ABOUT DATAMONITOR HEALTHCARE 2
About the cardiovascular pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the Non-insulin antidiabetics disease market 4
Key metrics 5
Datamonitor pipeline assessment summary 6
Related reports 9
Upcoming report 10
CHAPTER 2 PIPELINE OVERVIEW AND DYNAMICS 12
Non-insulin antidiabetics: a diverse pipeline 19
Huge increase in development candidates as Western World focuses on diabetes 24
Market dominated by Big Pharma and single candidate companies 25
Current leaders - Pipeline management 31
Takeda 31
GlaxoSmithKline 32
Sanofi-Aventis 34
Others 34
CHAPTER 3 NON-INSULIN ANTIDIABETIC OVERVIEW - MARKET POTENTIAL 35
Definition of diabetes 35
Segmentation of diabetes 35
Type 1 diabetes 35
Type 1.5 diabetes 35
Type 2 diabetes 36
Epidemiology of diabetes 38
Current prevalence of type 1 and type 2 diabetes 38
Methodology 40
Epidemic rise in incidence of Type 2 diabetes 41
Etiology 42
Mechanisms of development of diabetes 42
Genetic or acquired causes 42
Risk factors 42
Obesity 43
Type 2 diabetes epidemic hand-in-hand with obesity epidemic 43
Race 44
Type 2 diabetes more prevalent in Hispanics and African Americans than in Caucasians 44
Family history 44
Type 2 diabetes in first-degree relatives is a strong prognostic indicator 44
Advanced age 45
Gender and other factors 45
Gestational diabetes mellitus 46
Unmet need in diabetes 46
Unmet market needs 46
Unmet market need 1: routine screening for the detection of type 2 diabetes mellitus 46
Unmet market need 2: greater patient awareness 49
Unmet market need 3: greater guideline awareness in physicians 50
Unmet clinical needs 58
Unmet clinical need 1: greater efficacy of non-insulin antidiabetics 59
Unmet clinical need 2: durability of therapy 60
Unmet clinical need 3: better tolerability of non-insulin antidiabetics 61
CHAPTER 4 R&D APPROACH 67
Therapy overview in type 1 and type 2 diabetes 67
Type 1 diabetes 67
Type 2 diabetes 69
Comparator therapies 70
Thiazolidinediones 70
Weight gain associated with TZD therapy 71
Actos (pioglitazone) 72
Avandia (rosiglitazone) 73
Sulfonylureas 76
Amaryl (glimepiride) 76
Glucotrol XL (glipizide) 77
Biguanides 77
Glucophage (metformin) 78
Alpha glucosidase inhibitors 78
Basen (voglibose) 79
Other classes 79
Classification of pipeline products 79
Incretin mimetics 79
Glucagon-like peptide-1 (GLP-1) 81
Dipeptidyl peptidase IV (DPP-IV) inhibition 85
PPAR agonists 86
PPAR-? agonists 86
Dual PPAR agonists and PPAR pan agonists 87
Sodium glucose co-transporter 2 (SGLT-2) inhibitors 88
Other classes of agents in development 90
Glucokinase activation 91
Inhibitors of glycogenolysis and gluconeogenesis 92
11ß-Hydroxysteroiddehydrogenase-1 inhibitors 93
Non-insulin antidiabetic pipeline 95
Incretin mimetics 95
DPP-IV inhibitors 95
GLP-1 agonists 103
GLP-1 fusion proteins 107
GPR119 agonist 108
Liver and muscle insulin sensitizers 109
PPAR system 109
Insulin sensitizers 112
Glucose excretion 113
Sodium dependent glucose transport-2 inhibitor 113
Fatty acid digestion and metabolism 117
Bile acid sequestrants 117
Carnitine palmitoyltransferase inhibitor 118
Farnesoid X receptor agonist 119
PPAR-a agonist 119
PPAR-d agonist 120
HM74a agonist 120
Phase I candidates 120
Glucose metabolism 121
Fructose 1,6 bisphosphatase inhibitor 121
Glucagon receptor agonist 122
Glucokinase activators 122
Glucagon receptor antisense oligonucleotide 123
Glycogen phosphorylase inhibitor 123
Autoimmune dysfunction 124
CD-3 monoclonal antibodies 124
Recombinant glutamic acid decarboxylase 126
Heat shock protein modulators 127
Cell adhesion molecule modulator 128
Steroid hormones and the stress response 128
11ß-Hydroxysteroid dehydrogenase type 1 inhibitors 128
Glucocorticoid receptor antagonist 130
Biotech therapies 130
Alginate encapsulated pancreatic islet product 130
Human islet allografts 130
Plasmid gene therapy 131
Cell based therapy 131
Insulin vaccine 131
Autonomic and central nervous system 131
Dopamine D2 agonist 131
Cannabinoid (CB) -1 antagonist 132
Anti-inflammatory agents 134
Vascular cell adhesion molecule -1 (VCAM-1) gene expression inhibitor 134
Cyclooxygenase inhibitor 134
IL-1ß antagonist/TNF-a antagonist/IL-6 antagonist 135
IL-1ß antagonist 136
NF-?B pathway inhibitor 136
Insulin release stimulators 137
ATP dependent potassium channel inhibitor 137
Unknown mechanisms 138
Insulin signaling modulators 138
Protein tyrosine phosphatase -1B (PTP-1B) antisense oligonucleotide 138
Adenosine monophosphate (AMP) protein kinase modulator 138
Undisclosed insulin modulator 139
Combination therapies 139
PPAR-a agonist based therapies 139
PPAR-? agonist and statin 140
GABA agonist and appetite suppressant 140
Gastrin agonist based therapies 141
Muscarinic acetyl choline receptor agonist and a mucolytic 142
Other therapeutic modes of action 143
Angiotensin converting enzyme inhibitors 143
NAD dependent deacetylase sirtuin-1 stimulator 143
Amyloid protein deposition inhibitor 144
Unknown mechanisms 144
Clinical trial issues in diabetes 145
Efficacy 146
Control of average blood glucose levels 146
Insulin 146
Blood markers 147
Weight loss 147
Safety and side effects 148
Weight gain 148
Cardiovascular endpoints 148
Comparators: add-on versus replacement therapy 149
Future trends 149
FDA guidance February 2008 149
Safety 150
Regulatory divergence - FDA versus EMEA 151
Combinations 153
Clinical endpoint selection 155
CHAPTER 5 NON-INSULIN ANTIDIABETIC LATE-STAGE DRUG ANALYSIS AND FORECASTS 156
Overview for non-insulin antidiabetics 156
Pipeline summary 156
Comparative forecasts 158
Definition of current comparator therapy 165
DPP-IV and SGLT-2 inhibitors 165
Saxagliptin 165
Drug overview 166
Forecasts to 2017 167
Datamonitor drug assessment summary 170
Marketing factors 171
Patient potential 172
Satisfaction of unmet needs 173
Clinical trial data 173
Intellectual property status 175
Alogliptin 175
Drug overview 175
Forecasts to 2017 176
Datamonitor drug assessment summary 179
Marketing factors 180
Patient potential 182
Satisfaction of unmet needs 183
Clinical trial data 183
Intellectual property status 185
BI-1356 185
Drug overview 185
Forecasts to 2017 186
Datamonitor drug assessment summary 189
Marketing factors 190
Patient potential 191
Satisfaction of unmet needs 191
Clinical trial data 191
Intellectual property status 194
Dapagliflozin 194
Drug overview 194
Forecasts to 2017 195
Datamonitor drug assessment summary 198
Marketing factors 199
Patient potential 200
Satisfaction of unmet needs 201
Clinical trial data 201
Intellectual property status 204
GLP-1 agonists 204
Byetta LAR 204
Drug overview 204
Forecasts to 2017 205
Datamonitor drug assessment summary 208
Marketing factors 209
Patient potential 212
Satisfaction of unmet needs 212
Clinical trial data 212
Intellectual property status 214
Liraglutide 214
Drug overview 214
Forecasts to 2017 216
Datamonitor drug assessment summary 218
Marketing factors 219
Patient potential 221
Satisfaction of unmet needs 221
Clinical trial data 221
Intellectual property status 224
PPAR modulators 224
Balaglitazone 225
Drug overview 225
Forecasts to 2017 226
Datamonitor drug assessment summary 229
Marketing factors 230
Patient potential 230
Satisfaction of unmet needs 231
Clinical trial data 231
Intellectual property status 233
MBX-102 233
Drug overview 233
Forecasts to 2017 234
Datamonitor drug assessment summary 237
Marketing factors 238
Patient potential 239
Satisfaction of unmet needs 239
Clinical trial data 239
Intellectual property status 242
Rivoglitazone 242
Drug overview 242
Forecasts to 2017 243
Datamonitor drug assessment summary 246
Marketing factors 247
Patient potential 248
Satisfaction of unmet needs 248
Clinical trial data 248
Intellectual property status 250
Autoimmune antibody 250
Teplizumab 250
Drug overview 250
Forecasts to 2017 251
Datamonitor drug assessment summary 254
Marketing factors 255
Patient potential 255
Satisfaction of unmet needs 256
Clinical trial data 256
Intellectual property status 258
Other late-stage candidates 258
Actoplus Met XR 258
Avandamet XR 258
Colesevelam 258
Completed trials 259
Ongoing trials 259
Summary 260
Cycloset 260
Completed trials 260
Summary 260
Diamyd 261
Completed trials 261
Ongoing trials 261
Summary 261
DiaPep277 262
Completed trials 262
Ongoing trials 262
Summary 262
Metformin + fenofibrate 263
Completed trials 263
Ongoing trials 263
Summary 263
Mitiglinide 264
Completed trials 264
On going trials 264
Summary 264
Ramipril 265
Ongoing trials 265
Summary 265
Rimonabant 265
Completed trials 266
On going trials 266
Summary 267
Rosiglitazone + simvastatin 268
Completed trials 268
Summary 269
Succinobucol 269
Completed trial 269
Ongoing trial 269
Summary 269
Late-stage development compounds recently discontinued 269
BIBLIOGRAPHY 272
Epidemiology sources 272
General and clinical trial data 273
APPENDIX 278
About Datamonitor 278
About Datamonitor Healthcare 278
Datamonitor Healthcare's therapy area capabilities 279
About the Disease analysis team 280
Disclaimer 281
List of Tables
Table 1: Key parameters of the diabetes market for the seven major markets, 2007 and 2017 5
Table 2: Forecast key pipeline products in diabetes, 2009- 2017 ($m) 6
Table 3: R&D pipeline in non-insulin antidiabetics, 2008 13
Table 4: Non-insulin antidiabetic pipeline by mechanism of action, 2007 20
Table 5: Big Pharma dominates the major mechanisms of action in the non insulin diabetes pipeline, 2008 28
Table 6: Big Pharma also dominates key early phase candidates in the non insulin diabetes pipeline, 2008 30
Table 7: Big Pharma's non-insulin antidiabetic pipeline, 2008 31
Table 8: Prevalence of diabetes mellitus in the seven major markets (millions), 2000 and 2030 38
Table 9: Prevalence rate of type 1 and type 2 diabetes in the seven major markets (%), 2007-2017 39
Table 10: Estimated absolute prevalence of diabetes in the seven major markets (millions), 2007-2017 41
Table 11: Safety of pioglitazone 64
Table 12: Weight gain associated with Actos (kg) 71
Table 13: Weight gain associated with Avandia (kg) 72
Table 14: Characteristics of GIP and GLP-1 81
Table 15: Key products in late-stage R&D pipeline for non-insulin antidiabetics, 2008 157
Table 16: Forecast key pipeline products in Diabetes in 2017 ($m) 165
Table 17: Impacting factors on the revenues of saxagliptin, 2008-2017 170
Table 18: Ongoing Phase III clinical trials of saxagliptin, 2008 174
Table 19: Completed Phase III clinical trials of saxagliptin, 2008 174
Table 20: Impacting factors on the revenues of alogliptin, 2008-2017 179
Table 21: Ongoing Phase III clinical trials of alogliptin, 2008 184
Table 22: Impacting factors on the revenues of BI-1356, 2008-2017 189
Table 23: Ongoing Phase III clinical trials of BI-1356, 2008 193
Table 24: Impacting factors on the revenues of dapagliflozin, 2008-2017 198
Table 25: Ongoing Phase III clinical trials of dapagliflozin 203
Table 26: Impacting factors on the revenues of Byetta LAR, 2008-17 208
Table 27: Ongoing Phase III clinical trials of Byetta LAR, 2008 213
Table 28: Impacting factors on the revenues of liraglutide, 2008-17 218
Table 29: Completed Phase III clinical trials of liraglutide, 2008 222
Table 30: Ongoing Phase III clinical trials of liraglutide, 2008 222
Table 31: Impacting factors on the revenues of balaglitazone, 2008-2017 229
Table 32: Ongoing Phase III clinical trial of balaglitazone, 2008 232
Table 33: Impacting factors on the revenues of MBX-102, 2008-2017 237
Table 34: Ongoing Phase III clinical trial of MBX-102, 2008 241
Table 35: Impacting factors on the revenues of rivoglitazone, 2008-2017 246
Table 36: On going Phase III clinical trial of rivoglitazone, 2008 249
Table 37: Impacting factors on the revenues of teplizumab, 2008-2017 254
Table 38: Ongoing clinical trials of teplizumab, 2008 257
Table 39: Terminated non-insulin antidiabetes programs, 2008 271
List of Figures
Figure 1: Datamonitor's competitive positioning analysis of oral non-insulin antidiabetics, 2008 7
Figure 2: Datamonitor's competitive positioning analysis of GLP-1 agonist non-insulin antidiabetics, 2008 8
Figure 3: Datamonitor's competitive positioning analysis of autoimmune antibody non-insulin antidiabetic, 2008 9
Figure 4: Non-insulin antidiabetic candidates in development by mechanism of action, 2008 23
Figure 5: Breakdown of PPAR mode of action in diabetes, 2008 24
Figure 6: Distribution of developmental candidates in the diabetes pipeline by phase, 2008 25
Figure 7: Candidate development in the diabetes pipeline split by company, 2008 26
Figure 8: Major mechanisms of action in the diabetes pipeline split by company, 2008 29
Figure 9: Comparison of glucose testing diagnostic criteria for prediabetes and diabetes 37
Figure 10: History of GLP-1, 1930-2006 80
Figure 11: Mechanism of action of GLP-1 82
Figure 12: GLP-1 effects on ß-cells 83
Figure 13: Functional pancreatic effects of GLP-1 84
Figure 14: Mechanism of action of GLP-1 agonists 85
Figure 15: Mechanism of action of DPP-IV inhibitors 86
Figure 16: Combined theoretical benefits of PPAR pan agonists 88
Figure 17: Control of insulin secretion in pancreatic ß-cells 92
Figure 18: Glucose metabolism in hepatocytes 93
Figure 19: Datamonitor's competitive positioning analysis of oral non-insulin antidiabetics, 2008 158
Figure 20: Datamonitor's competitive positioning analysis of GLP-1 agonist non-insulin antidiabetics, 2008 159
Figure 21: Datamonitor's competitive positioning analysis of autoimmune antibody non-insulin antidiabetic, 2008 160
Figure 22: Datamonitor forecasts for DPP-IV and SGLT-2 inhibitors across the seven major markets, 2008-2017 161
Figure 23: Datamonitor forecasts for GLP-1 agonists across the seven major markets, 2008-2017 162
Figure 24: Datamonitor forecasts for PPAR modulators across the seven major markets, 2008-2017 163
Figure 25: Datamonitor forecasts for autoimmune antibodies across the seven major markets, 2008-2017 164
Figure 26: SWOT analysis of Saxagliptin 167
Figure 27: Datamonitor forecast for Saxagliptin in type 2 diabetes across the seven major markets, 2009-2017 168
Figure 28: Datamonitor forecast for saxagliptin in type 2 diabetes in the US, Japan and 5EU, 2009-2017 169
Figure 29: Datamonitor's competitive positioning analysis of saxagliptin, 2008 171
Figure 30: SWOT analysis of alogliptin 176
Figure 31: Datamonitor forecast for alogliptin in type 2 diabetes across the seven major markets, 2009-2017 177
Figure 32: Datamonitor forecast for alogliptin in type 2 diabetes in the US, Japan and 5EU, 2009-2017 178
Figure 33: Datamonitor's competitive positioning analysis of Alogliptin, 2008 180
Figure 34: SWOT analysis of BI-1356 186
Figure 35: Datamonitor forecast for BI-1356 in type 2 diabetes across the seven major markets, 2012-2017 187
Figure 36: Datamonitor forecast for BI-1356 in type 2 diabetes in the US, Japan and 5EU, 2012-2017 188
Figure 37: Datamonitor's competitive positioning analysis of BI-1356, 2008 190
Figure 38: SWOT analysis of dapagliflozin 195
Figure 39: Datamonitor forecast for dapagliflozin in type 2 diabetes across the seven major markets, 2011-2017 196
Figure 40: Datamonitor forecast for dapagliflozin in type 2 diabetes in the US, Japan and 5EU, 2011-2017 197
Figure 41: Datamonitor's competitive positioning analysis of dapagliflozin, 2008 199
Figure 42: SWOT analysis of Byetta LAR 205
Figure 43: Datamonitor forecast for Byetta LAR in type 2 diabetes across the seven major markets, 2009-2017 206
Figure 44: Datamonitor forecast for Byetta LAR in type 2 diabetes in the US, Japan and 5EU, 2009-2017 207
Figure 45: Datamonitor's competitive positioning analysis of Byetta LAR, 2008 209
Figure 46: SWOT analysis of liraglutide 215
Figure 47: Datamonitor forecast for liraglutide in type 2 diabetes across the seven major markets, 2008-2017 216
Figure 48: Datamonitor forecast for liraglutide in type 2 diabetes in the US, Japan and 5EU, 2008-2017 217
Figure 49: Datamonitor's competitive positioning analysis of liraglutide, 2008 219
Figure 50: SWOT analysis of balaglitazone 226
Figure 51: Datamonitor forecast for balaglitazone in type 2 diabetes across the seven major markets, 2011-2017 227
Figure 52: Datamonitor forecast for balaglitazone in type 2 diabetes in the US, Japan and 5EU, 2011-2017 228
Figure 53: Datamonitor's competitive positioning analysis of balaglitazone, 2008 230
Figure 54: SWOT analysis of MBX-102 234
Figure 55: Datamonitor forecast for MBX-102 in type 2 diabetes across the seven major markets, 2012-2017 235
Figure 56: Datamonitor forecast for MBX-102 in type 2 diabetes in the US, Japan and 5EU, 2012-2017 236
Figure 57: Datamonitor's competitive positioning analysis of MBX-102, 2008 238
Figure 58: SWOT analysis of rivoglitazone, 2008 243
Figure 59: Datamonitor forecast for rivoglitazone in type 2 diabetes across the seven major markets, 2011-2017 244
Figure 60: Datamonitor forecast for rivoglitazone in type 2 diabetes in the US, Japan and 5EU, 2011-2017 245
Figure 61: Datamonitor's competitive positioning analysis of rivoglitazone, 2008 247
Figure 62: SWOT analysis of teplizumab, 2008 251
Figure 63: Datamonitor forecast for teplizumab in type 1 diabetes across the seven major markets, 2012-2017 252
Figure 64: Datamonitor forecast for teplizumab in type 1 diabetes in the US, Japan and 5EU, 2012-2017 253
Figure 65: Datamonitor's competitive positioning analysis of teplizumab, 2008 255
