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Cardiac Market Outlook - 2016 by Nitesh bhele

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Cardiac Market Outlook - 2016 by Nitesh bhele
Nitesh Bhele - Marketer, Writer | Healthcare & Pharmaceutical Industry

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Cardiac Market Outlook - 2016 by Nitesh bhele

  1. 1. 1 The Cardiovascular Market Outlook to 2016 Competitive landscape, global market analysis, key trends, and pipeline analysis Reference Code: BI00042-007 Publication Date: June 2011
  2. 2. 2 About Business Insights Business Insights has a team of in-house pharmaceutical and regulatory analysts drawn from consulting, R&D and competitive intelligence life sciences backgrounds. Our analysts specialize in providing detailed insight into the future of therapeutic drug markets and emerging pharmaceutical markets and have extensive analytical, forecasting and research experience in the pharmaceutical, biotech and outsourcing sectors. Our team maintains regular contact with industry executives to track market developments and base their market models on a wide range of proprietary drug sales, pipeline and epidemiological databases to provide up to date, accurate strategic insight on the future of the pharmaceutical market. Disclaimer Copyright © 2011 Business Insights Ltd This report is published by Business Insights (the Publisher). This report contains information from reputable sources and although reasonable efforts have been made to publish accurate information, you assume sole responsibility for the selection, suitability and use of this report and acknowledge that the Publisher makes no warranties (either express or implied) as to, nor accepts liability for, the accuracy or fitness for a particular purpose of the information or advice contained herein. The Publisher wishes to make it clear that any views or opinions expressed in this report by individual authors or contributors are their personal views and opinions and do not necessarily reflect the views/opinions of the Publisher.
  3. 3. 3 Table of Contents About Business Insights 2 Disclaimer 2 Executive Summary 13 Overview and epidemiology of cardiovascular disorders 13 Global market analysis 13 Pipeline analysis 14 Competitive landscape 15 Chapter 1 Overview and epidemiology of cardiovascular disorders 17 Summary 17 Introduction 17 Risk factors 18 Predisposing risk factors 18 Modifiable risk factors 21 Hypertension 21 Diagnosis, treatment and management 22 Epidemiology 24 Forecast epidemiology 26 Dyslipidemia 27 Diagnosis, treatment, and management 29 Epidemiology 30 Forecast epidemiology 31 Cardiovascular diseases 33 Arteriosclerosis/atherosclerosis 33
  4. 4. 4 Thrombosis 33 Cardiac arrhythmias 33 Myocardial infarction (MI) 33 Acute coronary syndrome (ACS) 34 Congestive heart failure (CHF) 34 Coronary artery disease (CAD) 34 Peripheral artery disease (PAD) 34 Pulmonary hypertension 34 Angina pectoris 35 Stroke 35 Epidemiology 35 Forecast epidemiology 36 Chapter 2 Global market analysis 38 Summary 38 Introduction 39 Market analysis by geography 40 Key events in the cardiovascular market 41 European approval for Rasilamlo 41 BMS/Pfizer’s apixaban likely to receive EU approval 41 Angiotensin receptor blockers (ARBs) may cause increased cancer risk 42 Crestor’s patent upheld in the US 43 Plavix boxed warning for poor metabolizers 43 Market analysis by drug class 44 Antihypertensives 46 Introduction 46 Antihypertensive drug classes 46 Leading treatment brands by drug class 47
  5. 5. 5 Key brands analysis 51 Diovan/Co-Diovan 51 Cozaar 51 Benicar 53 Antidyslipidemics 54 Introduction 54 Antidyslipidemic drug classes 54 Leading treatment brands by drug class 55 Key brands analysis 57 Lipitor 57 Crestor 59 Future blockbusters in the antidyslipidemic drug class 63 Antithrombotics 65 Introduction 65 Antithrombotics drug classes 66 Leading treatment brands by drug class 67 Key brands analysis 68 Plavix 68 Lovenox 71 Future blockbusters in the antithrombotic drug class 72 Other cardiovascular agents 75 Introduction 75 Leading treatment brands by drug class 76 Tracleer 77 Leading brands dynamics and sales forecasts 78 Product growth-share matrix for leading brands 78 Chapter 3 Pipeline analysis 81 Summary 81
  6. 6. 6 Introduction 82 Key events in the cardiovascular market 82 First advanced therapy certificate for t2cure’s somatic cell therapy 82 Clear evidence of safety leads to termination of apixaban’s Phase III AVERROES trial 83 FDA panel to review AstraZeneca’s Brilinta 83 Novartis presents successful Phase II results of LCZ696 84 Daiichi Sankyo’s CS-8635 shows promising results in pivotal trial 84 Sanofi (Genzyme)/Isis’ mipomersen clears second Phase III trial, but raises safety concerns 85 Cardiovascular pipeline 85 Leading drugs in development 86 Profiles of key pipeline products 88 Key antihypertensive pipeline drugs 90 LCZ696 – Novartis 90 Cinaciguat – Bayer 92 Riociguat – Bayer 93 Key antidyslipidemic pipeline drugs 95 Livalo (pitavastatin) – Kowa Pharmaceuticals 95 Dalcetrapib – Roche 96 Anacetrapib – Merck 97 Darapladib – GlaxoSmithKline 99 Key antithrombotic pipeline drugs 100 Xarelto (rivaroxaban) – Bayer/J&J 100 Apixaban – Bristol-Myers Squibb (BMS)/Pfizer 102 Brilinta (ticagrelor) – AstraZeneca 104 Betrixaban – Portola/Merck 106 Chapter 4 Competitive landscape 109 Summary 109 Introduction 109 Competitive positioning of top players in the cardiovascular market 110
  7. 7. 7 Pfizer 111 Overview 111 Marketed product portfolio 112 Lipitor (atorvastatin) 112 Norvasc (amlodipine) 114 Caduet (atorvastatin/amlodipine) 114 Revatio (sildenafil) 115 Fragmin (dalteparin) 115 R&D pipeline analysis 116 Strategic and growth analysis 116 Drivers of growth 116 Resistors of growth 117 Sanofi 118 Overview 118 Marketed product portfolio 119 Lovenox (enoxaparin) 120 Plavix (clopidogrel) 121 R&D pipeline analysis 122 Strategic and growth analysis 122 Drivers of growth 122 Resistors of growth 123 AstraZeneca 124 Overview 124 Marketed product portfolio 125 Crestor (rosuvastatin) 126 Atacand (candesartan cilexetil) 127 R&D pipeline analysis 127 Strategic and growth analysis 128 Drivers of growth 128 Resistors of growth 129 Novartis 130
  8. 8. 8 Overview 130 Marketed product portfolio 130 Diovan (valsartan) 131 Exforge (amlodipine/valsartan) 132 Lescol (fluvastatin) 132 Lotrel (amlodipine/benazepril) 133 R&D pipeline analysis 133 Strategic and growth analysis 134 Drivers of growth 134 Resistors of growth 135 Bristol-Myers Squibb (BMS) 136 Overview 136 Marketed product portfolio 136 Plavix (clopidogrel) 137 Avalide/Avapro (irbesartan HCT) 138 Coumadin (warfarin) 138 R&D pipeline analysis 138 Strategic and growth analysis 139 Drivers of growth 139 Resistors of growth 140 Merck 141 Overview 141 Marketed product portfolio 142 Cozaar/Hyzaar (losartan/losartan HCT) 143 Vytorin (ezetimibe/simvastatin) 143 R&D pipeline analysis 144 Strategic and growth analysis 145 Drivers of growth 145 Resistors of growth 146 Appendix 147 Scope and methodology 147
  9. 9. 9 Scope 147 Methodology 148 Market size methodology 148 Epidemiology 148 Market forecast 148 Abbreviations 149 References 155
  10. 10. 10 Table of figures Figure 1: Cardiovascular disease etiology 20 Figure 2: Cardiovascular risk factors and definitions 21 Figure 3: Definition and classification of hypertension 22 Figure 4: Hypertension treatment options 24 Figure 5: Types of lipoproteins 28 Figure 6: Interpretation of blood lipid levels 29 Figure 7: LDL levels and therapy patterns 30 Figure 8: Geographical segmentation of the global cardiovascular market, 2010 and 2016 41 Figure 9: Global market share of major cardiovascular drug classes (%), 2010–16 45 Figure 10: Sales of potential antidyslipidemic drugs versus Lipitor ($m), 2010–16 65 Figure 11: Sales of antithrombotic drugs by disease conditions in the US ($m), 2010–16 73 Figure 12: Forecast market share of antithrombotic drugs under development, 2010–16 75 Figure 13: Leading brands product growth BCG matrix 79 Figure 14: Cardiovascular pipeline by key indications and stages of development, 2010 86 Figure 15: Leading pipeline drugs in various cardiovascular sub-categories, 2010 89 Figure 16: US FDA drug approval activities, 2000–2010 90 Figure 17: Pfizer cardiovascular portfolio by brand (%), 2010 114 Figure 18: Sanofi cardiovascular portfolio by brand (%), 2010 120 Figure 19: AstraZeneca cardiovascular portfolio by brand (%), 2010 125 Figure 20: Novartis cardiovascular portfolio by brand (%), 2010 131 Figure 21: BMS cardiovascular portfolio by brand (%), 2010 137 Figure 22: Merck cardiovascular portfolio by brand (%), 2010 142
  11. 11. 11 Table of tables Table 1: Estimated prevalence of cardiovascular disorders across the 7MM, 2010 18 Table 2: Estimated prevalence of hypertension across the 7MM, 2010 25 Table 3: Forecast epidemiology of hypertension across the 7MM, 2010–16 26 Table 4: Estimated prevalence of dyslipidemia across the 7MM, 2010 31 Table 5: Forecast epidemiology of dyslipidemia across the 7MM, 2010–16 32 Table 6: Estimated prevalence of stroke across the 7MM, 2010 36 Table 7: Forecast epidemiology of stroke across the 7MM, 2010–16 37 Table 8: Geographical segmentation of the global cardiovascular market, 2010 40 Table 9: Global market size of major cardiovascular drug classes ($m), 2010–16 44 Table 10: Sales of leading antihypertensive drugs ($m), 2010 49 Table 11: Sales of leading antidyslipidemic drugs ($m), 2010 56 Table 12: Sales of leading antithrombotic drugs ($m), 2010 68 Table 13: Snapshot of the major antithrombotic drugs under development 74 Table 14: Sales of leading “Other” cardiovascular drugs ($m), 2010 76 Table 15: Sales of leading cardiovascular brands ($m), 2010 78 Table 16: Leading pipeline drugs in the cardiovascular market, 2010 (part 1) 87 Table 17: Leading pipeline drugs in the cardiovascular market, 2010 (part 2) 88 Table 18: An overview of LCZ696 91 Table 19: An overview of cinaciguat 92 Table 20: An overview of riociguat 94 Table 21: An overview of Livalo 95 Table 22: An overview of dalcetrapib 97 Table 23: An overview of anacetrapib 98 Table 24: An overview of darapladib 99 Table 25: An overview of Xarelto 101 Table 26: An overview of apixaban 103 Table 27: An overview of Brilinta 105 Table 28: An overview of betrixaban 106 Table 29: Sales of leading players in the global cardiovascular market ($m), 2010 111 Table 30: Pfizer sales of leading cardiovascular brands ($m), 2010 113 Table 31: Pfizer late-stage cardiovascular pipeline, 2010 116 Table 32: Sanofi sales of leading cardiovascular brands ($m), 2010 120 Table 33: AstraZeneca sales of leading cardiovascular brands ($m), 2010 125 Table 34: AstraZeneca late-stage cardiovascular pipeline, 2010 127
  12. 12. 12 Table 35: Novartis sales of leading cardiovascular brands ($m), 2010 131 Table 36: Novartis late-stage cardiovascular pipeline, 2010 134 Table 37: BMS sales of leading cardiovascular brands ($m), 2010 137 Table 38: BMS cardiovascular portfolio, 2010 139 Table 39: Merck sales of leading cardiovascular brands ($m), 2010 142 Table 40: Merck late-stage cardiovascular pipeline, 2010 144
  13. 13. 13 Executive Summary Overview and epidemiology of cardiovascular disorders Cardiovascular diseases encompass a range of ailments such as hypertension, dyslipidemia, stroke, atherosclerosis, thrombosis, and coronary artery disease. The risk factors for cardiovascular diseases can be classified broadly into two groups: immutable factors such as age, sex, heredity, and modifiable factors that are largely lifestyle-related such as diet, obesity, tobacco consumption, stress, and physical inactivity. Dyslipidemia was the indication with the highest reported prevalence in 2010, with an estimated 336 million cases in the seven major markets (7MM). According to World Health Organization (WHO) estimates, stroke was one of the leading causes of mortality in 2010, and its prevalence rate across the seven major markets was estimated at approximately 0.2%. Global market analysis The global cardiovascular market recorded sales of $170bn in 2010 and is set to grow to $187bn in 2016 at a CAGR of 1.6%. The US continued to be the largest market, with a share of 40% of the overall market. After a decline in sales in 2008 due to maturity of key drug categories and the increasing generic presence, the US witnessed a resurgence in 2009. Antihypertensives remained the largest drug class in 2010, with global sales of $37.6bn and a global market share of 22%. Novartis’s Diovan led the antihypertensives segment with $3.6bn in sales, followed by Benicar with sales of $2.9bn. Pfizer’s Norvasc, one of the blockbusters in this sub-category suffered strong sales erosion and lost significant market share to Diovan. Angiotensin receptor blockers (ARBs) remained the most prescribed therapeutic class within antihypertensives, driven by key brands such as Diovan, Cozaar, and Avapro. However, the advent of
  14. 14. 14 Cozaar generics in 2010 is expected to erode sales significantly. Angiotensin converting enzyme (ACE) inhibitors have also been on the decline due to competition from ARBs and increased genericization. Antidyslipidemics remained the second largest therapeutic sub-category with $29.9bn in sales and a market share of 18% in 2010. The entry of Lipitor generics in 2011 is expected to negatively impact future prospects of sales in this segment. Dalcetrapib, manufactured by Roche, is a potential blockbuster in this category and could serve to offset the negative impact in the antidyslipidemic market created by the genericization of Lipitor. Antithrombotics recorded $18.7bn in sales in 2010 and a market share of 11%. This segment is forecast to deliver strong growth in the next two years owing to the commercialization of recently approved products such as Pradaxa and Xarelto and the expected launch of Pfizer/BMS’s apixaban. The antiarrythmic market is likely to remain a relatively smaller opportunity owing to the limitation of drug therapy. However, promising products such as Sanofi’s Multaq are expected to provide a fillip to the segment by 2013. Pipeline analysis Anticoagulants are expected to be the subject of intensive R&D activity, with the presence of promising products such as BMS/Pfizer’s apixaban and Bayer/J&J’s Xarelto. Since most of the factor Xa inhibitors are in oral form, they are expected to widen the market significantly. The superior effectiveness and better bleeding profile of Brilinta (ticagrelor) over Plavix make it a key antithrombotic drug that could be a major player in acute coronary syndrome (ACS). Brilinta also has a potential therapeutic advantage in atherosclerosis and can be administered to 15–30% of atherosclerosis patients who do not respond to Plavix. Moreover, its use could be initially confined to ACS with no significant patient monitoring anticipated for respiratory or cardiac function or post- marketing surveillance requirements. LCZ696, one of Novartis’s key pipeline products, delivered favorable Phase IIb results. The data demonstrated that LCZ696 not only improved blood pressure significantly in patients with mild-to-
  15. 15. 15 moderate hypertension but also provided complementary action with neprilysin inhibition and ARB blockade. Merck/Portola’s betrixaban appears to have a differentiated half-life (19 hours), competitive bioavailability, and minimal renal excretion which theoretically could result in a superior bleeding profile and allow recruitment of patients irrespective of renal function. In its Phase IIb results announced in March 2010, betrixaban demonstrated strong bleeding benefits over warfarin, further strengthening its case. The antidyslipidemic category is set to undergo significant declines in sales owing to the patent expiry of Lipitor. Falling sales could be rescued with the approval of dalcetrapib, a potent CETP inhibitor that treats dyslipidemia through increasing the levels of HDL cholesterol. Early trial results indicate that anacetrapib is a more potent CETP inhibitor than dalcetrapib. However, the early entry of dalcetrapib could serve to establish it as a prescription drug of choice, thus giving it a significant advantage over anacetrapib. Competitive landscape The global cardiovascular market registered $170bn in sales in 2010. Pfizer retained its position as the market leader with $15.2bn in 2010 sales, led by key brands such as Lipitor, Norvasc, Caduet, and Viagra. The top 10 companies in the cardiovascular market registered $76.4bn in combined sales in 2010, accounting for a substantial 44.9% of the global cardiovascular market. Sanofi remained the second largest company, registering $10.5bn in 2010 sales and a 6.2% share of the global cardiovascular market. The company has benefited strongly from the performance of Lovenox and Plavix, which generated $3.8bn and $2.8bn respectively in 2010 sales. AstraZeneca was the third largest company in the global cardiovascular market, recording sales of $9.4bn in 2010. Sales were strongly driven by the blockbuster drugs Crestor and Atacand
  16. 16. 16 Novartis was the fourth largest company, with 2010 sales of $8.6bn. Its position was strongly supported by the ARBs, ARBs in combination with diuretics, and the statins. All Novartis’s leading brands, including Diovan ($3.6bn), Co-Diovan ($2.4bn), and Exforge ($904m) registered strong Y-o-Y growth in 2010. Merck and BMS were the other leading companies, registering 2010 sales of $7.5bn and $8.4bn respectively.
  17. 17. 17 Chapter 1 Overview and epidemiology of cardiovascular disorders Summary Cardiovascular diseases encompass a range of ailments such as hypertension, dyslipidemia, stroke, atherosclerosis, thrombosis, and coronary artery disease. The risk factors for cardiovascular diseases can be classified broadly into two groups: immutable factors such as age, sex, heredity, and modifiable factors that are largely lifestyle-related such as diet, obesity, tobacco consumption, stress, and physical inactivity. Dyslipidemia was the indication with the highest reported prevalence in 2010, with an estimated 336 million cases in the seven major markets (7MM). According to World Health Organization (WHO) estimates, stroke was one of the leading causes of mortality in 2010, and its prevalence rate across the seven major markets was estimated at approximately 0.2%. Introduction This chapter provides a background to the cardiovascular therapeutic category by identifying the key indications, providing detailed overviews of each of the indications, and listing their current and forecast prevalence through 2016. In accordance with the scope of this report, the primary focus of this chapter is restricted to hypertension, dyslipidemia, and stroke. The chapter also provides a brief overview of the predisposing factors that lead to cardiovascular diseases. Among the various cardiovascular diseases, dyslipidemia had the highest prevalence in 2010, with 336 million reported cases. The following table provides the consolidated estimates of the prevalence of cardiovascular diseases discussed in this chapter.
  18. 18. 18 Table 1: Estimated prevalence of cardiovascular disorders across the 7MM, 2010 Country Hypertension (000s) Dyslipidemia (000s) Stroke (000s) France 16,372 31,877 80 Germany 29,612 54,780 127 Italy 22,376 20,582 112 Spain 18,715 9,712 90 UK 23,649 29,625 103 EU5 110,724 146,576 512 US 76,198 162,716 759 Japan 47,085 26,710 247 Total 234,007 336,002 1,518 Source: American Heart Association, National Health Statistics, CDC, WHO BUSINESS INSIGHTS Risk factors Predisposing risk factors Predisposing factors are those conditions and lifestyle habits that put people at a greater risk of developing cardiovascular diseases. They can be broadly classified into two categories: immutable factors such as age, sex, heredity, and modifiable factors that are largely lifestyle-related such as diet, tobacco consumption, physical inactivity, obesity, and stress. While having a certain predisposing factor or set of factors increases the likelihood of an individual developing a cardiovascular disease, it does not always lead to the condition. Conversely, the absence of a predisposing factor does not nullify the possibility of the individual developing a particular disease. In essence, the factors have a cumulative effect, that is, the presence of a large number of identifiable factors increases the probability of an individual developing cardiovascular disease. Owing to the statistical relationship between these factors and cardiovascular disease, a treatment for the predisposing factor may not entirely eliminate the possibility of the disease. Similarly, if the factor is very prominent in an individual, treating it even with a very effective treatment may not reduce the disease risk.
  19. 19. 19 However, studies have shown that the treatment of predisposing risk factors such as smoking, high blood pressure, and high cholesterol, can reduce the likelihood of a heart attack. Given the rather complicated nature of this association between predisposing/risk factors and cardiovascular disease, demonstrating it is considered to be a major scientific challenge. For instance, a disease such as atherosclerosis can be caused by various factors and is found to some degree in all individuals. Thus, it is difficult to design and implement studies that show the effectiveness of a particular treatment.
  20. 20. 20 Figure 1: Cardiovascular disease etiology Non-manageable Age Sex Heredity Race Predisposing factors Manageable Diet Smoking Physical inactivity Stress Substance abuse Risk factors Glucose intolerance Dyslipidemia Diabetes High blood pressure Myocardial infarction Acute coronary syndrome Congestive heart failure Coronary artery disease Peripheral artery disease Pulmonary hypertension Stroke Cardiovascular diseases Arteriosclerosis Thrombosis Clinical manifestations Angina pectoris Aneurysm Edema Non-manageable Age Sex Heredity Race Predisposing factors Manageable Diet Smoking Physical inactivity Stress Substance abuse Risk factors Glucose intolerance Dyslipidemia Diabetes High blood pressure Myocardial infarction Acute coronary syndrome Congestive heart failure Coronary artery disease Peripheral artery disease Pulmonary hypertension Stroke Cardiovascular diseases Arteriosclerosis Thrombosis Clinical manifestations Angina pectoris Aneurysm Edema Source: Yale Heart Book BUSINESS INSIGHTS
  21. 21. 21 Modifiable risk factors Modifiable risk factors primarily include high blood pressure, high cholesterol, tobacco consumption, and type 2 diabetes. Research has indicated that the treatment of the major risk factors can greatly reduce the possibility of a heart attack. Moreover, some of these factors are lifestyle-related, and a combination of diet and exercise can work as a protective factor and reduce the likelihood of cardiovascular disease. Figure 2: Cardiovascular risk factors and definitions 2 hour glucose levels of 140–199mg/dL (7.8 to 11.0mmol) on the 75g oral glucose tolerance test Type 2 diabetes Fasting plasma glucose of 126mg/dL or 7mmol/L Low HDL Hypertriglyceridemia High LDL Hypertension 40mg/dL 200mg/dL 160mg/dL 140/90mmHg Impaired glucose tolerance Risk Factor Definition 2 hour glucose levels of 140–199mg/dL (7.8 to 11.0mmol) on the 75g oral glucose tolerance test Type 2 diabetes Fasting plasma glucose of 126mg/dL or 7mmol/L Low HDL Hypertriglyceridemia High LDL Hypertension 40mg/dL 200mg/dL 160mg/dL 140/90mmHg Impaired glucose tolerance Risk Factor Definition Source: Yale Heart Book BUSINESS INSIGHTS Hypertension High blood pressure or hypertension is the most important risk factor for cardiovascular disease. Physiologically, it is defined as a condition wherein the pressure of the blood flowing through blood vessels remains high for a prolonged period irrespective of the body’s need. An increased blood pressure leads the heart to work harder, which makes the heart and arteries more susceptible to injury. Hypertension further increases the risk of incidents such as heart attack, heart failure, and atherosclerosis.
  22. 22. 22 There are several factors that lead to hypertension, such as a sedentary lifestyle, alcohol consumption, high sodium diet, high fat diet, high alcohol intake, obesity, and age. Furthermore, people with indications such as diabetes mellitus or kidney disease, and even those with social or occupational stress, are in the high-risk group. Figure 3: Definition and classification of hypertension Normal blood pressure Stage I hypertension Occasional or intermittent Low 140–159mm Hg 90–99mm Hg Normal or rare None Less than 130mmHg Less than 85mm Hg Category Blood pressure elevations Risk of CVD Systolic blood pressure Diastolic blood pressure Stage II hypertension Sustained 160mm Hg 100mm Hg Stage III hypertension Marked and sustained Advanced 161–179mm Hg 101–109mm Hg Progressive Normal blood pressure Stage I hypertension Occasional or intermittent Low 140–159mm Hg 90–99mm Hg Normal or rare None Less than 130mmHg Less than 85mm Hg Category Blood pressure elevations Risk of CVD Systolic blood pressure Diastolic blood pressure Stage II hypertension Sustained 160mm Hg 100mm Hg Stage III hypertension Marked and sustained Advanced 161–179mm Hg 101–109mm Hg Progressive Source: Writing Group of The American Society of Hypertension, 2005 BUSINESS INSIGHTS Diagnosis, treatment and management In over 90% of cases there may be no identifiable cause of hypertension, in which case the condition is known as essential hypertension. Some researchers believe that this may be due to hormonal factors, which control the salt-handling ability of the kidney, while others believe that it is genetically determined and environmentally controlled. In the remaining 10% of cases, hypertension may be secondary in nature as a consequence of another medical problem, such as kidney disorders, adrenal tumors, or some drugs.
  23. 23. 23 Diagnosis of hypertension involves inspection of the eyes, examination of the heart, arterial blood flow check, examination of the kidneys, and checking for an enlarged thyroid. There are also some costly and less frequently used diagnostic methods for hypertension, such as an echocardiogram (ECHO), 24-hour blood pressure monitoring, and stress test. Treatment of essential hypertension targets symptomatic relief, which implies achieving a target blood pressure. Treatment of secondary hypertension involves symptomatic relief but also treatment of the primary cause of elevated blood pressure. All treatment strategies include strict dietary regulations.
  24. 24. 24 Figure 4: Hypertension treatment options Note: ACEI = ACE inhibitors; ARB = angiotensin II receptor blockers; BB = beta-blockers; CCB = calcium channel blockers; TD = thiazide diuretics. Source: Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure BUSINESS INSIGHTS Epidemiology As detailed in Table 2 the prevalence of hypertension was very high across all the 7MM (France, Germany, Italy, Spain, UK, US, and Japan), with an estimated 234 million reported cases in 2010. The US accounted for approximately 33% of the total cases, followed by Japan at 20%.
  25. 25. 25 In terms of prevalence rate, Spain led the way at 42.1%, followed by Japan at 36.9%. The average prevalence rate across the 5EU was around 35.6%, significantly higher than that in the US at 24.3%. Table 2: Estimated prevalence of hypertension across the 7MM, 2010 Country Prevalence (000s) Prevalence (%) Share (%) France 16,372 26.2 7 Germany 29,612 35.7 13 Italy 22,376 37.9 10 Spain 18,715 42.1 8 UK 23,649 38.6 10 EU5 110,724 35.6 47 US 76,198 24.3 33 Japan 47,085 36.9 20 Total 234,007 31.1 100 Source: American Heart Association, National Health Statistics, CDC, WHO BUSINESS INSIGHTS
  26. 26. 26 Forecast epidemiology Table 3: Forecast epidemiology of hypertension across the 7MM, 2010–16 Country 2010 2011(f) 2012(f) 2013(f) 2014(f) 2015(f) 2016(f) France Prevalence (000s) 16,372 16,495 16,619 16,744 16,869 17,051 17,149 Prevalence (%) 26.2 26.3 26.4 26.4 26.5 26.7 26.7 Germany Prevalence (000s) 29,612 29,701 29,791 29,881 29,971 29,994 30,112 Prevalence (%) 35.7 35.8 36.0 36.1 36.2 36.2 36.4 Italy Prevalence (000s) 22,376 22,388 22,401 22,413 22,426 22,474 22,471 Prevalence (%) 37.9 37.9 37.9 37.8 37.9 38.0 37.9 Spain Prevalence (000s) 18,715 18,818 18,922 19,026 19,131 19,392 19,428 Prevalence (%) 42.1 42.3 42.7 42.5 42.7 42.8 43.0 UK Prevalence (000s) 23,649 23,795 23,942 24,089 24,237 24,450 24,567 Prevalence (%) 38.6 38.7 38.8 38.9 38.6 38.8 38.9 5EU Prevalence (000s) 110,724 111,197 111,675 112,153 112,634 113,361 113,727 Prevalence (%) 35.6 35.7 35.7 35.8 35.9 36.0 36.0 US Prevalence (000s) 76,198 77,335 78,488 79,659 80,847 82,584 83,475 Prevalence (%) 24.3 24.4 24.5 24.7 25.3 25.6 25.7 Japan Prevalence (000s) 47,085 47,396 47,709 48,024 48,341 48,667 48,973 Prevalence (%) 36.9 37.2 37.5 37.8 38.4 38.8 39.1 Total Prevalence (000s) 234,007 235,928 237,872 239,836 241,822 244,612 246,175 Prevalence (%) 31.1 31.2 31.3 31.4 31.8 32.1 32.1 Source: American Heart Association, National Health Statistics, CDC, WHO, Business Insights BUSINESS INSIGHTS
  27. 27. 27 The prevalence of hypertension is forecast to grow from 234 million in 2010 to 246 million in 2016 across the seven major markets. In 2016, the US is still expected to be the largest market for hypertension, with an anticipated 83 million sufferers, followed by Japan at 49 million. In terms of prevalence rate, Spain is expected to lead the way in 2016 at 43% followed by Japan at 39.1%. The average prevalence rate across the 5EU in 2016 is expected to be around 36%, a slight increase over 2010. Furthermore, an increase in the mean age of the population is expected to put a significant number of individuals at hypertensive risk. According to the International Society of Hypertension, there is a clear recognition of hypertension as a major public health issue across all the 7MM. Although the awareness level differs from country to country, lifestyle changes in general are expected to play a significant role in reducing the risk factors among larger population groups. Dyslipidemia Dyslipidemia refers to an alteration in the level of blood lipids. It is of two types, hyperlipidemia and hypolipidemia, with the commonest being hyperlipidemia.
  28. 28. 28 Figure 5: Types of lipoproteins Chylomicrons Very low density lipoprotein (VLDL) Intermediate density lipoprotein (IDL) Low density lipoproteins (LDL) High density lipoproteins (HDL) Carries triglycerides from food in intestines to liver, skeletal muscle, and adipose tissue. Carries newly synthesized triglycerides from liver to adipose tissue. Intermediate between VLDL and LDL (very low blood levels). Carries cholesterol from liver to other body parts (“bad cholesterol’) Collects cholesterol from body parts and carries to the liver (“good cholesterol”). Type Description Hyperlipidemia Chylomicrons Very low density lipoprotein (VLDL) Intermediate density lipoprotein (IDL) Low density lipoproteins (LDL) High density lipoproteins (HDL) Carries triglycerides from food in intestines to liver, skeletal muscle, and adipose tissue. Carries newly synthesized triglycerides from liver to adipose tissue. Intermediate between VLDL and LDL (very low blood levels). Carries cholesterol from liver to other body parts (“bad cholesterol’) Collects cholesterol from body parts and carries to the liver (“good cholesterol”). Type Description Hyperlipidemia Source: Business Insights BUSINESS INSIGHTS Lipids include cholesterol, cholesterol esters, phospholipids, and triglycerides, which are transported in the blood stream as large molecules called lipoproteins. There are five major lipoprotein families, as illustrated in the above figure. The international committee for the evaluation of hypertriglyceridemia as a vascular risk factor has classified hypertriglyceridemias (hyperlipidemias) into three groups: Isolated moderate hypertriglyceridemia – triglycerides 200–400mg/dL, total cholesterol <200mg/dL. Mixed hypertriglyceridemia – triglycerides 200–400mg/dL, LDL cholesterol >130mg/dL. Severe hypertriglyceridemia – triglycerides >400mg/dL.
  29. 29. 29 Diagnosis, treatment, and management Diagnosis of dyslipidemia involves the measurement of blood levels of various lipoproteins. The National Cholesterol Education Program Adult Treatment Panel III Guidelines provide a comprehensive approach to the treatment of dyslipidemia. It primarily focuses on controlling elevated LDL-cholesterol (LDL-C) levels. Figure 6 illustrates the interpretation of blood lipid levels. Figure 6: Interpretation of blood lipid levels Total cholesterol Lipid LDL cholesterol HDL cholesterol < 200 Desirable Blood levels (mg/dL) Comment 200–239 Borderline high > 240 High < 100 Optimal 100–129 Near optimal/ above optimal 130–159 Boderline high 160–189 High ≥ 190 Very high < 40 Low ≥ 60 High Total cholesterol Lipid LDL cholesterol HDL cholesterol < 200 Desirable Blood levels (mg/dL) Comment 200–239 Borderline high > 240 High < 100 Optimal 100–129 Near optimal/ above optimal 130–159 Boderline high 160–189 High ≥ 190 Very high < 40 Low ≥ 60 High Source: National Cholesterol Education Program Adult Treatment Panel III Guidelines BUSINESS INSIGHTS The priority of dyslipidemia treatment is reduction of LDL-C to less than 100mg/dL and the ratio of total cholesterol to HDL-cholesterol (HDL-C) to less than four. The American Heart Association (AHA) recommends a set of guidelines for the treatment of dyslipidemia, which is also designed for lowering LDL levels. The following figure illustrates LDL levels and therapy patterns.
  30. 30. 30 Figure 7: LDL levels and therapy patterns Level for drug consideration Therapy Goal of therapyLDL cholesterol ≥ 220mg/dL ≥ 190mg/dL 160–189mg/dL ≥ 160mg/dL ≥ 130 mg/dL 100–129mg/dL Diet and drug ≤ 160mg/dL Diet and drug ≤ 160mg/dL Diet (drug therapy optional) ≤160mg/dL Diet and drug ≤ 130mg/dL Diet and drug ≤ 100mg/dL Diet (drug therapy optional) ≤ 100mg/dL Without coronary heart disease and with ≥ 2 risk factors Without coronary heart disease and with < 2 risk factors With coronary heart disease Level for drug consideration Therapy Goal of therapyLDL cholesterol ≥ 220mg/dL ≥ 190mg/dL 160–189mg/dL ≥ 160mg/dL ≥ 130 mg/dL 100–129mg/dL Diet and drug ≤ 160mg/dL Diet and drug ≤ 160mg/dL Diet (drug therapy optional) ≤160mg/dL Diet and drug ≤ 130mg/dL Diet and drug ≤ 100mg/dL Diet (drug therapy optional) ≤ 100mg/dL Without coronary heart disease and with ≥ 2 risk factors Without coronary heart disease and with < 2 risk factors With coronary heart disease Source: American Heart Association BUSINESS INSIGHTS Epidemiology Among all the cardiovascular diseases covered in this report, dyslipidemia had the highest prevalence, with 336 million affected patients across the 7MM in 2010. The US was the largest market, accounting for 48% of the total prevalence followed by Germany at 16%. The highest prevalence rate was recorded by Germany at 65.7%, followed by the US at 51.8%. The average prevalence rate in the EU5 was comparable to the US at 47.1%. Out of the 7MM, Japan had the lowest prevalence rate at 20.9%. Table 4 shows the estimated prevalence rate of dyslipidemia across the seven major markets in 2010.
  31. 31. 31 Table 4: Estimated prevalence of dyslipidemia across the 7MM, 2010 Country Prevalence (000s) Prevalence (%) Share (%) France 31,877 51.0 9 Germany 54,780 65.7 16 Italy 20,582 34.9 6 Spain 9,712 21.9 3 UK 29,625 48.3 9 EU5 146,576 47.1 44 US 162,716 51.8 48 Japan 26,710 20.9 8 Total 336,002 44.6 100 Source: American Heart Association, National Health Statistics, CDC, WHO BUSINESS INSIGHTS Forecast epidemiology The prevalence of dyslipidemia across the 7MM is forecast to increase from 336 million in 2010 to 356 million in 2016, at a CAGR of 0.97%. The US is expected to retain its position as the largest pool for dyslipidemics, with an expected prevalence of 175 million in 2016. In terms of prevalence rate, Germany is expected to retain its top spot in 2016, with an expected 68%, followed by the US at 53.7% and France at 52.6%. The EU5 is forecast to have a prevalence rate of 48.4%, lower overall than in the US. Of the 7MM, Japan is expected to have the lowest prevalence rate at 22.8% in 2016.
  32. 32. 32 Table 5: Forecast epidemiology of dyslipidemia across the 7MM, 2010–16 Country 2010 2011(f) 2012(f) 2013(f) 2014(f) 2015(f) 2016(f) France Prevalence (000s) 31,877 32,183 32,491 32,802 33,117 33,399 33,716 Prevalence (%) 51.0 51.3 51.5 51.8 52.1 52.3 52.6 Germany Prevalence (000s) 54,780 55,046 55,312 55,580 55,849 56,425 56,558 Prevalence (%) 65.7 65.8 66.0 66.1 67.4 68.1 68.0 Italy Prevalence (000s) 20,582 20,676 20,770 20,865 20,960 21,114 21,182 Prevalence (%) 34.9 35.0 35.1 35.2 35.4 35.7 37.6 Spain Prevalence (000s) 9,712 9,823 9,936 10,050 10,165 10,240 10,368 Prevalence (%) 21.9 22.1 22.3 22.6 22.5 22.6 22.9 UK Prevalence (000s) 29,625 29,841 30,058 30,277 30,497 30,752 30,952 Prevalence (%) 48.3 48.5 48.7 48.9 48.6 48.8 49.0 5EU Prevalence (000s) 146,576 147,569 148,567 149,574 150,588 151,930 152,776 Prevalence (%) 47.1 47.3 47.5 47.7 48.0 48.2 48.4 US Prevalence (000s) 162,716 164,590 166,486 168,403 170,343 173,232 174,687 Prevalence (%) 51.8 51.9 52.1 52.2 53.2 53.7 53.7 Japan Prevalence (000s) 26,710 27,034 27,362 27,694 28,030 28,222 28,605 Prevalence (%) 20.9 21.2 21.5 21.8 22.3 22.5 22.8 Total Prevalence (000s) 336,002 339,193 342,415 345,671 348,961 353,384 356,068 Prevalence (%) 44.6 44.9 45.1 45.3 46.0 46.4 46.6 Source: American Heart Association, National Health Statistics, CDC, WHO, Business Insights BUSINESS INSIGHTS
  33. 33. 33 Cardiovascular diseases Cardiovascular diseases are a broad term, the definition of which includes a number of indications related to the heart and the vascular network. These are interrelated indications, which tend to be linked in a complex cascade; one may lead to another if not treated properly. Risk factors such as dyslipidemia and diabetes, among others, may cause cardiovascular disease. Arteriosclerosis/atherosclerosis Arteriosclerosis is the thickening of the arteries and hence the loss of flexibility of the vessel walls. This leads to a restricted supply of blood to the tissues and organs. Thickening of the vessel walls can occur for several reasons, the most common being a build up of fats, known as plaques, on the artery walls. Arteriosclerosis leads to complications such as coronary artery disease (CAD), stroke, peripheral artery disease (PAD), aneurysms, and so on. Atherosclerotic plaques can also break, leading to thrombosis and probable thromboembolism. Thrombosis Thrombosis is the formation of a blood clot, or thrombus, inside blood vessels, obstructing blood flow. Thromboembolism is the condition wherein the blood clot breaks loose and is carried along the vessel, until it clogs a narrower vessel. This may occur in the lungs (pulmonary embolism), brain (stroke), gastrointestinal tract, or limbs (deep vein thrombosis-DVT). Cardiac arrhythmias Arrhythmias are heart rhythm problems, which occur when heart beats are not well coordinated owing to improper electric impulses. This may cause the heart to beat too fast (tachycardia) or too slowly (bradycardia). Arrhythmias are generally harmless and momentary, but frequent rhythm disturbances increase the risk of stroke and congestive heart failure. Myocardial infarction (MI) Myocardial infarction, commonly known as heart attack, is a rapidly occurring myocardial necrosis due to interruption of blood supply to a part of the heart. Angina is frequently classified according to electrocardiogram (ECG) changes as non-ST segment elevation MI or subendocardial MI (NSTEMI –
  34. 34. 34 necrosis with no ST elevation), and ST segment elevation MI or transmural MI (STEMI – necrosis with ST elevation). Acute coronary syndrome (ACS) ACS is a term used to cover a group of clinical symptoms compatible with acute myocardial infarction, which is chest pain due to insufficient blood supply to the heart muscle, resulting from coronary artery disease. Congestive heart failure (CHF) CHF is a condition wherein the heart fails to supply blood to the various parts of the body. This may be due to narrowed arteries, myocardial infarction, heart valve disease, high blood pressure, cardiomyopathy, or congenital abnormalities. Coronary artery disease (CAD) CAD results from the effects of atherosclerotic plaque formation in coronary arteries. The reduction in blood supply to the heart muscles will reduce the heart’s efficiency and can cause heart failure. One of the first and major symptoms of this condition is angina. Peripheral artery disease (PAD) PAD is a vascular disorder in which the thickening of arteries causes reduction in blood flow to limbs, leading to intermittent leg pain while walking. The disease is an indicator of atherosclerosis. It leads to sores (that do not heal) and gangrenes. Pulmonary hypertension Pulmonary hypertension is a disorder of the pulmonary circulatory system, wherein the pulmonary arteries and capillaries become narrowed or blocked by emboli. This causes build up of pressure in the arteries, which is translated to the right ventricle, unlike hypertension where the left ventricle is affected. It can also lead to heart failure.
  35. 35. 35 Angina pectoris Angina pectoris is severe chest pain due to ischemia (lack of blood and oxygen supply) of the myocardium. The main causes of ischemia are blockade or spasm of coronary vessels. Angina can occur during activity (stable angina), which is most common, or during rest (unstable angina). Stroke The WHO estimates that 15 million people suffer from stroke each year worldwide, 5.7 million of whom die. This makes stroke the second-leading cause of death globally, responsible for 9.7% of deaths. These WHO estimates also indicate that the share of deaths due to stroke may rise to 12.1% globally in 2030. A stroke occurs when brain cells die owing to a lack of blood supply, resulting from thrombosis, embolism, or hemorrhage. This may lead to permanent neurological damage. Some studies have concluded that transient ischemic attack (TIA), caused by extracranial emboli or atherosclerosis of intracranial small arteries, may be considered a warning signal for strokes. Strokes may be classified as ischemic or hemorrhagic. Ischemic stroke involves decreased blood supply to parts of the brain, leading to brain cell death and thus brain dysfunction. Hemorrhagic stroke is due to rupture of blood vessels or abnormal vascular structure, causing accumulation of blood in a part of the brain. The majority of strokes (80%) are ischemic in nature. Epidemiology Table 6 shows the prevalence of stroke across the seven major markets in 2010. Epidemiological data indicates a prevalence of 0.2% in 2010 for stroke across the major markets. Countries such as the US, Spain, Germany, Italy, UK, and Japan had a relatively high prevalence when compared with France.
  36. 36. 36 Table 6: Estimated prevalence of stroke across the 7MM, 2010 Country Prevalence (000s) Prevalence (%) Share (%) France 80 0.1 5 Germany 127 0.2 8 Italy 112 0.2 7 Spain 90 0.2 6 UK 103 0.2 7 EU5 512 0.2 34 US 759 0.2 50 Japan 247 0.2 16 Total 1518 0.2 100 Source: American Heart Association, National Health Statistics, CDC, WHO BUSINESS INSIGHTS Forecast epidemiology The overall patient potential for stroke is expected to rise from 1.5 million in 2010 to 1.6 million in 2016 with the prevalence rate remaining constant at 0.2%.
  37. 37. 37 Table 7: Forecast epidemiology of stroke across the 7MM, 2010–16 Country 2010 2011(f) 2012(f) 2013(f) 2014(f) 2015(f) 2016(f) France Prevalence (000s) 80 80 80 80 80 80 80 Prevalence (%) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Germany Prevalence (000s) 127 127 127 127 127 127 127 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Italy Prevalence (000s) 112 112 112 112 112 112 112 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Spain Prevalence (000s) 90 91 91 91 91 92 92 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 UK Prevalence (000s) 103 103 104 104 110 112 112 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 5EU Prevalence (000s) 512 513 514 514 520 523 523 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 US Prevalence (000s) 759 764 769 774 779 783 788 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Japan Prevalence (000s) 247 251 255 259 264 271 273 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Total Prevalence (000s) 1,518 1,528 1,538 1,547 1,563 1,577 1,584 Prevalence (%) 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Source: American Heart Association, National Health Statistics, CDC, WHO, Business Insights BUSINESS INSIGHTS
  38. 38. 38 Chapter 2 Global market analysis Summary The global cardiovascular market recorded sales of $170bn in 2010 and is set to grow to $187bn in 2016 at a CAGR of 1.6%. The US continued to be the largest market, with a share of 40% of the overall market. After a decline in sales in 2008 due to maturity of key drug categories and the increasing generic presence, the US witnessed a resurgence in 2009. Antihypertensives remained the largest drug class in 2010, with global sales of $37.6bn and a global market share of 22%. Novartis’s Diovan led the antihypertensives segment with $3.6bn in sales, followed by Benicar with sales of $2.9bn. Pfizer’s Norvasc, one of the blockbusters in this sub-category suffered strong sales erosion and lost significant market share to Diovan. Angiotensin receptor blockers (ARBs) remained the most prescribed therapeutic class within antihypertensives, driven by key brands such as Diovan, Cozaar, and Avapro. However, the advent of Cozaar generics in 2010 is expected to erode sales significantly. Angiotensin converting enzyme (ACE) inhibitors have also been on the decline due to competition from ARBs and increased genericization. Antidyslipidemics remained the second largest therapeutic sub-category with $29.9bn in sales and a market share of 18% in 2010. The entry of Lipitor generics in 2011 is expected to negatively impact future prospects of sales in this segment. Dalcetrapib, manufactured by Roche, is a potential blockbuster in this category and could serve to offset the negative impact in the antidyslipidemic market created by the genericization of Lipitor. Antithrombotics recorded $18.7bn in sales in 2010 and a market share of 11%. This segment is forecast to deliver strong growth in the next two years owing to the commercialization of recently approved products such as Pradaxa and Xarelto and the expected launch of Pfizer/BMS’s apixaban. The antiarrythmic market is likely to remain a relatively smaller opportunity owing to the limitation of drug therapy. However, promising products such as Sanofi’s Multaq are expected to provide a fillip to the segment by 2013.
  39. 39. 39 Introduction The global cardiovascular market, valued at $170bn in 2010, continues to remain a dynamic therapy area with excellent growth potential owing to the vast pipeline of promising products. One of the most significant developments in this market in the recent past has been the ruling of the Plavix case in favor of the innovators Sanofi/Bristol Myers-Squibb (BMS) in April 2010. According to this judgment, Apotex, which briefly infringed on Plavix’s ’265 patent by launching clopidogrel generics, is liable to pay economic damages to the innovators. Moreover, Plavix is patent-protected in the US until November 2011. However, widespread generic adoption is expected to negatively impact Plavix from 2012 onwards. The antidyslipidemics category has also been exhibiting value erosion following the entry of generic Zocor (simvastatin) in the US in 2006. However, the imminent patent expiry of Pfizer’s Lipitor (atorvastatin) in 2011, is expected have significant ramifications for the cardiovascular market. Lipitor has already been losing market share to generic simvastatin and the entry of atorvastatin generics are likely to further contribute to the decline. Although the agreement with Ranbaxy regarding the manufacture and sale of a generic version of Lipitor allows Pfizer to enjoy a six month post-patent expiration exclusivity, generic versions of Lipitor will be marketed by Ranbaxy in November 2011. Thus, the revenue loss due to Lipitor patent expiration is likely to impact the cardiovascular pharmaceutical market in 2012. In contrast, the growth outlook for the antithrombotics segment is very promising with the expected launch of Pfizer/BMS’s apixaban and Bayer J&J’s Xarelto. This chapter focuses on many such strategic issues concerning the global cardiovascular market, with a comprehensive review and analysis of the current market dynamics and recent key R&D events shaping the market. The major cardiovascular therapeutic classes such as antihypertensives, antidyslipidemics, antithrombotics, and cardiac therapies are analyzed alongside the leading brand dynamics for each of the indications. The sales data captured in this report are global in scope and sourced from scientific journals, company reports, and brokerage reports. Sales forecasts were made based on regression modeling, and cause-and-effect analysis of data (based on growth drivers and resistors).
  40. 40. 40 Market analysis by geography The global cardiovascular market was valued at $170bn in 2010 and is expected to grow to a value of $187bn in 2016 at a CAGR of 1.6%. The US accounts for about 40% of the entire cardiovascular market, while the five major EU nations (UK, Germany, Italy, Spain, and France; collectively EU5) account for 18% of the entire market, as shown in Table 8 and Figure 8. Both the US and EU5 regions are characterized by a negative CAGR from 2010 to 2016, based on the expected decline in sales values of major blockbuster drugs (such as Lipitor and Cozaar) after genericization. The growth is likely to be positive in Japan and the rest of the world (ROW), (including Asia-Pacific (APAC), Latin America, Central America, Africa, and Canada). Sales volumes in APAC will be driven by the strong adoption of generics, following the patent expiry of the major blockbuster drugs in the cardiovascular segment. Cardiovascular drugs are also likely to enjoy a sustained demand in Japan, owing to the aging population, and consequently an increase in age- related diseases. Table 8: Geographical segmentation of the global cardiovascular market, 2010 Geographical region Market size 2010 ($bn) Market share 2010 (%) CAGR 2010–16 (%) US 68 40 -8.5 EU5 30.6 18 -0.1 Japan 28.9 17 0.6 ROW 42.5 25 1.9 Total 170 100 1.6 Source: company reported sales BUSINESS INSIGHTS The US market delivered $68bn in sales in 2010, and continued to be the single largest market with a share of 40% of the global market. In 2007–08, the US market recorded a slight decline, but it staged a remarkable recovery in 2009, driven by the statins and beta blockers. Nonetheless, the impending patent expiration of major cardiovascular drugs, including Lipitor and Plavix, will lead to a decline in sales values in these regions, and the US is likely to occupy only a 27% share of the global market in 2016.
  41. 41. 41 Figure 8: Geographical segmentation of the global cardiovascular market, 2010 and 2016 27% 21% 20% 32% 40% 18% 17% 25% US EU5 Japan ROW 2010 2016 100% = $170bn 100% = $187bn 27% 21% 20% 32% 40% 18% 17% 25% USUS EU5EU5 JapanJapan ROWROW 2010 2016 100% = $170bn 100% = $187bn Source: company reported sales BUSINESS INSIGHTS Key events in the cardiovascular market European approval for Rasilamlo Rasilamlo, a single pill combination of a rennin inhibitor (aliskiren) and a calcium channel blocker (amlodipine), manufactured by Novartis, received approval from the European Commission in April 2011 for the treatment of high blood pressure in patients who are not controlled by either one of the antihypertensive molecules. The approval is based on studies in more than 5,000 patients with mild to severe blood pressure, and establishes the superiority of the combined therapy over the use of a single therapy. Novartis also filed a request for EU approval for a triple combination product in May 2010. The triple combination product, Amturnide, consists of aliskiren, amlodipine, and hydrochlorothiazide (a diuretic). BMS/Pfizer’s apixaban likely to receive EU approval Bristol-Myers Squibb (BMS) and Pfizer are likely to receive EU approval for their novel factor-Xa inhibitor, apixaban (Eliquis), after receiving positive reviews from the Committee for Medicinal Products for Human
  42. 42. 42 Use (CHMP). If granted, the approval will be for the use of apixaban for venous thrombolic events (VTE) in adults who have undergone knee and hip replacement surgeries. The approval will closely follow study results published by Lassen et al. (2010), which established the clinical superiority of apixaban in reducing the incidence of venous thromboembolism (VTE) over Sanofi’s Lovenox (enoxaparin). The approval is likely to pave the way for future usage of apixaban in other indications such as atrial fibrillation (AF). Angiotensin receptor blockers (ARBs) may cause increased cancer risk ARBs, which form the mainstay of hypertension treatment, have recently been found to have a link to an increased risk of cancer in a meta-analysis published by Sipahi et al. (2010). The study involved analyzing new cancer data from 61,590 patients from five clinical trials, common types of solid organ cancers involving 68,402 patients participating in five trials, and cancer deaths for 93,515 patients in eight trials. The results of the study revealed that patients who were undergoing treatment with ARBs had a risk of new cancer occurrence of 7.2%, compared with 6.0% risk of new cancer occurrence in control groups. Among different types of solid organ cancers studied, only lung-cancer occurrence was found to be significantly higher in patients treated with ARBs. Approximately 86% of all the patients in the trial received Boehringer Ingelheim/Astellas’s Micardis (telmisartan). However, enough data was not generated to ascertain if this was a class effect shared by all ARBs or an effect specific to any particular ARB. While the repercussions of this finding on the ARB market in the short term are expected to be minimal, further studies are expected to be undertaken, which could potentially raise concerns among the medical community about the safety of ARBs. With stronger results to support this theory, ARB use would be likely to become more selective, with applications reserved to specific patient groups such as the ACE inhibitor intolerant population. Following this publication, Boehringer Ingelheim claimed that these findings contradicted internal safety data that indicated that Micardis has an acceptable safety profile in over 50,000 patients. AstraZeneca is yet to review the study and issue a statement. Other leading drugs in the ARB class include Novartis’s Diovan, Sanofi and BMS’s Avapro, and Daiichi Sankyo’s Benicar.
  43. 43. 43 Crestor’s patent upheld in the US AstraZeneca’s blockbuster antidyslipidemic Crestor, the biggest growth driver within the cholesterol-lowering drugs category received a fillip after its patent was upheld by a US district court in June 2010. The challengers – Aurobindo, Cobalt, Apotex, Mylan, Sandoz, Sun, and Par – claimed that the drug’s original patent filing by AstraZeneca’s partner, Shionogi, omitted material information. However, after a four-month trial that began in February 2010, the court concluded that Crestor’s ’314 patent is valid until 2016, and none of the generic challengers would be allowed to file abbreviated new drug approvals (ANDAs) before the patent expiration date. Crestor is currently the only branded statin in the US market that is witnessing positive growth and the court judgment is expected to improve its prospects through the forecast period. The ruling also had a positive impact on the company’s stock, with a 9% increase in its share price on the London Stock Exchange (LSE) following the news. Plavix boxed warning for poor metabolizers Sanofi/BMS’s Plavix received a boxed warning to its US label in March 2010, indicating the diminished effectiveness of the drug in patients with a variant of the CYP2C1P liver enzyme, which can lead to reduced formation of the active metabolite. According to the label, this pool of patients, termed as poor metabolizers, represents “approximately 14% of Chinese, 4% of blacks, and 2% of Caucasians.” The warning also includes information about genetic tests to identify such patients. Further, the FDA added that this group is less likely to benefit from Plavix and is at a high risk for heart attack, stroke, and cardiovascular death. Although the information about poor metabolizers was added to the label in May 2009 as a precaution, further evidence has prompted the companies to extend it to a warning. This was based on a study in 40 subjects, with 10 each in the four metabolizer types, which found that the poor metabolizers had notably lower levels of Plavix and antiplatelets (FDA Drug Safety Communication, 2010; www.fda.gov).
  44. 44. 44 Market analysis by drug class The global cardiovascular market registered sales of $170bn in 2010. Antihypertensives accounted for about 22% of the market, with total sales of about $37.7bn. Antithrombotics accounted for about 11% of sales in 2010, with total revenues of $18.7bn. However, the antithrombotics category is likely to experience a slower decline than the other drug classes, owing to the relatively rapid innovation in the warfarin-replacement market. Sales in the major drug classes are shown in Table 9.The forecast sales of the various drug classes are based upon the forecast sales of existing drugs only; these numbers to not take into account pipeline drugs that are likely to be approved over the forecast period. Table 9: Global market size of major cardiovascular drug classes ($m), 2010–16 Drug class 2010 2011 2012 2013 2014 2015 2016 CAGR 2010– 16 (%) Antihyper -tensives 37,657 36,392 34,307 30,791 29,637 29,283 28,413 -4.6 Antidys- lipidemics 29,899 29,822 25,230 24,744 24,459 23,828 20,156 -6.4 Antithrom -botics 18,687 18,185 14,403 13,030 14,294 15,360 16,126 -2.4 Others 84,216 89,306 95,240 101,544 108,238 115,199 122,206 6.4 Total 170,460 173,706 169,179 170,109 176,629 183,671 186,901 1.6 Source: company reported sales BUSINESS INSIGHTS A comparison of the current market share of the major drug classes and future, projected market share (as shown in Figure 9) indicates a future decline in the market share of all three major drug classes. This is concomitant with the likely decrease in sales values after patent-expiration of major drugs, especially in the antihypertensive (Cozaar) and antidyslipidemic (Lipitor) categories.
  45. 45. 45 Figure 9: Global market share of major cardiovascular drug classes (%), 2010–16 22% 18% 11% 49% 15% 11% 9% 65% Antihypertensives Antidyslipidemics Antithrombotics Total others 2010 2016 100% = $170bn 100% = $187bn 22% 18% 11% 49% 15% 11% 9% 65% AntihypertensivesAntihypertensives AntidyslipidemicsAntidyslipidemics AntithromboticsAntithrombotics Total othersTotal others 2010 2016 100% = $170bn 100% = $187bn Source: Business Insights BUSINESS INSIGHTS Novartis’s Diovan and Daiichi Sankyo’s Benicar were the leading antihypertensive drugs in 2010, with sales of $3.6bn and $2.9bn respectively. Pfizer’s Norvasc, which was the leading antihypertensive until 2007, has been registering a steady decline and Diovan has taken its place as the frontrunner within this segment. Hypertension patients have increased pressure in their arteries leading to heightened risk of indications such as hemorrhagic stroke, congestive heart failure, myocardial infarction, and kidney damage. Diuretics, ACE inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), beta-blockers, and calcium channel blockers (CCBs) are the key drugs prescribed for hypertension. Whereas Norvasc is a CCB, newer blockbusters such as Diovan, Cozaar, Blopress, and Micardis are all ARBs. ARBs have emerged as the definitive successor to CCBs and the largest prescribed category within antihypertensives. However, the entry of Cozaar generics in 2011 is expected to restrict the growth of ARBs. ACE inhibitors are another sub-category that is witnessing a decline in sales due to rapid genericization and competition from ARBs. Growth in the hypertension market is likely to be driven by novel therapies such as Novartis’s Tekturna and increased use of ARBs and their combinations. Another trend observed in this market is the increased use of combination therapies, which helps to build patience compliance by reducing the pill burden and intensity of side effects. Some frequently
  46. 46. 46 used combinations include an ACE-I or ARB with CCB and a diuretic. Rasilamlo is one such combination product, manufactured by Novartis. It is a combination of an ARB (aliskiren) and a CCB (amlodipine). Antidyslipidemics were the second largest drug class within the cardiovascular market, registering global sales of $29.9bn in 2010, with a total market share of 18%. Antihypertensives Introduction Antihypertensives represent the largest drug class within the cardiovascular market, accounting for 22% of the overall market. The major drug classes falling within this category are: angiotensin receptor blockers (ARB) calcium channel blockers (CCB) ACE inhibitors (ACE-I) diuretics beta blockers. ARBs are a recently introduced class of antihypertensives that are increasingly prescribed and considered to be one of the growth drivers in this market. Angiotensin II is a blood vessel constrictor that causes vasoconstriction throughout the body, and angiotensin II receptor antagonists are known to have good efficacy and side-effect profiles. The antihypertensives market is expected to undergo value erosion due to increased genericization of leading therapies during the forecast period. However, increased adoption of recently launched novel products such as Tekturna and Exforge is likely to provide an impetus to the market. Antihypertensive drug classes The antihypertensives market is complex, with the presence of an array of drug classes, ranging from traditional therapies to novel combination products, each differing in its mechanism of action.
  47. 47. 47 Blood pressure is maintained at a certain level by a chain of hormonal reactions in the body. The first of these steps is the production of renin by the kidneys when they sense a lowered blood pressure. Renin, in turn, helps in the production of angiotensin I, a protein that is converted to angiotensin II in the lungs by the action of an enzyme (angiotensin-converting enzyme). Angiotensin II is a blood-vessel constrictor that causes vasoconstriction throughout the body. It also leads to the secretion of aldosterone, an adrenal glands hormone that helps in elevating blood pressure. This hormonal system is known as the renin-angiotensin- aldosterone (RAA) hormonal system. The difference between the antihypertensives’ drug classes lies in the step of the RAA hormonal system that they act on. Two drug classes are known to have the maximum effect on this system, ARBs and ACE-Is. ARBs block chemical receptors for angiotensin II so that it does not cause the arteries to constrict. ACE-Is, on the other hand, prevent angiotensin I conversion to angiotensin II. ACE-Is may also have additional effects, such as increasing the amount of chemicals that widen the arteries. A third drug class, CCBs, acts on the calcium channel of the arteries. They prevent calcium from entering into the artery muscles, keeping the arteries from contracting. One of the erstwhile leaders in the antihypertensive market, Norvasc, is a CCB. Beta-receptor blockers have been available for more than 35 years. They have been used for migraine, congestive heart failure, cardiac arrhythmias, and even as a secondary prevention after myocardial infarction. Beta blockers block sympathetic effects of the nervous system on the heart, reducing its workload, which lowers blood pressure. Diuretics help the body in getting rid of excess fluid and salt through urine, which helps to lower blood pressure. Leading treatment brands by drug class The top ten products in the cardiovascular market predominantly belong to the ARB sub-category, a trend that is expected to continue up to 2012–13. However, rapid genericization across other sub-categories is expected to negatively affect the prospects of ARBs. The popularity of ARBs has been primarily due to their favorable side-effect profile, which has given them a competitive edge over several ACE inhibitors. In addition, the ARB class has benefited from positive outcomes data from key studies such as VAL-HeFT and
  48. 48. 48 LIFE, which have clearly demonstrated the superiority of ARBs over other sub-categories. The calcium channel blockers, another leading sub-category is currently in decline due to the patent expiration of Norvasc, the former top-selling drug. Growth in the antihypertensive category is likely to be driven by products with novel mechanisms of action, and combination therapies involving the use of multiple drugs with different mechanisms that complement each other. Novartis’s Tekturna, launched in March 2007 was initially approved as an add-on therapy for hydrochlorothiazide, ARBs, and ACE inhibitors and as a monotherapy for uncontrolled hypertensives. However, a fixed dose combination of Tekturna/hydrochlorothiazide (HCT) was approved in 2009 for patients likely to receive multiple therapies, thus boosting the growth prospects. In addition, Novartis is expected to file two other Tekturna combinations in 2010 (Tekturna/amlodipine, and Tekturna/amlodipine/HCT), which if approved could further help Tekturna consolidate its position as a potential blockbuster. Table 10 shows the leading antihypertensive drugs in 2010.
  49. 49. 49 Table 10:Sales of leading antihypertensive drugs ($m), 2010 Brand name Generic name Category Sales 2010 ($m) Market share 2010 (%) CAGR 2010–16 (%) Patent expiry Diovan valsartan ARB 3,632 9.6 -14.6 2012 Benicar olmesartan ARB 2,891 7.7 0.8 2016 Blopress candesartan ARB 2,449 6.5 -3.8 2014* Co- Diovan valsartan /HCT ARB 2,421 6.4 -8.8 2012 Cozaar losartan ARB 2,105 5.6 -14.0 Expired 2010 Aprovel irbesartan ARB 1,758 4.7 -3.3 NA Norvasc amlodipine CCB 1,506 4.0 -7.5 Expired Micardis telmisartan ARB 1,329 3.5 -10.8 2017* Seloken metoprolol Beta blocker 1,210 3.2 0.5 NA Exforge amlodipine/ valsartan CCB 904 2.4 3.4 2017 Total leading 20,205 53.6 Others 17,452 46.4 Grand total 37,657 100 * Japanese patent expiry Source: company reported sales, FDA Orange Book BUSINESS INSIGHTS Novartis’s Diovan led the antihypertensives market in 2010, registering sales of $3.7bn. Its HCT combination, Co-Diovan achieved $2.4bn in sales and was the fourth largest selling antihypertensive drug in 2010. Pfizer’s former blockbuster Norvasc, which was the market leader in 2007, has suffered severe sales erosion due to genericization and is expected to exhibit a negative CAGR of -7.5% from 2010 to 2016. Diovan’s market position has been strengthened further by its label expansion, supported by clinical programs such as Val-HeFT (Valsartan Heart Failure Trial). This trial supported the use of Diovan for the
  50. 50. 50 treatment of heart failure in cases where patients are not able to tolerate ACE-I. Another study, VALIANT (VALsartan In Acute Myocardial Infarction Trial), supported its label expansion for patients who have suffered a heart attack, to reduce cardiovascular death. A third study, VALUE (Valsartan Antihypertensive Long-term Use Evaluation), supports its long-term use in preference to Norvasc. In 2007, Novartis launched Exforge (Diovan/amlodipine), an expanded formulation of Diovan. The drug is a fixed dose combination, which is also approved in the US for first-line use in the treatment of high blood pressure. As the revenues indicate, Exforge has performed well in the US market, where fixed dose combinations have had moderate success at best. The second largest ARB, Benicar, generated $2.9bn in 2010. Blopress was the third largest selling antihypertensive drug in 2010 and achieved $2.5bn in sales. Sales of Blopress can be attributed to the fact that it is the first ARB to be approved for the treatment of chronic heart failure in three major markets (Japan, US, and Europe). Cozaar was the fifth largest selling drug and generated revenues of $2.1bn. Over the past few years, Cozaar’s sales have been largely driven by positive data from clinical trials such as LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) and RENAAL (Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II antagonist Losartan). However, following its patent expiry in 2011, Cozaar’s sales are expected to erode significantly. One of the biggest drawbacks for Cozaar has been the lack of a first-line congestive heart failure (CHF) claim worldwide, thus losing out to key competitor brands such as Diovan. Beta blockers are dominated by generics of atenolol, metoprolol, nadolol, pindolol, and propranolol. In 2008, Forest laboratories launched a third-generation beta blocker, Bystolic (nebivolol) with a differentiated mechanism of action. Bystolic was also being tested in patients with chronic heart failure, an indication for which the FDA declined approval in February 2010. Despite this setback, there is still a potential market for Bystolic in the elderly heart failure patient population, owing to positive data from a European pivotal CHF trial (SENIORS). However, the biggest challenge for Bystolic is expected to be from generic Seloken (metoprolol) and Coreg (carvedilol), which are known to have better safety profiles.
  51. 51. 51 Key brands analysis Diovan/Co-Diovan Novartis’s Diovan franchise collectively generated sales of $6bn in 2010. Diovan and Co-Diovan have both grown largely by capturing Norvasc sales following its patent expiry in 2007. Additionally, positive outcomes data from key clinical studies such as Val-HeFT, VALIANT, and VALUE covering over 55,000 patients has helped in extending the Diovan label beyond hypertension, thus consolidating its position in the market. Clinical The Val-HeFT trial supported Diovan’s claim in heart failure treatment for patients who cannot tolerate ACE-I (Cohn et al., 1999) while VALIANT supported the drug’s label expansion for the reduction of cardiovascular death in patients at high risk (with left ventricular failure or dysfunction) following a heart attack (Pfeffer et al., 2000), and VALUE (Julius et al., 2004) supported long-term use when compared with Norvasc. The ABCD- 2V study (Bedigian et al., 2000) demonstrated that intensive diastolic blood pressure control also returned diabetic patients’ return to normoalbuminuria. Regulatory/commercial Novartis launched two versions of Diovan HCT in the EU in 2009 with higher doses of diuretic (12.5mg and 25mg). The Diovan/amlodipine fixed-dose combination Exforge is one of the key products in the antihypertensive market, registering $904m in sales in 2010. Exforge/HCT consists of a CCB (amlodipine), an ARB (valsartan), and a diuretic (HCT), making it the first three-in-one combination treatment in the antihypertensives market. These Diovan line extensions are part of Novartis’s strategy to offset lost sales due to generic erosion following the loss of patent exclusivity in major EU markets in mid 2011. Cozaar Cozaar belongs to the ARBs, the most prescribed antihypertensive class. Angiotensin-II is a powerful blood- vessel constrictor, and can cause vasoconstriction throughout the body. In general, angiotensin-II receptor antagonists have very good efficacy and side-effect profiles. Their major advantage is a favorable side-effect profile, such as the absence of cough.
  52. 52. 52 Clinical Cozaar is supported by indications for reduction in end-stage renal disease in diabetic patients, stemming from the results of the RENAAL trial, and a stroke indication based on the LIFE study. RENAAL (Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) was a 1,513 patient study of type 2 diabetics that assessed Cozaar’s impact on renal insufficiency and diabetic nephropathy. Patients received Cozaar 50mg, 100mg, or placebo once daily, and were studied for 3.4 years. Cozaar reduced the primary endpoint of either a doubling of serum creatinine, kidney failure, or death by 16% compared with placebo (p = 0.024). It also reduced the risk of progression to end-stage renal disease requiring dialysis or kidney transplantation by 28% compared with placebo (p = 0.002) (Brenner et al., 2001). LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) was revealed at the American College of Cardiology meeting in March 2002. The trial compared Cozaar (Losartan) with atenolol (beta blocker) and was designed to conclude after 1,040 cardiovascular events and a duration of four years. The overall results were positive for Cozaar, as it showed a 13% risk reduction in the primary endpoint of cardiovascular mortality, stroke, and myocardial infarction (p = 0.009) (Dalhöf et al., 1997). Cozaar reduced total mortality in diabetics by 39% versus atenolol (p < 0.05). However, the data raised some questions. Stroke was the only component of the primary endpoint that contributed a statistically significant improvement when assessed separately, with risk of stroke reduced by 25% for patients taking Cozaar compared with atenolol (p = 0.001) (Dalhöf et al., 1997). Data assessing Cozaar versus atenolol for the reduction of cardiovascular death and MI were not statistically significant. Overall, the results of LIFE are viewed as impressive, given the sizable mortality benefit that was observed with Cozaar, particularly in diabetics. Furthermore, LIFE was the first outcomes study which showed that mechanisms are important; Cozaar led to similar blood pressure reduction versus atenolol, yet delivered more powerful reductions in events. Cozaar will likely become the ARB of choice in patients with hypertension and left ventricular hypertrophy, the latter being sometimes viewed as a proxy for high-risk hypertension. Beta blockers are considered to be less effective than ACE-I due to a lack of impact on the kidney. Cozaar received an expanded indication approval for the prevention of stroke based on the LIFE data.
  53. 53. 53 Regulatory/commercial Cozaar lacks a first-line CHF claim worldwide, giving Diovan a significant competitive advantage. Furthermore, the loss of patent protection in 2011 will further erode its sales and alter the dynamics of the ARB market. Benicar Scientific Benicar (olmesartan) is an ARB in the same class as Diovan and Co-Diovan, launched by a joint venture between Forest and Sankyo in 2002. The results of a clinical study sponsored by Sankyo, and announced at the American Society of Hypertension meetings in 2000, demonstrated Benicar’s statistically significant superiority in starting doses over other ARBs, including Cozaar, Diovan, and Avapro, in the reduction of diastolic pressure. Clinical Benicar is currently undergoing a trial called ROADMAP (Randomised Olmesartan and Diabetes MicroAlbuminuria Prevention Study), a first-of-its-kind trial in which the effect of an ARB on the prevention of microalbuminuria in patients with type 2 diabetes is being studied. The final results of this study are expected in 2012. Regulatory/commercial Although Benicar was launched in 2002, it underwent an upsurge in sales after the commercialization of its diuretic combination version with HCT (hydrochlorothiazide) in September 2003. Despite the lack of significant differentiation from other ARBs, aggressive marketing has allowed Benicar to capture $2.9bn in sales in 2010, making it the second largest selling drug in the cardiovascular category. Mylan challenged the Benicar HCT combination in February 2007, but in March 2009 a lower court found the patent valid. The Benicar patent is currently valid up to 2016, with peak sales expected in 2013. Sales are expected to diminish after 2014 owing to increasing competition from the genericization of key brands, including Blopress.
  54. 54. 54 Antidyslipidemics Introduction Antidyslipidemics remain the second-largest drug class in the cardiovascular market, generating $29.9bn in sales in 2010, and accounting for a market share of 18%. The antidyslipidemics drug class includes the following sub-categories: statins fibrates non-statins. The current outlook of the dyslipidemia market has been shaped by several key events: the appearance of Zocor generics in 2006 torcetrapib’s clinical setback in 2006 the FDA’s “not approvable” letter given to Merck’s Tredaptive in April 2008 Vytorin’s clinical data from the ENHANCE and SEAS trials. In addition to all these developments, generic simvastatin has captured a significant share of the statins market, leading to a decline in the sales of its branded counterparts Genericization of leading dyslipidemic drugs such as Lipitor is likely to offset the growth driven by factors such as Crestor’s expanded approval following the JUPITER (Justification for the Use of Statins in Primary Prevention ) trial data, which has the potential to expand the market to include patients with normal levels of LDL and high C-reactive protein (CRP). The market share of branded statins is declining due to recent patent expirations of key products such as that of Zocor (2006). Antidyslipidemic drug classes The antidyslipidemics market consists of statins, fibrates, and a few other non-statin products, such as Zetia (ezetimibe; Merck), and Niaspan (niacin; Abbott). Statins dominate the market, with most of the key drugs falling into this class. Statins reduce blood cholesterol by lowering its production from the liver. Scientifically
  55. 55. 55 referred to as HMG-CoA reductase inhibitors, statins block hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the enzyme responsible for making cholesterol. They are prescribed for the treatment of atherosclerosis (which causes stroke, heart attack, and chest pain) or for people with high blood cholesterol levels. Individual statins differ in their ability to lower blood cholesterol. Lipitor (atorvastatin) and Crestor (rosuvastatin), for instance, are the most potent statins, while Lescol (fluvastatin) is the least potent. Statins also differ in their interactions with other drugs, several of which are known to block the enzymes that eliminate statins. When taken with statins, these may lead to increased statin levels, leading to inflammation of the muscles, a condition called myopathy. Pravachol (pravastatin) and Crestor (rosuvastatin) are two statins that are less likely to increase in level when taken with other drugs. Fibrates are fibric acid derivatives that help in lowering blood triglyceride levels. Two ways in which fibrates act are by reducing very low density lipoprotein (VLDL) (a triglyceride-carrying particle in blood) production in the liver and speedy removal of triglycerides from the blood. They may also help in increasing HDL cholesterol, although they are not effective in reducing LDL cholesterol levels. Leading treatment brands by drug class The antidyslipidemics market is dominated by statins, which are predominant among the top 10 brands. The top ten brands in the market recorded sales of $27.8bn accounting for over 90% of the market. Lipitor was the top-selling drug, occupying 39.7% of the market. However, Lipitor’s growth has stagnated in the past four years. Other than Lipitor, some of the top brands include Crestor at $6.8bn and Zetia at $2.3bn. Table 11 illustrates the leading antidyslipidemic brands in 2010.
  56. 56. 56 Table 11:Sales of leading antidyslipidemic drugs ($m), 2010 Brand name Generic name Category Sales 2010 ($m) Market share 2010 (%) CAGR 2010–16 (%) Patent expiry Lipitor atorvastatin statin 11,873 39.7 -23.9 2011 Crestor rosuvastatin statin 6,767 22.6 3.8 2016 Zetia ezetimibe others 2,298 7.7 -1.8 2016 Vytorin ezetimibe/ simvastatin statin 2,014 6.7 -8.2 2017 TriCor/TRI LIPIX fenofibrate fibrate 1,582 5.3 -7.4 Expired Niaspan niacin GPR109 agonist 927 3.1 -53.0 2013 Lovaza omega-3- acid ethyl esters - 819 2.7 -8.0 Mevalotin parvastatin statin 538 1.8 -6.9 Expired Caduet amlodipine/ atorvastatin statin 527 1.8 -6.1 2018 Zocor simvastatin statin 468 1.6 -13.6 Expired Total – leading 27,813 93 Others 2,086 7 Grand total 29,899 100 Source: company reported sales, FDA Orange Book BUSINESS INSIGHTS Sales of Lipitor have exhibited a steady decline in the past three to four years owing to the availability of generic simvastatin since 2006 and also the emergence of Crestor as a leading treatment alternative. Sales of Lipitor are set to decline at a CAGR of -23.9% from 2010 to 2016. AstraZeneca’s Crestor (rosuvastatin) is another leading statin, with 2010 sales of $6.7bn. The sales of Crestor have continually risen since launch and are likely to grow at a strong positive CAGR of 3.8%. Favorable clinical trial results, diminishing safety concerns, and heavy promotions have assisted in boosting Crestor’s uptake. Furthermore, the increasing use of high-potency statins among primary care physicians continues to drive growth for Crestor.
  57. 57. 57 Pfizer’s Caduet (amlodipine and atorvastatin) registered sales of $527m in 2010 and is set to experience a decline in sales at the rate of -6.1% from 2010 to 2016. The drug is a fixed dose combination of Lipitor and Norvasc, and is one of the many options for treating high blood pressure and high cholesterol. Overall, Caduet’s launch has been disappointing owing to slow managed-care acceptance, as the drug is viewed by many formulary managers as a franchise extension strategy for Norvasc, which suffers from generic competition. Key brands analysis Lipitor Scientific Lipitor (atorvastatin) is the largest selling drug globally, a mega blockbuster with 2010 sales of $11.8bn. It is a liver-selective HMG-CoA reductase inhibitor and also one of the most researched drugs, backed by over 15 years of research data. The drug is estimated to lower LDL levels by 39–60%, depending on dosage. It has received additional FDA approval for stroke, heart attack, chest pain (in patients with risk factors for heart diseases), and some types of heart surgeries. Clinical Observational studies undertaken by Pfizer after the launch of generic Zocor have indicated that patients on Lipitor had a 12% lower risk of a cardiovascular event compared with simvastatin. Lipitor patients also had a 15% lower risk of heart attack. Pfizer aggressively promoted the uptake of Lipitor 80mg formulations based on the data from the REVERSAL (Reversal of atherosclerosis with aggressive lipid lowering), PROVEIT (pravastatin or atorvastatin evaluation and infection therapy) and TNT (Treating to New Targets) studies. The TNT results indicated a 22% reduction in cardiovascular events with 80mg, relative to 10mg, as well as only a slight difference in muscle-related side effects including rhabdomyolysis (Waters et al., 2004). However, in the IDEAL study Lipitor 80mg versus Zocor 20mg and 40mg indicated only an 11% relative reduction (non- significant) in cardiovascular events, the primary composite endpoint (Pedersen et al., 2005). The trial provided support for managed care to push generic Zocor over branded statins. An analysis conducted after IDEAL indicated that patients taking Lipitor 80mg had their risk of experiencing another heart attack reduced by 46%. Additionally, the risk of experiencing major coronary events, such as
  58. 58. 58 heart attack, cardiac arrest, and cardiac death, was found to be reduced by 34% relative to simvastatin 20– 40mg doses. Lipitor 80mg also significantly reduced the risk of stroke, unstable angina, death, and revascularization by 18% relative to 20–40 mg simvastatin. The safety profiles of the two groups were found to be comparable. The REVERSAL (Cannon et al., 2004) and PROVE-IT (Nissen et al., 2004) studies that compared Lipitor 80mg to Pravachol 40mg found Lipitor to be superior to Pravachol in reducing cardiovascular events (PROVE-IT) and plaque volume (REVERSAL). Both the trials’ data showed Lipitor 80mg to be very safe over the two-year period. ALLIANCE (Aggressive Lipid Lowering Initiation Abates New Cardiac Events) compared the effects of an aggressive lipid-lowering regimen with atorvastatin in patients after myocardial infarction versus a control group receiving the usual care (lipid lowering drugs including statins at a dosage of 20–40mg, diet modifications, and lifestyle changes). The results showed a reduction in non-fatal MI with atorvastatin by 47%, relative to the alternative therapeutic options (Koren et al., 2004). Regulatory/commercial The availability of generic simvastatin in the market, as well as competition from AstraZeneca’s Crestor, has led to increasing therapeutic substitution and a declining market share for Lipitor. All this has resulted in a waning of Lipitor’s dominance in the lipid control market, though it still continues to be the top-selling statin globally. The drug is expected to lose patent exclusivity in the US in November 2011, which will lead to severe erosion of sales. Pfizer has recently filed a 5mg formulation of the drug in the EU for pediatric use. This filing is for the use of Lipitor in six to 18 year-old patients who have familial hypercholesterolemia. The filing was supported by data from new studies of the drug in heterozygous familial hypercholesterolemia (HeFH) patients in the age group of six to 18 years, together with older data that was used to support its US pediatric filing. This is an effort by the company to extend Lipitor’s patent protection; if approved, the drug would be eligible for patent term extensions in some EU nations such as France and the UK. In the US, the drug has been approved for use in adolescent HeFH patients since 2002.
  59. 59. 59 Pfizer had been contesting Ranbaxy in a bid to delay generic competition for Lipitor until 2016. The two companies finally entered into a settlement in June 2008. According to the settlement, Ranbaxy will not sell the drug’s generic version until November 30, 2011. After this date, Ranbaxy will share a six-month market exclusivity period with Cobalt (a subsidiary of Watson). Cobalt had filed an ANDA for the approval of a product containing atorvastatin sodium, a salt form that is different from the atorvastatin calcium used in Lipitor. In 2007, Pfizer filed a suit against Cobalt, leveling allegations of infringement of the enantiomer patent. Pfizer and Cobalt had then (April 2008) entered into an agreement which gave Cobalt the right to make authorized generics for a period of five years, wherein Pfizer will provide API through its subsidiary Greenstone. In April 2009, Teva had also entered into a settlement with Pfizer. Ranbaxy’s ability to manufacture generic Lipitor has become unclear owing to safety concerns raised by the FDA. Inspections of Ranbaxy plants in India have found several quality control issues such as the lack of proper GMPs and falsification of stability data. This has led to the halting of pending and future drug review applications for drugs manufactured at Ranbaxy’s Paonta Sahib plant, the originally intended site of atorvastatin manufacture. Ranbaxy has now requested permission to manufacture atorvastatin from its plant in New Jersey (US), but it is unclear whether it will be granted. These regulatory issues have made it uncertain whether Ranbaxy will be in a position to begin marketing atorvastatin in November 2011. Since Ranbaxy was the first to file its application for the manufacture of generic Lipitor, the lack of a clear regulatory decision from FDA would also prevent other generic manufacturers from manufacturing the drug. Meanwhile, Pfizer intends to manufacture its own generic version of Lipitor, which will be distributed through Watson Pharmaceuticals. The lack of a generic entry from other manufacturers would mean that Pfizer could sell generic Lipitor at about 70-80% of the current Lipitor price even after the expiration of the patent exclusivity period in November 2011. This in turn could be disadvantageous for managed care providers, who are under pressure to contain costs. Crestor Scientific Crestor (rosuvastatin calcium), a statin from AstraZeneca, registered 2010 sales of $6.7bn and holds a market share of 22.6%. The drug is considered a preferred therapeutic option for high-risk patients owing to
  60. 60. 60 its potency in lowering LDL-C, while raising HDL-C. In October 2009, Crestor received FDA approval for pediatric use (patients aged 10–17 years) in treating those suffering from HeFH. This extended approval for the drug was based on 12-week PLUTO (pediatric lipid-reduction trial of rosuvastatin) trial data. Based on this data, the FDA also granted an additional six-month licensing exclusivity to Crestor for its approved atherosclerosis and cholesterol indications through to July 2016. Further, in February 2010 Crestor received FDA approval for use in the prevention of heart disease in individuals with normal LDL (low density lipoprotein) levels and no clinically relevant heart disease in the presence of other risk factors. In November 2007, the FDA approved Crestor for atherosclerosis, demonstrating its efficacy in slowing the disease progression in adult patients with elevated cholesterol, as an adjunct to diet. This approval was based on the METEOR trial data. Currently, Crestor is the only statin in the US with a broad atherosclerosis indication. In April 2010, the EU approved Crestor for patients with a high risk of experiencing a cardiovascular event. The European Medicines Agency (EMA) approval followed a similar move by the FDA in 2009, and was based on positive evidence from the 18,000-patient JUPITER trial. Crestor has been shown to reduce LDL-C by up to 52% and raise HDL-C by up to 14% (Ridker et al., 2008). Sales of Crestor grew over the period 2005–09, likely driven by several factors including: new clinical data from trials such as JUPITER expanded label approval as a result of the METEOR trial increasing use of high potency statins the ENHANCE and SEAS trial data that caused a shift away from Vytorin. Clinical JUPITER trial data released in November 2008 indicated that rosuvastatin lowered strokes and heart attacks in people with elevated high-sensitivity C-reactive protein (hsCRP) levels, but not high cholesterol. The trial tested Crestor versus placebo in people with low to normal LDL but an elevated hsCRP, who therefore exhibit an increased cardiovascular risk profile.
  61. 61. 61 AstraZeneca announced a new clinical trial for Crestor, SATURN, in January 2008. SATURN is designed to measure the impact of 40mg Crestor and 80mg Lipitor (atorvastatin) on the progression of atherosclerosis in high-risk patients. This study will enroll more than 1,000 patients globally and should be completed in 2011. Data from the multinational study CORONA were presented at the AHA in November 2007. CORONA examined the effect on cardiovascular mortality and morbidity of the addition of 10mg Crestor to optimized treatment. It further studied overall survival from advanced heart failure in older patients who were not on statin therapy. The study failed to show an improvement in morbidity and mortality when Crestor was added on top of standard-of-care heart failure medication in CHF patients. Patients who were on 10mg Crestor experienced an 8% reduction in the combined primary endpoint of myocardial infarction or stroke, or cardiovascular death, which was statistically insignificant (Kjekshus et al., 2007). The majority of deaths in this study were sudden, or due to non-ischemic causes, neither of which appeared to be impacted by statin therapy. GALAXY, a long-term global clinical research program that started in 2002, investigates the effect of Crestor on cardiovascular risk reduction and patient outcomes. The study showed an 8% reduction in the combined primary endpoint of myocardial infarction, stroke, or cardiovascular death, which was not statistically significant. This reduction was driven by decreased atherosclerotic events (stroke and myocardial infarction). Additionally, fewer hospitalizations were observed in patients on Crestor in comparison with placebo. Furthermore, Crestor 10mg was well tolerated and had a safety profile similar to placebo. Additional clinical trials as part of the GALAXY program are continuing and are likely to be reported in the next few years. METEOR data indicated that Crestor slowed the progression of atherosclerosis significantly in comparison with placebo in people who are at a lower risk of coronary heart disease and those with early signs of carotid artery disease. Additionally, LDL-C reduced by 48.8%, in comparison with 0.3% with placebo, while HDL-C increased by 8.0%, as against 2.8% with placebo (Crouse et al., 2007). The study met its primary endpoint, slowing plaque progression, although treatment did not result in plaque reversal. In July 2007, Crestor prescribing information was updated in the EU to incorporate positive atherosclerosis data from the METEOR study.
  62. 62. 62 Regulatory/commercial In February 2010, Crestor received FDA approval for the prevention of cardiovascular disease. The drug is now approved for use to reduce the risk of heart attack, stroke, and arterial revascularization procedures in individuals without any clinically evident heart disease but at a high risk. This was based on the JUPITER trial data which had shown that the disease prevention benefits of the drug outweighed the risks of adverse effects. According to FDA documents, the drug’s wider indication is likely to increase the statin therapy target population’s size by 15%. Following this approval, Crestor would be the first statin for which hsCRP (high sensitivity C-reactive protein) levels would be considered during prescribing. Individuals with hsCRP levels of greater than 2mg/L are at a high risk of developing heart disease. In light of this expanded approval, the drug could experience higher sales growth through 2011 until Lipitor generics reach the market. The upside for Crestor could be significant if AstraZeneca is able to significantly promote the drug’s expanded indication with physicians as a compound-specific advantage such that it is not viewed as a class effect. Crestor’s US patent was upheld in June 2010 by a US district court after a trial that began in February 2010. The challenge was raised by generic manufacturers Aurobindo, Cobalt, Apotex, Mylan, Sandoz, Sun, and Par on claims that the drug’s original patent filing by AstraZeneca’s partner, Shionogi, omitted material information. This is considered to be a major victory for Crestor and is expected to provide a boost to the overall antidyslipidemics market. There are some concerns over the drug’s expanded approval. One of the key issues is that the expanded patient base results are due to the inclusion of individuals with increased CRP levels (and normal LDL levels). Elevated CRP is not a very good indicator of cardiovascular risk. Individuals who have higher than normal CRP do have a higher risk of heart attack (as well as diseases such as cancer and diabetes), and statins have been shown to lower circulating CRP levels. But CRP is a marker for several other indications as well, such as arthritis, vitamin D deficiency, viral infections, and excess weight, which implies that high CRP levels may not necessarily equate to cardiovascular risk.
  63. 63. 63 Besides this, there are concerns about the JUPITER trial as well. In the study, 13 deaths occurred due to gastrointestinal disorders among the Crestor group of patients (compared with one in the placebo group). There were also 18 cases of neurocognitive dysfunction (as against four in the placebo group). Additionally, there was a 27% rise in reported cases of diabetes in the Crestor group of patients. Based on this data, the FDA committee had concluded that Crestor’s benefits outweighed the risks. However, diabetes itself is a risk factor for cardiovascular disease. This further raises concern over whether Crestor could increase cardiovascular risk in some cases. Further to this, muscle pain is also one of the side-effects of Crestor. Therefore, if asymptomatic individuals are given the medication only as a preventive measure, compliance is likely to be low. Appearance of any side effects may act as a further deterrent toward compliance. There is also the question of reimbursement, as insurers may not be keen to pay for the drug’s administration in otherwise healthy individuals. Another question that arises is whether the ability to reduce cardiovascular risk is limited to Crestor or extends to other statins as well (a class effect). If the effectiveness of other statins in preventing cardiovascular disease is proved, Crestor’s commercial prospects are likely to be jeopardized. This is especially so because generics of Merck’s Zocor (simvastatin) and Bristol-Myers Squibb’s Pravachol (pravastatin) are already available and may encroach on Crestor sales. Another issue that plagues the drug is whether physicians would order a CRP assay for all potential patients, as primary care physicians do not routinely screen CRP levels. Future blockbusters in the antidyslipidemic drug class Lipitor was a major blockbuster drug in the cardiovascular market segment, with worldwide sales of $11.8bn in 2010. The impending patent expiry of Lipitor is likely to impact the antidyslipidemic market severely. Torcetrapib, developed by Pfizer, showed early promise of being a potential replacement for Lipitor. Torcetrapib acts as an inhibitor of cholesteryl ester transfer protein (CETP) and the expectation was that this would raise HDL levels and reduce LDL to provide improvement in cardiovascular health. However, torcetrapib failed in Phase III clinical trials owing to an unexpected increase in cardiovascular events associated with its use. Although this initially cast doubt on the potential for CETP inhibitors to replace statins, extensive studies of newer lipid-lowering compounds developed by Roche and GSK show that they

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