CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Experts interviewed for this report (interviewed in April 2008) 3
Experts interviewed for Pipeline Insight 2006: Acute Stroke, DMHC2167 (interviewed in February 2006) 3
Experts interviewed for Stakeholder Insight 2007: Acute Stroke, DMHC2286 (interviewed in October 2007) 4
Datamonitor insight into the acute stroke market 5
The R&D pipeline for acute stroke is a diverse and bisegmental collection of 34 novel agents at the clinical stages of drug development 5
The R&D landscape in the setting of acute stroke is not dominated by any one company. It is shaped by the need to minimize the commercial risk associated with developing drugs for the acute-care stroke market 6
The acute stroke market is characterized by high unmet market need as well as high unmet clinical need 7
The numerous failures of agents in development for acute stroke management result mainly from clinical trial design issues 8
Datamonitor has identified four candidate drugs that have potential to be launched into the acute stroke market within the near future - the vasoprotectant clazosentan, the thrombolytics desmoteplase and tenecteplase and the defibrinogenating agent Viprinex (ancrod) 8

CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS 12
Pipeline overview 12
Acute stroke: a diversified pipeline 19
Acute stroke: a balanced pipeline 20
The R&D landscape is not dominated by any one company 23

CHAPTER 3 PATIENT POTENTIAL 28
Disease definition and segmentation 28
Symptoms 28
Epidemiology and patient potential 29
Epidemiology methodology 32
US 32
Japan 32
Europe 32
Incidence of pre-hospital mortality in stroke 34
Types of stroke: relative frequency of ischemic stroke over hemorrhagic stroke 35
Ischemic stroke 35
Patient potential: incidence of patients presenting with ischemic stroke 36
Hemorrhagic stroke 36
Intracerebral hemorrhage 37
Subarachnoid hemorrhage 38
Patient potential: incidence of patients presenting with hemorrhagic stroke 40
Transient ischemic attack 40
Marketability considerations: barriers to market entry and uptake 41
Points of consideration: factors influencing market entry and uptake 41
Unmet market needs 43
Physician education: tackling physician competence and attitude 43
Patient education: raising stroke-symptom awareness 49
Infrastructural unmet needs: establishing, maintaining and expanding the network of dedicated stroke units 52
Unmet clinical needs 55
Procoagulation 55
Neuroprotection 56
Revascularization 56

CHAPTER 4 R&D APPROACH 64
Classification of pipeline products 64
Acute stroke pipeline 64
Mechanisms affecting the status of hemostasis 64
Hemostasis and the coagulation cascade 64
Coagulation factors (procoagulants) 68
Thrombolytics 69
The current comparator therapy: alteplase 78
Mechanisms affecting the status of neuronal tissue 95
Neurotrophic drugs 98
Glutamate antagonists 98
GABA agonists 99
Ion channel modulators 99
Free radical scavengers 100
Other mechanisms 101
The current comparator therapies: citicoline and edavarone 102
Mechanisms affecting the status of vasospasm 107
ET-A antagonists 107
The current comparator therapy: nimodipine 109
Clinical trial design 111
Patient population should be assessed for severity and potential responders. 111
The concept of the ischemic penumbra: the potential of diagnosing salvageable tissue 111
Safety endpoints 114
Efficacy endpoints 116
Critique of previous failures 118
Currently available neuroprotectants - failure to make an impact? 118
Neuroprotectants - brief history of development 119
Recent failures 123
Neuroprotectants - potential reasons for failure 136
Possible answers for future clinical trials 143

CHAPTER 5 LATE-STAGE DRUG ANALYSIS & FORECASTS: VASOPROTECTIVE THERAPIES 147
Overview of vasoprotective therapies in late-stage development for acute stroke 147
Pipeline summary 147
Comparator therapy 148
Nimodipine 148
Clazosentan 148
Drug overview 148
Preclinical data 150
Clinical data 154
Phase I 154
Phase II 155
Phase II/III - CONSCIOUS-I 156
Phase III - CONSCIOUS-II 157
Patient potential 158
Marketing factors 159
Satisfaction of unmet needs 160
Forecast to 2017 160
Datamonitor comments 161
Datamonitor drug assessment summary 162

CHAPTER 6 LATE-STAGE DRUG ANALYSIS & FORECASTS: REPERFUSION THERAPIES 164
Overview of reperfusion therapies in late-stage development for acute stroke 164
Pipeline summary 164
Comparator therapy 164
Desmoteplase 165
Drug overview 165
Preclinical data 166
Pharmacokinetics 168
Toxicity 168
Neuroprotection 169
Clinical data 171
Phase II: DIAS 171
Phase II: DEDAS 173
Phase III: DIAS-2 174
Phase III: new trial 177
Patient potential 177
Marketing factors 180
Satisfaction of unmet needs 182
Forecast to 2017 182
Datamonitor comments 183
Datamonitor drug assessment summary 185
Viprinex (ancrod) 187
Drug overview 187
Clinical data 189
Phase II clinical trials 189
Phase III clinical trials 190
Patient potential 194
Marketing factors 196
Satisfaction of unmet needs 197
Forecast to 2017 198
Datamonitor comments 199
Datamonitor drug assessment summary 199
Tenecteplase 201
Drug overview 201
Clinical data 203
Phase I clinical trials 203
Phase II clinical trials 203
Patient potential 204
Marketing factors 205
Satisfaction of unmet needs 205
Forecast to 2017 206
Datamonitor comments 207
Datamonitor drug assessment summary 207

CHAPTER 7 OTHER ACUTE STROKE DRUGS 209
AEOL-10150 209
Drug overview 209
Preclinical data 209
Clinical data 211
AGY-94806 (SA-4503, Msc-1) 212
Drug overview 212
Preclinical data 212
AL-208 214
Drug overview 214
Preclinical data 214
Clinical data 215
Phase I 215
AX-200 215
Drug overview 215
Preclinical data 216
Clinical data 217
Caffeinol 218
Drug overview 218
Preclinical data 218
Clinical data 218
Candesartan 220
Drug overview 220
Clinical data 221
Phase III - ACCESS 221
Phase III - SCAST 224
CellBead Neuro 224
Drug overview 224
DP-b99 225
Drug overview 225
Preclinical data 225
Clinical data 227
Phase I 227
Phase II 228
Enecadin 229
Drug overview 229
Preclinical development 230
HTU-PA 230
Drug overview 230
Preclinical data 231
Clinical data 231
Phase I 231
KN-38-7271 231
Drug overview 231
Preclinical data 232
MC-1 232
Drug overview 232
Preclinical data 233
Clinical data 233
Phase I 233
Phase II 233
MC-1 (IV) 234
Drug overview 234
Microplasmin 234
Drug overview 234
Preclinical data 235
Clinical data 236
Phase I 236
Phase II 236
Neu-2000 236
Drug overview 236
Preclinical data 237
Clinical data 238
Phase I 238
NH-02D 239
Drug overview 239
NTx-265 240
Drug overview 240
Preclinical data 240
Clinical data 240
Phase I 240
Phase II 240
ONO-2506 (proglia, Arocyte) 241
Drug overview 241
Preclinical data 242
Clinical data 243
ONO-2231 243
Drug overview 243
Preclinical data 244
PGX-100 245
Drug overview 245
Preclinical data 245
RVX-208 245
Drug overview 245
Preclinical data 246
Clinical data 247
Phase I 247
S-0139 247
Drug overview 247
Solulin 247
Drug overview 247
Preclinical data 248
Clinical data 248
Phase I 248
SonoLysis+tPA 249
Drug overview 249
S-18986 249
Drug overview 249
Preclinical data 250
SUN-N4057 253
Drug overview 253
Preclinical data 253
Clinical data 254
SUN-N8075 254
Drug overview 254
Preclinical data 255
Clinical data 256
TAT-NR2B9c 256
Drug overview 256
Preclinical data 257
Tissue protective cytokines, Warren/Lundbeck/Shire 257
Drug overview 257
Preclinical data 258
V10153 258
Drug overview 258
Preclinical data 259
Clinical data 260
APPENDIX A 261

Bibliography 261
Epidemiology 261
Other 262
Forecasting methodology 280
Datamonitor drug assessment methodology 280
Report methodology 282

APPENDIX B 283
About Datamonitor 283
About Datamonitor Healthcare 283
Datamonitor Healthcare's therapy area capabilities 284
About the cardiovascular analysis team 285
Disclaimer 286

List of Tables 
Table 1: Products in clinical development for acute stroke, 2008 13
Table 2: Acute stroke pipeline (agents acting on CNS), 2008 16
Table 3: Acute stroke pipeline (agents acting on hemostasis), 2008 18
Table 4: Acute stroke pipeline by mechanism of action, 2008 19
Table 5: Acute stroke pipeline by company, 2008 24
Table 6: Estimated incidence of acute stroke across the seven major markets, 2008-2017 31
Table 7: Overall stroke patients: annual pre-hospital mortality, 2007 34
Table 8: Overall stroke patients: future estimated incidence of pre-hospital mortality in the seven major markets, 2008-2017 (000s) 34
Table 9: Proportion of stroke patients with ischemic stroke versus hemorrhagic stroke, 2007 35
Table 10: Estimated incidence of patients presenting with ischemic stroke in the seven major markets, 2008-2017 (000s) 36
Table 11: Estimated incidence of patients presenting with hemorrhagic stroke in the seven major markets, 2008-2017 (000s) 40
Table 12: Standardized outcome scales frequently used in clinical trials for acute stroke 117
Table 13: Key pipeline vasoprotective therapies in late-stage development for acute stroke, 2008 147
Table 14: Ability of clazosentan to satisfy the unmet needs, 2008 160
Table 15: Clazosentan sales forecast for acute stroke across the seven major markets, 2011-2017 161
Table 16: Key pipeline reperfusion therapies late-stage development for acute stroke, 2008 164
Table 17: DEDAS: safety endpoints 173
Table 18: Ability of desmoteplase to satisfy the unmet needs, 2008 182
Table 19: Desmoteplase sales forecast for acute stroke across the seven major markets, 2012-2017 183
Table 20: Percentage of stroke patients presenting to hospital within 6 hours (cumulative), 2007 194
Table 21: Ability of ancrod to satisfy the unmet needs, 2008 197
Table 22: Viprinex sales forecast for acute stroke across the seven major markets, 2011-2017 198
Table 23: Comparison of alteplase and tenecteplase 202
Table 24: Ability of tenecteplase to satisfy the unmet needs, 2008 205
Table 25: Tenecteplase sales forecast for acute stroke across the seven major markets, 2012-2017 207
Table 26: Datamonitor drug assessment parameters 281

List of Figures 
Figure 1: Acute stroke pipeline, 2008 12
Figure 2: Pipeline maturity: percentage of R&D products in each phase of development, 2008 20
Figure 3: Acute stroke pipeline maturity: percentage of R&D products in each phase of development by class, 2008 22
Figure 4: Acute stroke pipeline maturity: percentage of R&D products in each phase of development by type of company, 2008 26
Figure 5: The targets of developmental antithrombotics in the setting of acute stroke 67
Figure 6: Urokinase mechanism of action 73
Figure 7: Ancrod acts indirectly on the thrombolytic pathways 74
Figure 8: ECASS-III trial: extending the treatment window of tPA 84
Figure 9: Trial design of EPITHET 86
Figure 10: The ischemic cascade 96
Figure 11: Clazosentan sales forecast for acute stroke across the seven major markets, 2010-2017 161
Figure 12: Datamonitor drug assessment summary for clazosentan and nimodipine in acute stroke. 162
Figure 13: Desmoteplase sales forecast for acute stroke across the seven major markets, 2012-2017 183
Figure 14: Datamonitor drug assessment summary of thrombolytic agents (desmoteplase according to the current data) 185
Figure 15: Datamonitor drug assessment summary of thrombolytic agents (desmoteplase according to Phase II data) 186
Figure 16: Viprinex sales forecast for acute stroke across the seven major markets, 2012-2017 198
Figure 17: Datamonitor drug assessment summary of thrombolytic agents (desmoteplase according to Phase II data) 200
Figure 18: Tenecteplase sales forecast for acute stroke across the seven major markets, 2012-2017 206
Figure 19: Datamonitor drug assessment summary of tenecteplase 208
Figure 20: Multimodal efficacy of AX-200 216
Figure 21: Datamonitor drug assessment summary of pipeline molecular targeted therapies in development for hematological malignancies, 2007 282