1 Table of Contents 1 Table of Contents 10 1.1 List of Tables 17 1.2 List of Figures 22 2 Introduction 24 2.1 Catalyst 24 2.2 Related Reports 24 3 Disease Overview 25 3.1 Etiology and Pathophysiology 25 3.1.1 Etiology 25 3.2 Classification and Staging Systems 32 3.3 Symptoms 33 3.4 Prognosis 34 3.5 Quality of Life 35 4 Epidemiology 37 4.1 Disease Background 37 4.2 Risk Factors and Comorbidities 38 4.3 Global Trends 40 4.3.1 US 40 4.3.2 5EU 41 4.3.3 Japan 42 4.4 Forecast Methodology 42 4.4.1 Sources Used 45 4.4.2 Forecast Assumptions and Methods 48 4.4.3 Sources Not Used 63 4.5 Epidemiological Forecast for HF (2015-2025) 63 4.5.1 Diagnosed Incident Cases 63 4.5.2 Diagnosed Prevalent Cases 77 4.6 Discussion 89 4.6.1 Epidemiological Forecast Insight 89 4.6.2 Limitations of the Analysis 89 4.6.3 Strengths of the Analysis 90 5 Disease Management 91 5.1 Diagnosis and Treatment Overview 91 5.1.1 Diagnosis 91 5.1.2 Treatment Guidelines and Leading Prescribed Drugs 94 5.1.3 Medical Devices 99 5.1.4 Clinical Practice 100 5.2 US 106 5.3 5EU 108 5.4 Japan 112 6 Competitive Assessment 115 6.1 Overview 115 6.2 Drug Profiles 116 6.2.1 Angiotensin-Converting Enzyme Inhibitors 116 6.2.2 Angiotensin Receptor Blockers 122 6.2.3 Entresto (sacubitril + valsartan) 126 6.2.4 Diuretics 141 6.2.5 Beta Blockers 146 6.2.6 Procoralan (ivabradine) 150 6.2.7 Mineralocorticoid Receptor Antagonists 158 6.2.8 Digoxin 162 6.2.9 Pharmacological Therapies for Acute HF 165 7 Unmet Needs and Opportunities 168 7.1 Overview 168 7.1.1 Acute HF - Target Opportunity Profile 170 7.1.2 HF with Preserved Ejection Fraction - Target Opportunity Profile 173 7.1.3 HF with Reduced Ejection Fraction - Target Opportunity Profile 176 7.2 Lack of Therapies for HF with Preserved Ejection Fraction Patients 181 7.2.1 Unmet Need 181 7.2.2 Gap Analysis 182 7.2.3 Opportunity 183 7.3 Lack of Therapies for Acute HF 183 7.3.1 Unmet Need 183 7.3.2 Gap analysis 184 7.3.3 Opportunity 185 7.4 Lack of Therapies for Acute HF Patients Experiencing Diuretic Resistance 186 7.4.1 Unmet Need 186 7.4.2 Gap Analysis 187 7.4.3 Opportunity 188 7.5 Lack of Therapies for Patients with Renal Impairment 188 7.5.1 Unmet Need 188 7.5.2 Gap Analysis 189 7.5.3 Opportunity 189 7.6 Treatment of Patients with Multiple Comorbidities 190 7.6.1 Unmet Need 190 7.6.2 Gap Analysis 191 7.6.3 Opportunity 191 7.7 Enhanced Diagnosis and Preventative Therapies for Patients at Risk of Developing HF 192 7.7.1 Unmet Need 192 7.7.2 Gap Analysis 193 7.7.3 Opportunity 194 7.8 Conducting Clinical Trials in Cohorts of Japanese Patients 195 7.8.1 Unmet Need 195 7.8.2 Gap Analysis 196 7.8.3 Opportunity 196 7.9 Use of Optimal Doses of HF Therapies 197 7.9.1 Unmet Need 197 7.9.2 Gap Analysis 198 7.9.3 Opportunity 199 7.10 Patient Compliance 199 7.10.1 Unmet Need 199 7.10.2 Gap Analysis 200 7.10.3 Opportunity 201 7.11 Early Detection and Treatment of Patients with Worsening Chronic HF 201 7.11.1 Unmet Need 201 7.11.2 Gap Analysis 202 7.11.3 Opportunity 203 7.12 Dynamic Management of Patients with HF 203 7.12.1 Unmet Need 203 7.12.2 Gap Analysis 205 7.12.3 Opportunity 205 7.13 Options for Advanced HF Patients Who Are Unable to Receive a Heart Transplant 206 7.13.1 Unmet Need 206 7.13.2 Gap Analysis 207 7.13.3 Opportunity 207 8 Pipeline Assessment 208 8.1 Overview 208 8.2 Promising Drugs in Late-Stage Clinical Development 210 8.2.1 Serelaxin 212 8.2.2 Ularitide 221 8.2.3 Omecamtiv Mecarbil 229 8.2.4 Vericiguat 238 8.2.5 Finerenone 245 8.2.6 Neucardin 251 8.2.7 Revatio 255 8.3 Promising Drugs in Early Stage Development 259 8.3.1 CXL-1427 259 8.3.2 Istaroxime 260 8.3.3 Perhexiline Maleate 260 8.3.4 TRV-027 261 8.4 Other Drugs in Development 261 9 Current and Future Players 263 9.1 Overview 263 9.2 Trends in Corporate Strategy 265 9.3 Company Profiles 266 9.3.1 Novartis 266 9.3.2 Les Laboratoires Servier 269 9.3.3 Cardiorentis 271 9.3.4 Bayer (and Merck & Co.) 272 9.3.5 Cytokinetics 274 10 Market Outlook 276 10.1 Global Markets 276 10.1.1 Forecast 276 10.1.2 Drivers and Barriers - Global Issues 281 10.2 US 285 10.2.1 Forecast 285 10.2.2 Key Events 289 10.2.3 Drivers and Barriers 290 10.3 France 291 10.3.1 Forecast 291 10.3.2 Key Events 295 10.3.3 Drivers and Barriers 296 10.4 Germany 297 10.4.1 Forecast 297 10.4.2 Key Events 300 10.4.3 Drivers and Barriers 301 10.5 Italy 302 10.5.1 Forecast 302 10.5.2 Key Events 305 10.5.3 Drivers and Barriers 306 10.6 Spain 307 10.6.1 Forecast 307 10.6.2 Key Events 310 10.6.3 Drivers and Barriers 311 10.7 UK 312 10.7.1 Forecast 312 10.7.2 Key Events 315 10.7.3 Drivers and Barriers 316 10.8 Japan 317 10.8.1 Forecast 317 10.8.2 Key Events 321 10.8.3 Drivers and Barriers 321 11 Appendix 324 11.1 Bibliography 324 11.2 Abbreviations 356 11.3 Methodology 364 11.4 Forecasting Methodology 364 11.4.1 Diagnosed Prevalent Chronic HF 364 11.4.2 Diagnosed Incidence of Acute HF 365 11.4.3 Percent Drug-Treated Patients 365 11.4.4 Treatment of HF with Reduced Ejection Fraction Versus HF with Preserved Ejection Fraction 365 11.4.5 Drugs Included in Each Therapeutic Class 365 11.4.6 Launch and Patent Expiry Dates 366 11.4.7 General Pricing Assumptions 367 11.4.8 Individual Drug Assumptions 368 11.4.9 Generic Erosion 373 11.4.10 Pricing of Pipeline Agents 373 11.5 Key Opinion Leaders Included in This Study 375 11.6 Payers Included in This Study 377 11.7 High-Prescribing Physician Survey 378 11.8 About the Authors 379 11.8.1 Author 379 11.8.2 Contributing Author 379 11.8.3 Therapy Area Director 379 11.8.4 Epidemiologist 380 11.8.5 Global Director of Therapy Analysis and Epidemiology 380 11.8.6 Global Head of Healthcare 381 11.9 About GlobalData 382 11.10 Disclaimer 382

1.1 List of Tables Table 1: Leading Causes of HF 27 Table 2: A Summary of the Compensatory Mechanisms in HF 28 Table 3: The Two Main Classification Systems in HF 33 Table 4: Typical Symptoms of HF 34 Table 5: Risk Factors and Comorbidities for HF 39 Table 6: NYHA Functional Classes I-IV 44 Table 7: ACCF/AHA Stages A, B, C, and D 44 Table 8: 7MM, Sources of Epidemiological Data Used for the Forecast of HF Diagnosed Incident Cases 45 Table 9: 7MM, Sources of Epidemiological Data Used for the Forecast of Chronic HF Diagnosed Prevalent Cases 46 Table 10: 7MM, Sources of Epidemiological Data Used for the Classification of Diagnosed Prevalent Cases of Chronic HF According to the NYHA Functional Classes I-IV 47 Table 11: 7MM, Sources of Epidemiological Data Used for Forecast of HF Diagnosed Incident Cases of Acute HF Hospitalizations 48 Table 12: 7MM, Sources Not Used in Epidemiological Analysis of HF 63 Table 13: 7MM, Diagnosed Incident Cases of HF, Ages ≥45 Years, Both Sexes, N, 2015-2025 64 Table 14: 7MM, Age-Specific Diagnosed Incident Cases of HF, Both Sexes, N (Row %), 2015 66 Table 15: 7MM, Sex-Specific Diagnosed Incident Cases of HF, Ages ≥45 Years, N (Row %), 2015 68 Table 16: 7MM, Diagnosed Incident Cases of Acute HF Hospitalizations, Ages ≥45 Years, Both Sexes, N, 2015-2025 73 Table 17: 7MM, Readmissions (Within Three Months) Post-Discharge After Acute HF Hospitalization Among Diagnosed Incident Cases of Acute HF, Ages ≥45 Years, Both Sexes, N, 2015-2025 75 Table 18: 7MM, Diagnosed Prevalent Cases of Chronic HF, Ages ≥45 Years, Both Sexes, N, 2015-2025 78 Table 19: 7MM, Age-Specific Diagnosed Prevalent Cases of Chronic HF, Both Sexes, N (Row %), 2015 80 Table 20: 7MM, Sex-Specific Diagnosed Prevalent Cases of Chronic HF, Ages ≥45 Years, N (Row %), 2015 82 Table 21: Guideline Recommended Tests for the Diagnosis of HF 92 Table 22: Common Factors that Precipitate Acute HF 94 Table 23: Treatment Guidelines for HF 95 Table 24: Comparison of the ACCF/AHA and NYHA HF Classification Systems 96 Table 25: Most Prescribed Drugs for HF by Class in the Global Markets, 2015 97 Table 26: Country Profile for HF - US 107 Table 27: Country Profile for HF - 5EU 110 Table 28: Country Profile for HF - Japan 113 Table 29: Efficacy of Enalapril 118 Table 30: Efficacy of Perindopril 120 Table 31: Global Sales Forecasts ($M) for ACE inhibitors, 2015-2025 122 Table 32: Global Sales Forecasts ($M) for ARBs, 2015-2025 126 Table 33: Product Profile - Entresto 133 Table 34: Efficacy of Entresto 134 Table 35: Safety of Entresto 136 Table 36: Entresto SWOT Analysis, 2015 138 Table 37: Global Sales Forecasts ($M) for Entresto, 2015-2025 141 Table 38: Global Sales Forecasts ($M) for Diuretics in the Chronic HF Market, 2015-2025 145 Table 39: Global Sales Forecasts ($M) for Loop Diuretics in the Acute HF Market, 2015-2025 145 Table 40: Global Sales Forecasts ($M) for Beta Blockers, 2015-2025 150 Table 41: Product Profile - Ivabradine 153 Table 42: Efficacy of Ivabradine 154 Table 43: Ivabradine SWOT Analysis, 2015 156 Table 44: Global Sales Forecasts ($M) for Procoralan/Corlanor (ivabradine), 2015-2025 158 Table 45: Global Sales Forecasts ($M) for MRAs, 2015-2025 162 Table 46: Global Sales Forecasts ($M) for Digoxin, 2015-2025 165 Table 47: Unmet Needs and Opportunities in HF 169 Table 48: Target Opportunity Profile for Acute HF 171 Table 49: Target Opportunity Profile for HF-PEF 175 Table 50: Target Opportunity Profile for HF-REF 178 Table 51: Chronic HF Comorbidities in the 7MM 192 Table 52: Comparison of Therapeutic Classes in Development for HF, 2015 212 Table 53: Product Profile - Serelaxin 215 Table 54: Efficacy of Serelaxin 217 Table 55: Serelaxin SWOT Analysis, 2015 220 Table 56: Global Sales Forecasts ($M) for Serelaxin, 2015-2025 221 Table 57: Product Profile - Ularitide 224 Table 58: Safety of Ularitide 226 Table 59: Ularitide SWOT Analysis, 2015 228 Table 60: Global Sales Forecasts ($M) for Ularitide, 2015-2025 229 Table 61: Product Profile - OM 232 Table 62: Efficacy of OM 233 Table 63: OM SWOT Analysis, 2015 236 Table 64: Global Sales Forecasts ($M) for OM (Chronic HF), 2015-2025 237 Table 65: Global Sales Forecasts ($M) for OM (Acute HF), 2015-2025 238 Table 66: Product Profile - Vericiguat 240 Table 67: Efficacy of Vericiguat 241 Table 68: Safety of Vericiguat 242 Table 69: Vericiguat SWOT Analysis, 2015 244 Table 70: Global Sales Forecasts ($M) for vericiguat, 2015-2025 245 Table 71: Product Profile - Finerenone 247 Table 72: Finerenone SWOT Analysis, 2015 250 Table 73: Product Profile - Neucardin 252 Table 74: Neucardin SWOT Analysis, 2015 255 Table 75: Product Profile - Revatio 256 Table 76: Efficacy of Revatio 257 Table 77: Revatio SWOT Analysis, 2015 259 Table 78: Drugs in Development, 2015 262 Table 79: Key Companies in the HF Market in the 7MM, 2015-2025 264 Table 80: Novartis’ HF Portfolio Assessment, 2015 268 Table 81: Serviers’ HF Portfolio Assessment, 2015 270 Table 82: Cardiorentis’ HF Portfolio Assessment, 2015 272 Table 83: Bayer’s HF Portfolio Assessment, 2015 274 Table 84: Cytokinetics’ HF Portfolio Assessment, 2015 275 Table 85: Global Sales Forecasts ($M) for Chronic HF, 2015-2025 277 Table 86: Global Sales Forecasts ($M) for Acute HF, 2015-2025 279 Table 87: HF Global Market - Drivers and Barriers, 2015-2025 281 Table 88: Sales Forecasts ($M) for HF in the US, 2015-2025 287 Table 89: Key Events Impacting Sales for HF in the US, 2015-2025 289 Table 90: US HF Market - Drivers and Barriers, 2015-2025 290 Table 91: Sales Forecasts ($M) for HF in France, 2015-2025 293 Table 92: Key Events Impacting Sales for HF in France, 2015-2025 295 Table 93: French HF market - Drivers and Barriers, 2015-2025 296 Table 94: Sales Forecasts ($M) for HF in Germany, 2015-2025 298 Table 95: Key Events Impacting Sales for HF in Germany, 2015-2025 300 Table 96: Germany HF market - Drivers and Barriers, 2015-2025 301 Table 97: Sales Forecasts ($M) for HF in Italy, 2015-2025 303 Table 98: Key Events Impacting Sales for HF in Italy, 2015-2025 305 Table 99: Italy HF market - Drivers and Barriers, 2015-2025 306 Table 100: Sales Forecasts ($M) for HF in Spain, 2015-2025 308 Table 101: Key Events Impacting Sales for HF in Spain, 2015-2025 310 Table 102: Spain HF market - Drivers and Barriers, 2015-2025 311 Table 103: Sales Forecasts ($M) for HF in the UK, 2015-2025 313 Table 104: Key Events Impacting Sales for HF in the UK, 2015-2025 315 Table 105: UK HF market - Drivers and Barriers, 2015-2025 316 Table 106: Sales Forecasts ($M) for HF in Japan, 2015-2025 318 Table 107: Key Events Impacting Sales for HF in Japan, 2015-2025 321 Table 108: Japan HF market - Drivers and Barriers, 2015-2025 321 Table 109: Key Launch Dates 366 Table 110: Key Patent Expiries 366 Table 111: High-Prescribing Physicians (non-KOLs) Surveyed, By Country 378 1.2 List of Figures Figure 1: RAAS Mechanism of Action 30 Figure 2: 7MM, Diagnosed Incident Cases of HF, Ages ≥45 Years, Both Sexes, N, 2015-2025 65 Figure 3: 7MM, Diagnosed Incident Cases of HF by Age Group, Both Sexes, N, 2015 67 Figure 4: 7MM, Sex-Specific Diagnosed Incident Cases of HF, Ages ≥45 Years, N, 2015 69 Figure 5: 7MM, Age-Standardized Diagnosed Incidence of HF (Cases per 100,000 Population), Ages ≥45 Years, by Sex, 2015 70 Figure 6: 7MM, Diagnosed Incident Cases of HF Segmented by EF, Ages ≥45 Years, Both Sexes, N, 2015 71 Figure 7: 7MM, Diagnosed Incident Cases of HF Segmented by Ventricular Dysfunction, Ages ≥45 Years, Both Sexes, N, 2015 72 Figure 8: 7MM, Diagnosed Incident Cases of Acute HF Hospitalizations, Ages ≥45 Years, Both Sexes, N, 2015-2025 73 Figure 9: 7MM, Diagnosed Incident Cases of Acute HF Hospitalizations, Ages ≥45 Years, Both Sexes, N, 2015 74 Figure 10: 7MM, Readmissions (Within Three Months) Post-Discharge After Acute HF Hospitalization Among Diagnosed Incident Cases of Acute HF, Ages ≥45 Years, Both Sexes, N, 2015-2025 76 Figure 11: 7MM, Hospital Length Of Stay For Acute HF Hospitalization, Ages ≥45 Years, Both Sexes, Days, 2015 77 Figure 12: 7MM, Diagnosed Prevalent Cases of Chronic HF, Ages ≥45 Years, Both Sexes, N, 2015-2025 79 Figure 13: 7MM, Age-Specific Diagnosed Prevalent Cases of Chronic HF, Both Sexes, N, 2015 81 Figure 14: 7MM, Sex-Specific Diagnosed Prevalent Cases of Chronic HF, Ages ≥45 Years, N, 2015 83 Figure 15: 7MM, Age-Standardized Diagnosed Prevalence of Chronic HF (%), Ages ≥45 Years, by Sex, 2015 84 Figure 16: 7MM, Diagnosed Prevalent Cases of Chronic HF Segmented by EF, Ages ≥45 Years, Both Sexes, N, 2015 85 Figure 17: 7MM, Diagnosed Prevalent Cases of Chronic HF Segmented by NYHA Classes, Ages ≥45 Years, Both Sexes, N, 2015 86 Figure 18: 7MM, Diagnosed Prevalent Cases of Chronic HF Segmented by ACCF/AHA Stages, Ages ≥45 Years, Both Sexes, N, 2015 87 Figure 19: 7MM, Prevalent Cases of Comorbidities Among Diagnosed Prevalent Cases of Chronic HF, Both Sexes, Ages ≥45 Years, N, 2015 88 Figure 20: HF treatment based on ACCF/AHA Stage 101 Figure 21: HF - Phase II-III Pipeline, 2015 210 Figure 22: Competitive Assessment of Late-Stage Pipeline Agents in HF, 2015-2025 211 Figure 23: Company Portfolio Gap Analysis in HF, 2015-2025 265 Figure 24: Global Sales for Chronic HF by Region, 2015-2025 278 Figure 25: Global Sales for Acute HF by Region, 2015-2025 280 Figure 26: Sales for Chronic HF in the US by Drug Class, 2015-2025 288 Figure 27: Sales for Acute HF in the US by Drug Class, 2025* 289 Figure 28: Sales for Chronic HF in France by Drug Class, 2015-2025 294 Figure 29: Sales for Acute HF in France by Drug Class, 2025* 295 Figure 30: Sales for Chronic HF in Germany by Drug Class, 2015-2025 299 Figure 31: Sales for Acute HF in Germany by Drug Class, 2025* 300 Figure 32: Sales for Chronic HF in Italy by Drug Class, 2015-2025 304 Figure 33: Sales for Acute HF in Italy by Drug Class, 2025* 305 Figure 34: Sales for Chronic HF in Spain by Drug Class, 2015-2025 309 Figure 35: Sales for Acute HF in Spain by Drug Class, 2025* 310 Figure 36: Sales for Chronic HF in the UK by Drug Class, 2015-2025 314 Figure 37: Sales for Acute HF in the UK by Drug Class, 2025* 315 Figure 38: Sales for Chronic HF in Japan by Drug Class, 2015-2025 319 Figure 39: Sales for Acute HF in Japan by Drug Class, 2015-2025 320

Novartis Les Laboratoires Servier Cardiorentis Bayer (and Merck & Co.) Cytokinetics