lipoproteins and blood lipids?
2.2.1 Cholesterol
2.2.2 Lipoproteins
2.2.3 Lipids
2.3 Pathophysiology of CHD – the role of atherosclerosis
2.4 Components of the atherosclerotic process
2.4.1 Response to injury hypothesis
2.4.2 Endothelial dysfunction
2.4.3 Cell migration and proliferation
2.4.4 Lipoproteins and cholesterol
2.5 The role of lipid lowering in CHD
2.5.1 National guidelines for cholesterol reduction
2.5.1.1 US NCEP guidelines
2.5.1.2 European guidelines
2.5.1.3 UK guidelines
2.5.1.4 Japanese guidelines
2.5.2 Landmark primary and secondary intervention trials
2.5.2.1 The Scandinavian Simvastatin Survival Study (4S)
2.5.2.2 The West of Scotland Coronary Prevention Study (WOSCOPS)
2.5.2.3 Cholesterol and Current Events (CARE)
2.5.2.4 Air Force/Texas Coronary Atherosclerosis Prevention Study (AF/TEXCAPS)
2.5.2.5 Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID)
2.5.2.6 Overview of major statin-lowering trials
2.5.2.7 Atherosclerotic plaque regression studies
CHAPTER 3 THE ESTABLISHED LIPID-LOWERING MARKET
3.1 Introduction
3.2 Traditional lipid-lowering products
3.2.1 Fibrates
3.2.2 Bile acid sequestrants
3.2.3 Nicotinic acid
3.2.4 Fish oils and other dietary therapies
3.3 Statins
3.3.1 Mechanism of action of the statins
3.3.1.1 HMG-CoA reductase inhibition – primary mechanism of action
3.3.1.2 Anti-atherogenic effects – secondary mechanisms of action
3.3.2 Class properties of the statins
3.3.2.1 Atorvastatin
3.3.2.2 Cerivastatin
3.3.2.3 Fluvastatin
3.3.2.4 Lovastatin
3.3.2.5 Pravastatin
3.3.2.6 Simvastatin
CHAPTER 4 LIPID-LOWERING PRODUCTS IN R&D
4.1 Introduction
4.2 Statins in development
4.2.1 Rosuvastatin
4.2.1.1 Efficacy and safety profile
4.2.1.2 Potential impact on the lipid-lowering market
4.2.2 Itavastatin (NK-104)
4.2.2.1 Efficacy and safety profile
4.2.2.2 Potential impact on the lipid-lowering market
4.3 New lipid-lowering/anti-atherosclerotic products in development
4.3.1 New bile acid sequestrants and bile acid transport inhibitors
4.3.1.1 GT-102-279
4.3.1.2 HBS-107
4.3.1.3 KBS-2750
4.3.1.4 BARI
4.3.1.5 SD-5613
4.3.1.6 S-8921
4.3.2 ACAT inhibitors
4.3.2.1 Avasimibe (CI-1011)
4.3.2.2 F-1394
4.3.2.3 Eflucimibe (F-12511)
4.3.2.4 CS-505
4.3.3 MTP inhibitors
4.3.3.1 Implitapide (BAY-13-9952)
4.3.4 Cholesterol transport/absorption inhibitors
4.3.4.1 Ezetimibe
4.3.5 CETP inhibitors
4.3.5.1 CP-529,414
4.3.5.2 CETi-1 atherosclerosis vaccine
4.3.6 Other hypolipidaemic/anti-atherosclerotic agents in development
CHAPTER 5 THE MARKET FOR LIPID-LOWERING PRODUCTS
5.1 Introduction
5.2 Market value
5.2.1 Total market estimates
5.2.2 Market value by major geographical region
5.3 Market growth
5.4 Market structure
5.5 Product positioning
5.6 Short- and long-term influences on the lipid-lowering market
5.6.1 Large treatment gaps
5.6.2 New licensed indications
5.6.3 New lipid targets
5.6.4 Epidemiological factors
5.6.5 Health educational programmes
5.6.6 Generic competition
5.6.7 The superstatins
5.6.8 Beyond statins
5.6.9 Constraints in healthcare spending
5.7 Conclusion
CHAPTER 6 PROFILES OF SELECTED COMPANIES IN THE LIPID-LOWERING MARKET
6.1 AstraZeneca
6.2 Bayer
6.3 Bristol-Myers Squibb
6.4 Groupe Fournier
6.5 Merck & Co
6.6 Novartis Pharma
6.7 Pfizer
6.8 Sankyo
6.9 Schering-Plough
6.10 Yamanouchi Pharmaceutical
REFERENCES
APPENDIX 1 EXCHANGE RATES
List of Tables
Table 1.1 Fredrickson (WHO) classification of lipid and lipoprotein abnormalities
Table 1.2 Epidemiological risk factors for atherosclerosis and CHD
Table 1.3 Summary of results from the Ni-Hon-San observational study
Table 1.4 Comparison of NCEP dietary regimen for CHD prevention in ATPII and ATPIII
Table 1.5 Drugs for primary and secondary prevention of atherosclerosis and CHD
Table 2.1 Lipid and lipoprotein levels associated with an increased risk of CHD
Table 2.2 Influence of OxLDL on the pathogenesis of atherosclerosis
Table 2.3 Summary of the main findings of the landmark statin intervention trials
Table 2.4 Summary of results from the Prospective Pravastatin Pooling Project
Table 3.1 Fibrates used for the treatment of atherosclerosis/CHD
Table 3.2 Summary of reductions in baseline LDL-C in the CURVES and CAVEAT studies
Table 4.1 New classes of hypolipidaemic and anti-atherosclerotic drugs
Table 4.2 Hypolipidaemic and anti-atherosclerotic agents in clinical development
Table 5.1 Sales of statins over the period 1998–2000
Table 5.2 Cost of statin therapy in the US
Table 5.3 Summary of the findings from EUROASPIRE I and II
Table 5.4 Summary of on-going trials to investigate the effects of greater reductions in LDL-C on coronary endpoints
Table 6.1 AstraZeneca's financial highlights ($ million), 1996–2000
Table 6.2 Bayer's financial highlights (Euro million), 1996–2000
Table 6.3 Bristol-Myers Squibb's financial highlights ($ million), 1996–2000
Table 6.4 Merck & Co's financial highlights ($ million), 1996–2000
Table 6.5 Novartis' financial highlights (SwFr million), 1996–2000
Table 6.6 Pfizer's financial highlights ($ million), 1996–2000
Table 6.7 Sankyo's financial highlights (¥ million), 1996–2000
Table 6.8 Schering-Plough's financial highlights ($ million), 1996–2000
Table 6.9 Yamanouchi's financial highlights (¥million), 1996–2000
Table A.1 Average exchange rates against $, 1998–2000
List of Figures
Figure 1.1 Age-related prevalence of CHD in men and women in the US, 1988–1994
Figure 1.2 Age-standardised death rates from CHD for men and women aged 35–74 years in different parts of Europe, 1994
Figure 1.3 Causes of death in European men under 75 years of age, latest available year
Figure 1.4 Causes of death in European women under 75 years of age, latest available year
Figure 1.5 Contribution of risk factors to the development of CHD
Figure 1.6 Adverse effects of high blood pressure on the heart
Figure 2.1 Cholesterol transport to and from the liver
Figure 2.2 Cross-sectional diagram of a healthy and an atherosclerotic artery
Figure 2.3 Stages of atheromatous plaque formation
Figure 3.1 Evolution of the statins
Figure 3.2 Competitive inhibition of HMG-CoA in the cholesterol biosynthetic pathway
Figure 4.1 The superstatins
Figure 4.2 Head-to-head comparisons of LDL-C reductions with rosuvastatin versus atorvastatin, pravastatin and simvastatin
Figure 4.3 Head-to-head comparisons of increases in HDL-C with rosuvastatin versus atorvastatin, pravastatin and simvastatin
Figure 4.4 Percentage of patients achieving recommended NCEP reductions in LDL-C with rosuvastatin, pravastatin and simvastatin
Figure 5.1 The global cardiovascular market, 2000
Figure 5.2 Percentage of lipid-lowering sales by geographic region, 2000
Figure 5.3 Past and projected sales of lipid-lowering therapies in the period 1999–2003
Figure 5.4 Market share of the leading statins in the US and Japan, 1998
Figure 5.5 Market share of the leading statins in the US and Japan, 2000
EXECUTIVE SUMMARY
With annual sales of over $50 billion in 2000, the market for cardiovascular drugs represents the largest segment of the prescription drug market. This reflects the continued need to manage heart disease and stroke. Indeed, heart disease and stroke still pose the greatest risk to life and well-being throughout the world. Drugs for the treatment of hypertension and lipid disorders dominate today's cardiovascular market, with lipid-lowering therapies showing the highest growth dynamic within the cardiovascular sector. Moreover, lipid-lowering therapies are poised to overtake the hugely successful anti-ulcer drugs to become the leading therapy class in the not too distant future.
The phenomenal growth of the lipid-lowering market, averaging 20% year-on-year, can be attributed to the introduction of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins as they are more widely known. Introduced into clinical practice in the late 1980s, this class of lipid-lowering drugs has revolutionised the treatment of dyslipidaemia, a major risk factor for coronary heart disease (CHD). The statins have been described as the most powerful 'heart drugs' available today, with the capacity to reduce coronary events by over 40%, almost twice that achieved with beta-blockers and aspirin.
The lipid-lowering market is predicted to undergo further rapid change in the next few years as a new generation of 'superstatins', epitomised by AstraZeneca's Crestor (rosuvastatin), enter the market and companies already fighting for greater market share seek ways to compete with these new superstatins. By 2010 it is anticipated that the lipid-lowering market will be twice its present size and embrace several new classes of hypolipidaemic drugs. Whether any of these new classes of lipid-lowering agents will achieve the phenomenal clinical and market success of the statins is doubtful but their potential to be used in combination with the statins suggests that we are entering an era of even more powerful hypolipidaemic agents. Potentially we may see even greater reductions in the incidence of CHD-related morbidity and mortality than can currently be achieved with the statins.
Chapter 1 of this report gives an insight into CHD, for which atherosclerosis is the primary cause, and the magnitude of the problem facing health professionals trying to reduce the prevalence of a disease which in the industrialised countries of the world still kills more people than any other. In the US, CHD affects over 12 million people, of whom half a million will die from the disease each year while the remainder suffer the debilitating effects of a myocardial infarction (MI) or angina. Among many risk factors for CHD, abnormal levels of serum lipoproteins (dyslipidaemia) have been found unequivocally to be aetiologically related to the risk of atherosclerosis and subsequent CHD. Together with smoking and hypertension, dyslipidaemia constitutes one of the 'big three' risk factors for CHD. Dyslipidaemia is a highly prevalent but insidious disorder, the effects of which are evident only when people develop the clinical manifestations of CHD, which include MI, angina, acute coronary syndromes (ACS) and sudden cardiac death.
The development of atherosclerosis is the primary cause of CHD and Chapter 2 of this report explores the role of cholesterol, lipoproteins and blood lipids in the atherosclerotic process, believed to be a chronic inflammatory disease in response to endothelial injury. Circulating lipoprotein particles are among the many factors that can injure the lining of the arteries, with low density lipoprotein cholesterol (LDL-C) considered the most atherogenic lipoprotein. Raised levels of LDL-C together with raised triglyceride levels constitutes a significant risk for CHD, while low levels of high density lipoprotein cholesterol (HDL-C) is now known to be another independent risk factor. Reductions in LDL-C in patients with elevated blood levels provides the rationale for using aggressive lipid-lowering therapy in patients with dyslipidaemia. The objective is to reduce the risk of coronary events and death in patients with CHD (secondary prevention) and to prevent CHD developing in patients with no clinical evidence of heart disease (primary prevention). Large-scale, long-term intervention trials have shown that active lipid lowering, especially of atherogenic LDL-C, can reduce the risk of recurrent ischaemic events and death in patients with CHD as well as the risk of ischaemic events and death in patients without CHD. Results from a series of landmark statin intervention trials have provided the most persuasive data to date. Indeed, data from these landmark studies lead to the explosive growth of the lipid-lowering market.
The current lipid-lowering market is the subject of Chapter 3, in which the main therapy classes are reviewed. This includes the traditional lipid-lowering agents, such as fibrates, bile acid sequestrants and nicotinic acid, together with the statins. Due to their superior efficacy combined with excellent tolerability and safety, the statins have largely superseded the traditional lipid-lowering agents to become first-line drugs in the treatment of hypercholesterolaemia. Currently there are six statins competing for a share of the lipid-lowering market. The earliest arrivals were Merck & Co's Mevacor (lovastatin) and Zocor (simvastatin), followed by Sankyo/Bristol-Myers Squibb's Pravachol (pravastatin) and Novartis' Lescol (fluvastatin). In 1997, the third generation statins Baycol (cerivastatin) and Lipitor (atorvastatin) arrived on the market, with Pfizer's Lipitor quickly assuming dominance of the key US market and threatening sales of the other leading statins in both Europe and Japan.
In the already crowded and highly competitive lipid-lowering market, the impending arrival of the new superstatins rosuvastatin (Crestor) and itavastatin promises to have a significant impact on the statins sector. Analysts are upbeat about Crestor's prospects. Results from recently completed Phase III clinical trials suggest that it will be well placed to challenge Lipitor as the 'best in class' statin and to undermine both Zocor and Pravachol's unique selling points. While Crestor is expected to have greatest impact on the US and European markets, Nissan Chemical and Kowa's itavastatin, which will be the first superstatin to hit the market, is expected to have greatest impact on the Japanese market.
Chapter 4 provides a focus on these new statins and beyond. Novel agents that target lipoprotein regulation in the liver, gastrointestinal-biliary tract and atherosclerotic tissues resulting in improved serum lipoprotein levels are currently undergoing clinical trials. After the highly potent superstatins, some of the most promising compounds in development include drugs that affect peroxisome proliferator-activated receptors (PPARs), bile acid transport mechanisms, cholesterol absorption and cholesterol acetyltransferase as well as other biochemical targets of lipoprotein regulation, such as the cholesterol ester transfer protein (CETP).
Chapter 5 contains an analysis of the lipid-lowering market, currently valued at just under $16 billion. The statins represent the dominant sector of this market, with the two top-selling statins alone generating revenues in excess of $5 billion each in 2000. Growth of the statins is projected to continue at current annual rates, fuelled by, among other things, large treatment gaps, new treatment guidelines, a rising prevalence of obesity and diabetes and a growing elderly population in whom the prevalence of CHD is greatest. In the US alone it is estimated that around 30% of all adults (over 56 million) have hypercholesterolaemia, the majority of whom currently receive no treatment. Even among high-risk patients with CHD only half receive lipid-lowering drugs. Thus, there is a huge opportunity to close the existing treatment gaps and with it substantial market growth. Indeed, new treatment guidelines could triple the use of lipid-lowering drugs in the US. The statins are predicted to remain drugs of first choice for dyslipidaemia with the most potent agents commanding the lion's share of the market. By 2002 eight statins will be competing for a share of the lipid-lowering market. AstraZeneca's Crestor is seen as a likely winner but will face stiff competition from Pfizer's Lipitor and Merck's Zocor. The dynamics of the market are also changing rapidly and the new superstatins can expect tough competition from emerging combination products. Combinations of Lipitor plus Norvasc, Lipitor plus avasimibe and Lipitor plus CP-529,414 (Pfizer's novel CETP inhibitor) as well as the combination of Zocor with Schering-Plough's ezetimibe are among those that could seriously challenge the new superstatins for market supremacy.
Chapter 6 provides a short profile on 10 of the companies which have drugs either marketed or in development to treat lipid disorders. It includes Pfizer, Merck & Co and Bristol-Myers Squibb, the companies which dominate the key US lipid-lowering market today, as well as the major players in the Japanese market and AstraZeneca, which hopes to become the dominant player in the cardiovascular market with the launch of Crestor in 2002.
© PJB Publications Ltd. 2001
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