Introduction
Novel oral anticoagulants and antiplatelet agents will have a profound impact on the antithrombotics market. Datamonitor expects Bayer's rivaroxaban and Sankyo/Eli Lilly's prasugrel to achieve blockbuster status. Parenteral anticoagulants are not expected to be large revenue generators, due to low clinical unmet need in this market segment and strong competition from current gold standard agents.
Scope
Event-driven sales projections for 2007-16 for key late-stage developmental antithrombotics in the seven major markets Commercial analysis of late-stage developmental compounds in terms of their ability to satisfy unmet clinical needs An overview of the antithrombotics R&D pipeline with a comprehensive assessment of all classes in development Analysis of the potential for developmental antithrombotics with respect to the patient populations for which they are indicated
Highlights
Following the abrupt withdrawal of AstraZeneca's Exanta in February 2006, Bayer Healthcare's rivaroxaban and Boehringer Ingelheim's Rendix are well positioned to profit from patients switching from warfarin, and market growth obtained by recruiting the previously untreated population. The highest selling brands in the antidiabetics market are Lovenox (enoxaparin) and Plavix (clopidogrel), but these agents will be genericized within our forecast period. Consequently, pipeline agents are expected to become significant drivers in the market. Acute Coronary Syndrome is usually the first indication for which novel anticoagulants are approved; this is a quick route to market, while drug companies then prepare to launch their products in more lucrative, chronic treatment markets.
Reasons to Purchase
Understand the factors that will drive the success of next-generation antithrombotics Overcome the barriers to entry generated by lifecycle strategies of key players in the market Assess the remaining market opportunity, where established therapies and other developmental compounds fail to address key unmet clinical needs
ABOUT DATAMONITOR HEALTHCARE 2
About the Disease pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 4
Scope of the analysis 4
Datamonitor insight into the antithrombotics market 5
Key metrics 6
Datamonitor pipeline assessment summary 7
Anticoagulants 7
Antiplatelet Agents 8
CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS 23
Pipeline overview 23
Antithrombotics segmented by mechanism of action 29
Redesigning heparin: the race for ideal coagulation cascade target is still open 30
Antiplatelet agents by drug class 31
Antithrombotics segmented by developing company 34
Japanese companies in the antithrombotics market 36
Key companies involved in the antithrombotics pipeline 37
Overview 37
AstraZeneca 38
Sanofi-Aventis 38
CHAPTER 3 PATIENT POTENTIAL 39
Definition of antithrombotic market 39
Antithrombotic launch indications 43
Venous thrombosis 43
VTE prophylaxis in patients undergoing major orthopedic surgery 43
Treatment and secondary prevention of acute venous thromboembolism 45
Arterial thrombosis 49
Coronary thrombosis 49
Acute coronary syndromes 49
Incidence of STEMI 50
Incidence of UA and NSTEMI 50
Cerebrovascular thrombosis 53
Stroke treatment 53
Stroke prevention in atrial fibrillation patients (SPAF) 55
Peripheral thrombosis 58
Peripheral arterial disease (PAD) 58
Marketing considerations: unmet needs, barriers to market entry and uptake 63
Anticoagulants 63
Unmet needs: parenteral anticoagulants 63
Unmet needs: oral anticoagulants 64
Unmet need: increased physician awareness of VTE 67
Points of consideration: factors influencing market entry and uptake 67
Unmet needs summary 72
Antiplatelets 73
Unmet needs 73
Unmet need for rapid onset of action in interventional cardiology 77
Unmet need: increased physician awareness for the need of therapy for PAD 78
Points of consideration: factors influencing market entry and uptake 79
Unmet needs summary 82
CHAPTER 4 R&D APPROACH 84
Classification of pipeline products 84
Anticoagulants 84
Hemostasis and the coagulation cascade 84
Indirect thrombin inhibitors 87
Unfractionated heparin (UFH) 87
Low molecular weight heparin (LMWH) 88
Direct thrombin inhibitors (DTIs) 89
Factor IXa inhibitors 91
Factor Xa inhibitors 92
Factor VIIa inhibitors/tissue factor pathway inhibitors 99
Anticoagulant activity 100
Antiplatelet Agents 102
Cyclo-oxygenase (COX) inhibitors: aspirin 103
ADP antagonists 106
GPIIb/IIIa inhibitors 111
PGE-1 antagonists 113
PI3-kinase antagonists 114
PGH2/TXA2 (TP) receptor antagonists 114
Clinical trial design for antithrombotics 133
Phase III sample size 134
Choice of control drug 134
Patient exclusion 135
Patient exclusion from efficacy analysis 136
Duration of drug intervention 136
Pre-operative or post-operative initiation of prophylaxis? 137
Dosing interval 138
Dose timing 138
Clinical trial endpoints for antithrombotics 139
Efficacy endpoints 139
VTE incidence 140
Diagnosis of VTE events 141
Central versus local adjudication 141
Safety endpoints 142
CHAPTER 5 ANTICOAGULANTS LATE-STAGE DRUG ANALYSIS AND FORECASTS 144
Overview of the key anticoagulants in late-stage development 144
Pipeline summary 144
Datamonitor drug assessment summary 146
Comparative forecasts 148
Rivaroxaban (BAY-59-7939) 149
Drug overview 149
Clinical data 149
Patient potential 150
Marketing factors 151
Forecasts to 2016 152
Dabigatran etexilate (BIBR-1048) - Rendix 153
Drug overview 153
Clinical data 154
Pharmacokinetics of dabigatran etexilate 155
Phase II clinical trial of Dabigatran etexilate in MOS versus enoxaparin: BISTRO II 155
Patient potential 156
SPAF - greatest potential for dabigatran etexilate 156
Potential device competitor for SPAF indication for high-risk patients? 157
Marketing factors 159
Forecast to 2016 160
Idraparinux 161
Drug overview 161
Clinical data 163
PERSIST trial 163
No significant effect on liver enzymes 164
Phase III VAN GOGH trial in PE patients 165
Phase III AMADEUS trial 166
Patient potential 167
Marketing factors 168
Strong presence and experience in the AF market 168
High price may pose a barrier to uptake 169
Lack of antidote raises concerns 169
Forecast to 2016 173
ART-123 174
Drug overview 174
Clinical data 174
Phase III trials 174
Phase I trials 175
Prevention of VTE after total hip replacement 176
Patient potential 177
Marketing factors 178
Forecast to 2016 179
CHAPTER 6 OTHER ANTICOAGULANTS 181
Antithrombin aptamers - NU-172 and ARC1779 181
Drug overview 181
Preclinical data 181
Clinical data 181
Apixaban (BMS-562247) 182
Drug overview 182
Clinical data 182
AVE-5026 183
Drug overview 183
Clinical data 183
AZD-0837 183
Drug overview 183
Clinical data 183
AZD-9684 184
Drug overview 184
Preclinical data 184
Biotinylated Idraparinux (SSR-126517) 184
Drug overview 184
Clinical data 185
DU-176b 185
Drug overview 185
Clinical data 185
E-5555 186
Drug overview 186
Preclinical data 186
Clinical data 186
Elaprin (Oral heparin) and Oral LMWH 186
Drug overview 186
Clinical data 187
Datamonitor comment 187
Flovagatran (TGN-255) 188
Drug overview 188
Clinical data 188
Datamonitor comments 189
GSK-813893 190
Drug overview 190
LY-517717 190
Drug overview 190
Clinical data 190
Odiparcil (SB-424323) 191
Drug overview 191
Clinical data 191
Otamixaban (XRP-0673) 192
Drug overview 192
Clinical data 192
PD-348292 193
Drug overview 193
Pegmusirudin (SPP-200; LU-57291) 193
Drug overview 193
Clinical data 193
PRT-54021 194
Drug overview 194
Clinical data 194
REG-1 195
Drug overview 195
Clinical data 195
SCH-530348 195
Drug overview 195
Preclinical data 196
Clinical data 196
Sofigatran (MCC-977) 196
Drug overview 196
SR-123781 197
Drug overview 197
Preclinical data 197
Clinical data 197
Tanogitran (BIBT-986) 198
Drug overview 198
Clinical data 198
TGN-167 198
Drug overview 198
Clinical data 199
TTP-889 199
Drug overview 199
Clinical data 199
Datamonitor comment 200
YM-150 200
Drug overview 200
Clinical data 200
CHAPTER 7 ANTIPLATELET AGENTS: LATE-STAGE ANALYSIS AND FORECASTS 202
Overview of the key antiplatelets in late-stage development 202
Pipeline summary 202
Datamonitor drug assessment summary 203
Comparative forecasts 204
Prasugrel (CS-747) 205
Drug overview 205
Clinical data 206
Phase IIa: Randomized two-way cross-over, open-label study in healthy subjects 206
Phase IIa : Randomized, partially blind, parallel group dose-ranging study 207
Patient potential 213
Marketing factors 214
Forecast to 2016 216
Cangrelor (AR-C69931) 217
Drug overview 217
Clinical Data 217
Patient potential 218
Marketing factors 219
Forecast to 2016 220
Ticagrelor (AZD-6140) 221
Drug overview 221
Clinical data 221
Patient Potential 223
Marketing Factors 224
Forecast to 2016 224
CHAPTER 8 OTHER ANTIPLATELET AGENTS 227
DA-697b 227
Drug overview 227
Preclinical data 227
DG-041 227
Drug overview 227
Preclinical data 227
Clinical data 228
Ecraprost 228
Drug overview 228
Clinical data 228
Datamonitor comment 229
Liprostin 229
Drug overview 229
Clinical data 230
Parogrelil (NM-702) 230
Drug overview 230
Clinical data 230
PR-15 231
Drug overview 231
Preclinical data 232
Clinical data 232
Datamonitor comment 232
S-18886 232
Drug overview 232
Clinical data 233
SL-650472 234
Drug overview 234
Preclinical data 234
Clinical data 235
BIBLIOGRAPHY 236
Epidemiology 236
National hospital discharge data 238
APPENDIX A 251
Methodology 251
Datamonitor forecast methodology 251
Product forecasts 251
Estimated 2006 sales revenue 251
Definition of a standard unit (only use if ForeSight model used to forecast) 251
Datamonitor drug assessment summary 252
Contributing experts 253
APPENDIX B 254
About Datamonitor 254
About Datamonitor Healthcare 254
Datamonitor Healthcare's therapy area capabilities 255
About the Disease analysis team 256
Key therapy team members 257
Disclaimer 257
List of Tables
Table 1: Forecast key pipeline products in Antithrombotics in 2016 ($m) 6
Table 2: Anticoagulant agents in the R&D pipeline, 2007 24
Table 3: Antiplatelet agents in the R&D pipeline, 2007. 27
Table 4: Key players in antithrombotic drug development, 2007 37
Table 5: Incidence of arthroplastic knee surgery in the seven major markets (000s), 2007-2017 44
Table 6: Incidence of arthroplastic hip surgery in the seven major markets (000s), 2007-2017) 44
Table 7: Incidence of deep vein thrombosis, pulmonary embolism and venous thromboembolism in the seven major markets(000s), 2007-2017 48
Table 8: Incidence of ST-segment elevation myocardial infarction (000s), 2007-2017 51
Table 9: Incidence of unstable angina and non-ST segment elevation myocardial infarction in the seven major markets (000s), 2007-2017 52
Table 10: Incidence of percutaneous coronary intervention in the seven major markets (000s), 2007-2017 53
Table 11: Incidence of stroke in the seven major markets (000s), 2007-2017 55
Table 12: Proportion of atrial fibrillation patients at risk of developing stroke 56
Table 13: Prevalence of chronic atrial fibrillation in the seven major markets (000s), 2007-2017 58
Table 14: Prevalence of peripheral arterial disease in the seven major markets (000s), 2007-2017 62
Table 15: Resistance to key oral antiplatelets 74
Table 16: Advantages of direct thrombin inhibitors over heparin 89
Table 17: OASIS-5/Michelangelo trial: efficacy 98
Table 18: OASIS-5/Michelangelo trial: safety 98
Table 19: Key results of CURE substudy 116
Table 20: CLARITY/TIMI-28: efficacy outcomes on angiography 120
Table 21: CLARITY/TIMI-28: safety outcomes 121
Table 22: COMMIT/CCS-2 trial: efficacy endpoints 123
Table 23: COMMIT/CCS-2 trial: safety endpoints 124
Table 24: COMMIT/CCS-2 trial: time to treatment 124
Table 25: COMMIT/CCS-2 trial: thrombolytic background therapy 124
Table 26: ARMYDA-2: number of events at 30 days 126
Table 27: ARMYDA-2: postprocedural peak biomarker levels 127
Table 28: ARMYDA-2: percentage of patients with an elevation of CKMB/troponin I 127
Table 29: ARMYDA-2: number of bleeding events at 30 days 127
Table 30: Key efficacy endpoints used in anticoagulant clinical trials 140
Table 31: Key safety endpoints used in anticoagulant clinical trials 142
Table 32: Key anticoagulants in late-stage development, 2007 144
Table 33: Sales forecasts for late-stage anticoagulants in the seven major markets ($m), 2007-2016 148
Table 34: Proportion of AF patients receiving antithrombotic therapy by level of risk of experiencing stroke 157
Table 35: Comparison of fondaparinux with idraparinux 162
Table 36: PERSIST trial results 164
Table 37: Result of dose-response trial examining ART-123 177
Table 38: Key pipeline antiplatelets, 2007 202
Table 39: Comparative Sales Forecast for late-stage antiplatelet agents 205
Table 40: JUMBO-TIMI 26: number of adverse events 208
Table 41: JUMBO-TIMI 26: patient characteristics 209
Table 42: JUMBO-TIMI 26: primary endpoint (significant bleeding) 210
Table 43: JUMBO-TIMI 26: TIMI major bleeding 210
Table 44: JUMBO-TIMI 26: total bleeding episodes (TIMI major/minor and minimal) 211
Table 45: JUMBO-TIMI 26: secondary endpoint (MACE) 211
Table 46: JUMBO-TIMI 26: MACE components 212
Table 47: Datamonitor drug assessment parameters 252
List of Figures
Figure 1: Datamonitor drug assessment summary of pipeline anticoagulants, , 2007-2016 7
Figure 2: Datamonitor drug assessment summary of pipeline antiplatelets, 2007-2016 8
Figure 3: The antithrombotics pipeline by development stage, 2007 29
Figure 4: Antithrombotics development pipeline segmented by mechanism of action, 2007 30
Figure 5: Pipeline antithrombotics segmented by developing company, 2007 34
Figure 6: Key players in the antithrombotics pipeline with products segmented by phase of development, 2007 35
Figure 7: Overlap of ischemic cardiovascular conditions 41
Figure 8: Frequency of disease with symptoms in the three organ systems and their overlap, from the CAPRIE trial 42
Figure 9: Risk of stroke increases with age 57
Figure 10: Breakdown of the peripheral arterial disease population by classification 60
Figure 11: The targets of developmental anticoagulants and selected thrombolytics 86
Figure 12: Aspirin inhibits platelet COX-1 irreversibly 105
Figure 13: The role of purinergic receptors as targets for antiplatelets 107
Figure 14: GPIIb/IIIa receptor antagonists act directly on the receptor 111
Figure 15: CLARITY/TIMI-28: study design 119
Figure 16: COMMIT/CCS-2 trial: dual antiplatelet therapy in acute myocardial infarction 123
Figure 17: ARMYDA-2: trial design 126
Figure 18: Datamonitor drug assessment summary of pipeline anticoagulants, 2007-2016 147
Figure 19: Comparative sales forecast for late-stage anticoagulants in the seven major markets, 2007-2016 148
Figure 20: Datamonitor's projected sales for rivaroxaban (BAY-59-7939) in across the seven major markets ($m), 2007-2016 152
Figure 21: Datamonitor's projected sales for Rendix (dabigatran etexilate, BIBR-1048) in across the seven major markets ($m), 2007-2016. 160
Figure 22: PERSIST trial design 163
Figure 23: Idraparinux Phase III program: VAN GOGH 166
Figure 24: Idraparinux Phase III program: AMADEUS 167
Figure 25: Is recombinant factor VIIa a valid antidote to idraparinux? 171
Figure 26: Datamonitor's projected sales for idraparinux in across the seven major markets ($m), 2007-2016 173
Figure 27: Datamonitor's projected sales for ART-123 in across the seven major markets ($m), 2007-2016 179
Figure 28: Datamonitor drug assessment summary of pipeline antiplatelet agents, 2007-2016 203
Figure 29: Comparative sales forecast for late-stage antiplatelet agents 204
Figure 30: JUMBO-TIMI 26: prasugrel in the setting of percutaneous coronary intervention 209
Figure 31: TRITON-TIMI-38: trial design 212
Figure 32: Datamonitor's projected sales for prasugrel in across the seven major markets ($m), 2007-2016 216
Figure 33: Datamonitor's projected sales for cangrelor in across the seven major markets ($m), 2007-2016 220
Figure 34: Ticagrelor (AZD-6140) is a potent inhibitor of platelet aggregation 223
Figure 35: Datamonitor's projected sales for ticagrelor in across the seven major markets ($m), 2007-2016 225
Figure 36: Datamonitor drug assessment summary of pipeline molecular targeted therapies in development for hematological malignancies, 2007 253