REFERENCE CODE GDHC45PIDR PUBLICATION DATE JUNE 2013

REFERENCE CODE GDHC45PIDR PUBLICATION DATE JUNE 2013 CHRONIC HEART FAILURE

Executive Summary CHF: Key Metrics in the Seven Major Pharmaceutical Markets* 2012 Epidemiology CHF prevalent population 2012 Market Sales US 5EU Japan Total Pipeline Assessment 14.9 billion $1.30bn $1.05bn $213.4m $2.56bn Number of drugs in Phase I II 5 Number of first-in-class drugs in Phase IIb and III Most Promising Pipeline Drug LCZ-696 (Novartis) Key Events (2012 2022) Launch of LCZ-696 in the US in 2015 Launch of LCZ-696 in the 5EU in 2016 Launch of generic competitors for Diovan (valsartan) and Atacand (candesartan) in 2013 in the US Launch of generic competitors for Inspra (eplerenone) in France, Germany, and the UK in 2015 Launch of generic competitors for Procoralan (ivabradine) in the EU in 2017 2022 Market Sales US 5EU Japan Total Source: GlobalData 2 2022 Sales *7MM = US, 5EU (France, Germany, Italy, Spain, UK), and Japan EU = European Union The values listed in this table have been rounded to the nearest decimal; totals were derived from the rounded numbers. $1.87bn Level of Impact $2.91bn $1.35bn $193.0m $4.45bn This table provides a summary of the key metrics for chronic heart failure (CHF) in the seven major pharmaceutical markets during the forecast period from 2012 2022. Sales for Chronic Heart Failure by Region 2012 2022 GlobalData estimates that sales of CHF therapeutics in 2012, the base year of the forecast period, totalled approximately $2.56 billion in the seven major markets (7MM): US, France, Germany, Italy, Spain, UK, and Japan. Branded drugs alone accounted for only $1.02 billion across the markets, while generics made up the majority of sales. As a result of higher drug prices and a large CHF population, the US dominated the 2012 base-year sales, with 51% of the overall market, totalling approximately $1.30 billion in sales. The CHF market has been slowly overtaken by generic drugs, and more branded products are expected to lose market exclusivity during the next few years. By the end of the forecast period in 2022, CHF sales will grow to $4.45 billion at a Compound Annual Growth Rate (CAGR) of 5.7%, as shown in the figure below 2

Executive Summary Sales for CHF by Region, 2012 2022 8% 2012 Total: $2.6bn 2% 6% United States 6% France Germany 51% Italy 19% Spain UK Japan 8% 4% 2022 Total: $4.5bn 2% 5% 4% United States France 14% Germany Italy Spain 65% 6% UK Japan Source: GlobalData The major drivers of CHF market growth over the forecast period are: The major barriers that will restrict the growth of the CHF market during the forecast period are: A significant barrier faced by the CHF market is the lack of late-stage pipeline drugs. Patent expirations of most of the drugs marketed for CHF have resulted in a market that is crowded with generics; the presence of inexpensive generics will diminish the overall value of the market and may hamper the uptake of LCZ-696. The table below represents the drivers and barriers in the global CHF market during the forecast period. CHF Market: Drivers and Barriers, 2012 2022 Drivers Approval of a novel therapy Increase in prescription of MRAs Increase in the total prevalent CHF population Barriers Sparsely populated CHF pipeline CHF market is crowded with generics Source: GlobalData, based on KOL interviews conducted in January 2013 The launch of Novartis novel combination drug LCZ-696 in 2015 will mark the first entrance of a novel branded CHF drug in the past five years, boosting the overall market size considerably during the forecast period. The prescription of mineralocorticoid receptor antagonists (MRAs), such as spironolactone, is expected to increase across the CHF markets within this report s 10-year forecast period. 3

Executive Summary Drug Developers Frequently Pursue Approval in Hypertension Prior to Seeking a Label Expansion into Chronic Heart Failure In recent years, pharmaceutical companies have entered the CHF market only after gaining initial approval of their drugs in hypertension (high blood pressure). While obtaining approval in CHF has not been an afterthought, it has been sought by companies to expand their products lifecycles, rather than serving as a leading aspect of their market entry strategies. Novartis LCZ-696 will follow in the footsteps of its predecessors by first filing for hypertension in 2013, followed by CHF in 2014. However, the similarity ends there. Unlike the currently marketed CHF drugs, LCZ-696 targets the underserved segment of the population with heart failure with preserved ejection fraction (HF-PEF); to date, no drug developer has successfully targeted this population. Furthermore, it is a first-in-class combination drug, whereas the majority of CHF therapies fall into well-established drug classes. Cardio3 BioSciences are developing stem cell therapies. In addition, other companies, including Bayer and Cytokinetics, both aim to break into the CHF market with novel drugs, in keeping with the trend started by Novartis. The Chronic Heart Failure Market Has Considerable Unmet Needs, Despite the Availability of Well-Established Treatments Although the CHF market has numerous wellestablished therapies, it is marked by the presence of a number of unmet needs in current treatments. All of the standard CHF therapies are easily accessible to patients because most treatments are generically available and are inexpensive. However, these standard therapies cater to the needs of many, but not all, CHF patients. GlobalData s research indicates that the overall attainment level of unmet needs in current treatments is within the moderate-to-high range, as shown in the table below. The CHF therapy market has been fairly stagnant for a number of years, and is marked by the presence of generics. However, LCZ-696 s launch is poised to mark the beginning of a new era in which companies will be pursuing truly novel approaches for treating CHF. These approaches include potentially game-changing nonpharmacological therapeutic approaches. For example, Celladon is developing the gene therapy Mydicar (raav1-serca2), while Bioheart and 4

Executive Summary Overall Unmet Needs Current Level of Attainment Unmet Need Therapies for HF-PEF patients Therapies for patients with renal impairment Diagnosis of asymptomatic left ventricular dysfunction (LVD) Treatment of patients with multiple comorbidities Increase in survival of CHF patients Current Level of Attainment Relative Importance 1 High 1 Moderate 2 High 1 Moderate 3 High Source: GlobalData, based on primary research and interviews with cardiologists in the 7MM Of the drugs that are in late stages of development specifically for chronic, rather than acute, heart failure (HF), only Novartis LCZ-696 is likely to address a major unmet need in the current treatment paradigm for CHF by providing a treatment for HF-PEF patients. LCZ-696 was tested in HF-PEF in a Phase II trial, with encouraging results. It is currently being evaluated in a Phase III trial in the US, Europe and Asia to investigate its efficacy in patients with New York Heart Association (NYHA) Class II III heart failure with reduced ejection fraction (HF-REF). GlobalData expects LCZ-696 to receive Food and Drug Administration (FDA) approval in 2015 for HF-REF and to launch shortly thereafter. At the time of the publication of this report, Novartis had not yet publically disclosed any plans to pursue further development of LCZ-696 in the HF-PEF population. However, given the lack of efficacious treatments and the corresponding high level of unmet need in this population segment, GlobalData expects that Novartis will conduct a Phase III trial in the HF-PEF population. In the event that Novartis pursues the development of LCZ-696 for HF-PEF and confirms its efficacy in this segment of the population, it will be the first drug to be approved for the HF-PEF and will fulfill the unmet need of treating this underserved population. Market Opportunities for New Entrants Although the CHF market has several efficacious treatments for HF-REF patients, there is a lack of efficacious therapies that can reduce morbidity and mortality in this population segment. To date, no drug has demonstrated sufficient efficacy in terms of reducing morbidity and mortality in HF-PEF in large-scale clinical trials. Therefore, this unmet need presents a significant opportunity for investment by drug developers. Novartis LCZ-696 is the only drug that has shown some promise in treating the HF-PEF population. In addition to the development of LCZ-696, a large-scale trial sponsored by the US National Institutes of Health (NIH) is currently underway for the treatment HF- PEF using the well-established MRA, spironolactone. The much-awaited results of this trial are expected in June 2013, and will shed more light on the possible role of MRAs in the HF-PEF population. 5

Executive Summary There is a significant need for CHF treatments that are safe to use in the presence of comorbidities such as renal impairment, anemia, arthritis, chronic obstructive pulmonary disease (COPD) and asthma. Due to the high prevalence of multiple comorbidities in the elderly population, physicians often face difficulties in treating these patients because many of the CHF drugs are contraindicated in them because of these comorbidities. There remains an opportunity to develop more efficacious treatments that could further increase survival times for CHF patients, particularly in patients who continue to suffer from worsening CHF, despite the use of the existing treatments. Novel Combination Drug LCZ-696 Will Be a Major Market Player by 2022 Novartis LCZ-696, a combination of Diovan (valsartan) and a new agent a neprilysin inhibitor, AHU-377 is the only drug forecast to be launched in the next 10 years. The market entry of this novel combination drug in 2015 will mark the first entrance of a novel branded CHF drug in the past five years, boosting the overall market size considerably during the forecast period. LCZ-696 has the potential to replace angiotensin-converting enzyme (ACE) inhibitors in the treatment paradigm for CHF. In addition, LCZ-696 will also steal patient share from Diovan and other angiotensin receptor blockers (ARBs), which are given to patients who cannot tolerate ACE inhibitors. GlobalData forecasts that LCZ-696 will achieve sales of approximately $1.87 billion by 2022, the final year of the forecast period. What Do the Physicians Think? Physician experts interviewed by GlobalData acknowledged that LCZ-696 could change the treatment paradigm for CHF if it shows significantly superior efficacy to ACE inhibitors in its ongoing trials. However, if LCZ-696 shows similar efficacy to ACE inhibitors, it is unlikely to have a significant impact on the CHF market. Although Phase II trials of LCZ-696 did not raise any safety concerns, one physician pointed out the risk of heightened adverse effects due to its dual action. The objective of the currently-running trial [for LCZ-696] is to see whether we can replace ACE inhibitors, which is one of the pillars, one of those foundations, of the pharmacological treatment of heart failure. That trial is a head-to-head trial of LCZ-696 versus the gold-standard ACE inhibitor treatment [enalapri]. So, if LCZ-696 were to be significantly superior to enalapril, then it would potentially replace ACE inhibitors and other key drugs [ARBs, MRAs, beta blockers]. So, absolutely, yes, of course, it could be at a very important position in the guideline. It could be right at the top where you start. Key opinion leader, January 2013 6

Executive Summary I am skeptical about the dual blockade because dual blockade in the RAAS [renin-angiotensinaldosterone] system does not really have convincing data. If you combine drugs that may induce hypotension, it may not be beneficial; in fact, it may be risky for the patients. So, the ongoing trial results need to show that this combination will provide benefit for the patient. Key opinion leader, January 2013 As indicated in the published treatment guidelines, all interviewed key opinion leaders (KOLs) agree that ACE inhibitors and beta blockers are the current standard care of therapy in CHF, and are likely to remain so during the next 10 years. Interviewed KOLs also indicated that MRAs are used more frequently in Europe than in the US for CHF treatment, and they anticipate that the use of MRAs will increase in the US and Japan during the forecast period. Mineralocorticoid receptor antagonists, even in 2012, are used much less in the US and Canada than they are in Europe and Latin America. That is because among some physicians, they have a bad reputation in the US and Canada, in terms of safety. Whereas in Eastern, Central, and Southern Europe, physicians use mineralocorticoid receptor antagonists very widely and very happily. Key opinion leader, January 2013 According to the guidelines, everyone should be started with an ACE inhibitor and a beta blocker. The order is usually to start with an ACE, reach a reasonable dose, then start a beta blocker and uptitrate. The order of this which one to use first is debated. A couple of trials looked at it and said it is clear now that it doesn t matter which one we use first. But because the trials for ACE inhibitors were done first, and those with beta blockers later, the convention is you start someone who comes in untreated with an ACE inhibitor for [a] few weeks, build up the dose to a middle region, and then start a beta blocker and then up-titrate it. Key opinion leader, January 2013 7

1 1... 8 1.1 List of Tables... 15 1.2 List of Figures... 18 2 Introduction... 20 2.1 Catalyst... 20 2.2 Related Reports... 20 2.3 Upcoming Related Reports... 20 3 Disease Overview... 21 3.1 Etiology and Pathophysiology... 21 3.1.1 Etiology... 21 3.1.2 Pathophysiology... 23 3.2 Prognosis... 27 3.3 Quality of Life... 27 3.4 Symptoms... 28 4 Epidemiology... 30 4.1 Risk Factors and Comorbidities... 30 4.1.1 Age and sex are highly associated with the risk of chronic heart failure... 32 4.1.2 History of cardiovascular disease increases the risk of developing chronic heart failure. 32 4.1.3 Unhealthy lifestyles increase the risk of chronic heart failure... 33 4.1.4 People with diabetes mellitus are twice as likely to develop chronic heart failure... 33 4.1.5 Nearly 20% of patients with chronic kidney disease develop chronic heart failure... 34 4.1.6 Comorbidities... 34 4.1.7 Prognosis for chronic heart failure remains poor... 35 4.2 Global Trends... 36 4.2.1 United States... 36 4.2.2 France... 37 8

4.2.3 Germany... 38 4.2.4 Italy... 38 4.2.5 Spain... 38 4.2.6 United Kingdom... 39 4.2.7 Japan... 39 4.2.8 China... 40 4.3 Forecast Methodology... 40 4.3.1 Sources Used... 40 4.3.2 Forecast Assumptions and Methods... 45 4.3.3 Forecast Assumptions and Methods for New York Heart Association Class Distributions... 48 4.3.4 Sources Not Used... 49 4.4 Epidemiology Forecast (2012 2022)... 49 4.4.1 Prevalent Cases of Chronic Heart Failure... 49 4.4.2 Age-Specific Prevalent Cases... 52 4.4.3 Sex-Specific Prevalent Cases... 54 4.4.4 Age-Standardized Prevalence... 59 4.4.5 New York Heart Association Class Distributions... 61 4.5 Discussion... 62 4.5.1 Limitations of Analysis... 64 4.5.2 Strengths of Analysis... 64 5 Disease Management... 65 5.1 Treatment Overview... 66 5.1.1 Pharmacological Treatments... 68 5.1.2 Mechanical Devices... 74 5.2 US... 75 5.2.1 Diagnosis and Referral Patterns... 75 5.2.2 Clinical Practice... 76 9

5.3 France... 77 5.3.1 Diagnosis and Referral Patterns... 77 5.3.2 Clinical Practice... 78 5.4 Germany... 80 5.4.1 Diagnosis and Referral Patterns... 80 5.4.2 Clinical Practice... 80 5.5 Italy... 82 5.5.1 Diagnosis and Referral Patterns... 82 5.5.2 Clinical Practice... 82 5.6 Spain... 84 5.6.1 Diagnosis and Referral Patterns... 84 5.6.2 Clinical Practice... 85 5.7 UK... 87 5.7.1 Diagnosis and Referral Patterns... 87 5.7.2 Clinical Practice... 88 5.8 Japan... 90 5.8.1 Diagnosis and Referral Patterns... 90 5.8.2 Clinical Practice... 90 6 Competitive Assessment... 92 6.1 Overview... 92 6.2 Strategic Competitor Assessment... 92 6.3 Drug Profiles... 95 6.3.1 Angiotensin-Converting Enzyme (ACE) Inhibitors... 95 6.3.2 Diuretics... 98 6.3.3 Angiotensin Receptor Blockers... 100 6.3.4 Beta Blockers... 113 6.3.5 Procoralan (ivabradine)... 125 10

6.3.6 Mineralocorticoid Receptor Antagonists... 129 6.3.7 Digoxin... 132 7 Opportunity and Unmet Need... 135 7.1 Overview... 135 7.2 Lack of Therapies for HF-PEF Patients... 136 7.3 Lack of Therapies for Patients with Renal Impairment... 137 7.4 Diagnosis of Asymptomatic Left Ventricular Dysfunction... 137 7.5 Treatment of Patients with Multiple Comorbidities... 138 7.6 Increase in Survival of CHF Patients... 138 7.7 Unmet Needs Gap Analysis... 139 7.8 Opportunity: Treatment of Patients with HF-PEF... 140 7.9 Opportunity: Therapies for Patients with Renal Impairment and Multiple Comorbidities... 140 7.10 Opportunity: New Drugs that Show Increase in Survival of CHF Patients... 140 8 Pipeline Assessment... 141 8.1 Overview... 141 8.1.1 Clinical Trials by Country... 142 8.2 Clinical Trials by Phase and Trial Status... 143 8.3 Promising Drugs in Clinical Development... 144 8.3.1 LCZ-696... 145 8.3.2 Tekturna (aliskiren)... 151 8.3.3 Neucardin (rhnrg-1)... 155 8.4 Innovative Early-Stage Approaches... 159 8.4.1 BAY 94-8862... 159 8.4.2 Omecamtiv mecarbil... 162 8.5 Promising Non-Pharmacological Approaches... 165 8.5.1 MyoCell... 166 8.5.2 C-Cure (C3BS-CQR-1)... 171 11

8.5.3 Mydicar (raav1-serca2a)... 174 9 Current and Future Players... 179 9.1 Overview... 179 9.2 Trends in Corporate Strategy... 180 9.3 Company Profiles... 181 9.3.1 Novartis... 181 10 Market Outlook... 185 10.1 Global Markets... 185 10.1.1 Forecast... 185 10.1.2 Drivers and Barriers Global Issues... 188 10.2 United States... 191 10.2.1 Forecast... 191 10.2.2 Key Events... 195 10.2.3 Drivers and Barriers... 195 10.3 France... 197 10.3.1 Forecast... 197 10.3.2 Key Events... 200 10.3.3 Drivers and Barriers... 200 10.4 Germany... 201 10.4.1 Forecast... 201 10.4.2 Key Events... 204 10.4.3 Drivers and Barriers... 204 10.5 Italy... 205 10.5.1 Forecast... 205 10.5.2 Key Events... 207 10.5.3 Drivers and Barriers... 208 10.6 Spain... 209 12

10.6.1 Forecast... 209 10.6.2 Key Events... 211 10.6.3 Drivers and Barriers... 212 10.7 United Kingdom... 213 10.7.1 Forecast... 213 10.7.2 Key Events... 216 10.7.3 Drivers and Barriers... 216 10.8 Japan... 217 10.8.1 Forecast... 217 10.8.2 Key Events... 220 10.8.3 Drivers and Barriers... 220 11 Appendix... 223 11.1 Bibliography... 223 11.2 Abbreviations... 240 11.3 Methodology... 244 11.4 Forecasting Methodology... 244 11.4.1 NYHA Class Segmentation of Total Prevalent CHF Population... 244 11.4.2 Diagnosed CHF Population... 245 11.4.3 Drug-Treated CHF Population... 246 11.4.4 Patient Population Breakdown: HF-REF versus HF-PEF... 246 11.4.5 Treatment of HF-REF versus HF-PEF... 246 11.4.6 Drugs Included in Each Therapeutic Class... 247 11.4.7 Launch and Patent Expiry Dates... 247 11.4.8 General Pricing Assumptions... 248 11.4.9 Drugs Assumptions... 249 11.4.10 Generic Erosion... 254 11.4.11 Pricing of Pipeline Agents... 254 13

11.5 Physicians and Specialists Included in this Study... 255 11.6 Survey of Prescribing Physicians... 256 11.7 About the Authors... 257 11.7.1 Author... 257 11.7.2 Epidemiologist... 257 11.7.3 Global Head of Healthcare... 258 11.8 About GlobalData... 259 14

1.1 List of Tables Table 1: Leading Causes of CHF... 22 Table 2: Other Causes of CHF... 22 Table 3: Compensatory Mechanisms in CHF... 23 Table 4: Typical Symptoms of CHF... 28 Table 5: NYHA Classification of HF Based on Symptoms and Physical Ability of Patients... 29 Table 6: Risk Factors and Comorbidities for CHF... 31 Table 7: Sources of Epidemiological Data Used for the Forecast... 41 Table 8: NYHA Class Distributions... 48 Table 9: All Markets, Prevalent Cases (N) of CHF, Ages 45 Years, Men and Women, 2012 2022... 50 Table 10:All Markets, Prevalent Cases of CHF, by Age, Men and Women, N (Row %), 2012... 53 Table 11:All Markets, Prevalent Cases of CHF, by Sex, Ages 45 Years, N (Row %), 2012... 55 Table 12:All Markets, Prevalent Cases of CHF by NYHA Class, Ages 45 Years, Men and Women, N (Row %), 2012... 61 Table 13:ACC/AHA Classification of HF Based on Disease Progression... 65 Table 14:NYHA Classification of HF Based on Symptoms and Physical Activity of Patients... 65 Table 15:Commonly Used Treatment Guidelines for CHF... 67 Table 16:Most Prescribed Drugs for CHF by NYHA Class in the Major Markets, 2012... 69 Table 17:Select Products Used for CHF Treatment, 2012... 94 Table 18:Global Sales Forecasts ($m) for ACE inhibitors, 2012 2022... 97 Table 19:Global Sales Forecasts ($m) for Diuretics, 2012 2022... 100 Table 20:Global Sales Forecasts ($m) for ARBs, 2012 2022... 103 Table 21:Product Profile Diovan... 105 Table 22:Diovan SWOT Analysis, 2012... 107 Table 23:Global Sales Forecasts ($m) for Diovan, 2012 2022... 108 15

Table 24:Product Profile Atacand... 110 Table 25:Atacand SWOT Analysis, 2012... 111 Table 26:Global Sales Forecasts ($m) for Atacand, 2012 2022... 112 Table 27:Global Sales Forecasts ($m) for Beta Blockers, 2012 2022... 116 Table 28:Product Profile Carvedilol... 117 Table 29:Carvedilol SWOT Analysis, 2012... 119 Table 30:Global Sales Forecasts ($m) for Carvedilol, 2012 2022... 120 Table 31:Product Profile Nebivilol... 122 Table 32:Nebivilol SWOT Analysis, 2012... 123 Table 33:Global Sales Forecasts ($m) for Nebilet, 2012 2022... 124 Table 34:Product Profile Procoralan... 126 Table 35:Procoralan SWOT Analysis, 2012... 127 Table 36:Global Sales Forecasts ($m) for Procoralan, 2012 2022... 128 Table 37:Global Sales Forecasts ($m) for MRAs, 2012 2022... 131 Table 38:Global Sales Forecasts ($m) for Digoxin, 2012 2022... 134 Table 39:Overall Unmet Needs Current Level of Attainment... 135 Table 40:Clinical Unmet Needs Gap Analysis, 2013... 139 Table 41:CHF Clinical Trials by Phase and Status, 2012... 143 Table 42:CHF Promising Late-Stage Pipeline, 2012... 144 Table 43:Comparison of Therapeutic Classes in Development for CHF, 2012... 144 Table 44:Product Profile LCZ-696... 146 Table 45:LCZ-696 SWOT Analysis, 2012... 149 Table 46:Global Sales Forecasts ($) for LCZ-696, 2012 2022... 150 Table 47:Product Profile Tekturna... 153 16

Table 48:Tekturna SWOT Analysis, 2012... 155 Table 49:Product Profile Neucardin... 156 Table 50:CHF Innovative Early-Stage Approaches, 2012... 159 Table 51:Product Profile BAY 94-8862... 161 Table 52:Product Profile Omecamtiv mecarbil... 164 Table 53:CHF Promising Non-Pharmacological Approaches, 2012... 165 Table 54:Product Profile MyoCell... 168 Table 55:Product Profile C-Cure... 172 Table 56:Product Profile Mydicar... 175 Table 57:Key Companies in the CHF Market, 2012... 180 Table 58:Novartis CHF Portfolio Assessment, 2012... 183 Table 59:Novartis SWOT Analysis, 2012... 184 Table 60:Global Sales Forecasts ($m) for CHF, 2012-2022... 186 Table 61:Global CHF Market Drivers and Barriers, 2012 2022... 188 Table 62:Sales Forecasts ($m) for CHF in the United States, 2012 2022... 193 Table 63:Key Events Impacting Sales for CHF in the United States, 2012 2022... 195 Table 64:CHF Market in the United States Drivers and Barriers, 2012 2022... 195 Table 65:Sales Forecasts ($m) for CHF in the France, 2012 2022... 198 Table 66:Key Events Impacting Sales for CHF in France, 2012 2022... 200 Table 67:CHF Market Drivers and Barriers in France, 2012 2022... 200 Table 68:Sales Forecasts ($m) for CHF in Germany, 2012 2022... 202 Table 69:Key Events Impacting Sales for CHF in Germany, 2012 2022... 204 Table 70:CHF Market in Germany Drivers and Barriers, 2012 2022... 204 Table 71:Sales Forecasts ($m) for CHF in Italy, 2012 2022... 206 17

Table 72:Key Events Impacting Sales for CHF in Italy, 2012 2022... 207 Table 73:CHF Market in Italy Drivers and Barriers, 2012 2022... 208 Table 74:Sales Forecasts ($m) for CHF in Spain, 2012 2022... 210 Table 75:Key Events Impacting Sales for CHF in Spain, 2012 2022... 211 Table 76:CHF Market in Spain Drivers and Barriers, 2012 2022... 212 Table 77:Sales Forecasts ($m) for CHF in the United Kingdom, 2012 2022... 214 Table 78:Key Events Impacting Sales for CHF in the United Kingdom, 2012 2022... 216 Table 79:CHF Market Drivers and Barriers in the United Kingdom, 2012 2022... 216 Table 80:Sales Forecasts ($m) for CHF in Japan, 2012 2022... 218 Table 81:Key Events Impacting Sales for CHF in Japan, 2012 2022... 220 Table 82:CHF Market in Japan Drivers and Barriers, 2012 2022... 220 Table 83:Key Launch or Approval Dates... 247 Table 84:Key Patent Expiries... 247 Table 85:Physicians Surveyed, By Country... 256 1.2 List of Figures Figure 1: Worsening HF Leading to Chronic Disease... 25 Figure 2: All Markets, Prevalent Cases (N) of CHF, Ages 45 Years, Men and Women, 2012 2022... 51 Figure 3: All Markets, Prevalent Cases of CHF, by Age, Men and Women, N, 2012... 54 Figure 4: All Markets, Prevalent Cases of CHF, by Sex, Ages 45 Years, %, 2012... 56 Figure 5: All Markets, Prevalent Cases of CHF, by Age and Sex, N, 2012... 57 Figure 6: China, Prevalent Cases of CHF by Age and Sex, N, 2012... 58 Figure 7: All Markets, Age-Standardized Prevalence of CHF, Ages 45 Years, Men and Women, %, 2012.. 60 Figure 8: Drug-Treatment Rates of Patients Diagnosed with CHF in the 7MM, by NYHA Class... 68 18

Figure 9: Treatment of CHF Patients by Drug Class, US, 2012... 77 Figure 10: Treatment of CHF Patients by Drug Class, France, 2012... 79 Figure 11: Treatment of CHF Patients by Drug Class, Germany, 2012... 81 Figure 12: Treatment of CHF Patients by Drug Class, Italy, 2012... 83 Figure 13: Treatment of CHF Patients by Drug Class, Spain, 2012... 86 Figure 14: Treatment of CHF Patients by Drug Class, UK, 2012... 89 Figure 15: Treatment of CHD Patients by Drug Class, Japan, 2012... 91 Figure 16: CHF Therapeutics Clinical Trials by Country, 2012... 142 Figure 17: Global Sales for CHF ($bn) by Region, 2012 2022... 187 Figure 18: Sales for CHF ($bn) in the United States, 2012 2022... 194 Figure 19: Sales for CHF ($m) in France, 2012 2022... 199 Figure 20: Sales for CHF in Germany ($m), 2012 2022... 203 Figure 21: Sales for CHF ($m) in Italy, 2012 2022... 207 Figure 22: Sales for CHF ($m) in Spain, 2012 2022... 211 Figure 23: Sales for CHF ($m) in the United Kingdom, 2012 2022... 215 Figure 24: Sales for CHF ($m) in Japan, 2012 2022... 219 19

Introduction 2 Introduction 2.1 Catalyst The chronic heart failure (CHF) market is a mature market that has been slowly overtaken by generic drugs, and more branded products are expected to lose market exclusivity during the next few years. GlobalData predicts that the major global barriers that will play a crucial role in narrowing the global growth of the CHF market over the forecast period include the sparsely populated CHF pipeline and an increasing number of generic competitors in a market that is already heavily laden with generic drugs. However, the market entry of entry of Novartis LCZ-696, the first novel, branded CHF drug to enter the market in five years, will noticeably enhance the overall market size during the forecast period. LCZ-696 is currently being evaluated in a trial for patients with heart failure with reduced ejection fraction (HF-REF), but if clinical trial data continue to demonstrate the drug s efficacy in patients with heart failure with preserved ejection fraction (HF- PEF), and it gains approval for use in this population, it will be the first drug to show efficacy in this largely underserved patient population. In addition, increased use of MRAs over the forecast period in all seven major markets (7MM) will contribute to the increase in the global CHF market size. 2.2 Related Reports GlobalData (2013), Osteoporosis Global Drug Forecast and Market Analysis to 2022, January, 2013, GDHC43PIDR. 2.3 Upcoming Related Reports GlobalData (2013) Type 2 Diabetes Global Drug Forecast and Market Analysis to 2022, June, 2013, GDHC54PIDR. GlobalData (2013) Obesity Global Drug Forecast and Market Analysis to 2022, June, 2013, GDHC50PIDR GlobalData (2013). Dyslipidemia Global Drug Forecast and Market Analysis to 2022, June, 2013, GDHC46PIDR. 20

Appendix 11.8 About GlobalData GlobalData is a leading global provider of business intelligence in the Healthcare industry. GlobalData provides its clients with up-to-date information and analysis on the latest developments in drug research, disease analysis, and clinical research and development. Our integrated business intelligence solutions include a range of interactive online databases, analytical tools, reports, and forecasts. Our analysis is supported by a 24/7 client support and analyst team. GlobalData has offices in New York, Boston, London, India, and Singapore. 259