Diabetes Therapeutics in the European Marketplace: Evolving Business Opportunities and Threats - Market Research Reports

Contents:

Diabetes Therapeutics in the European Marketplace… Evolving Business Opportunities and Threats

EXECUTIVE SUMMARY................................................................................................................................... I
SECTION 1 INTRODUCTION TO DIABETES ............................................................................................... 1
1.1 SCOPE AND OBJECTIVES OF RESEARCH INVESTIGATION.....................................................................1
1.2 METHODOLOGY OF INVESTIGATION...............................................................................................................1
1.3 LIMITATIONS OF INVESTIGATION......................................................................................................................2
SECTION 2 DESCRIPTION AND ANALYSIS OF THE CLINICAL PROBLEMS AND THE FUTURE
ROLE OF DIABETIC MANAGEMENT.................................................................................5
2.1 THE PROBLEM OF DIABETES..................................................................................................................................5
2.1.1 Incidence and Prevalence.......................................................................................................................................5
2.1.2 Epidemiology ...........................................................................................................................................................6
2.1.3 Etiology .....................................................................................................................................................................7
2.1.4 Role and Regulation of Glucose.........................................................................................................................11
2.2 TYPE I DIABETES - INSULIN DEPENDENT DIABETES MELLITUS (IDDM) .....................................12
2.2.1 Definition................................................................................................................................................................12
2.2.2 Epidemiology .........................................................................................................................................................12
2.2.3 Etiology ...................................................................................................................................................................13
2.2.4 Pathophysiology.....................................................................................................................................................13
2.2.5 Diagnosis of Type I Diabetes..............................................................................................................................17
2.3 TYPE II DIABETES – NON-INSULIN DEPENDENT DIABETES MELLITUS (NIDDM) ...................19
2.3.1 Definition................................................................................................................................................................19
2.3.2 Epidemiology .........................................................................................................................................................20
2.3.3 Etiology ...................................................................................................................................................................20
2.3.4 Pathophysiology.....................................................................................................................................................23
2.3.5 Complications ........................................................................................................................................................27
2.3.6 Diagnosis of Type II Diabetes............................................................................................................................29
2.3.7 Treatment Goals....................................................................................................................................................29
2.4 DIABETIC RETINOPATHY.......................................................................................................................................36
2.4.1 Definition................................................................................................................................................................36
2.4.2 Angiogenesis...........................................................................................................................................................37
2.4.3 Neovascular Diseases of the Eye........................................................................................................................39
2.4.4 Epidemiology .........................................................................................................................................................40
2.4.5 Nonproliferative Diabetic Retinopathy .............................................................................................................40
2.4.6 Proliferative Diabetic Retinopathy .....................................................................................................................41
2.4.7 Etiology and Pathophysiology ............................................................................................................................42
2.4.8 Diagnosis.................................................................................................................................................................43
2.4.9 Treatment................................................................................................................................................................43
2.5 DIABETIC NEUROPATHY ........................................................................................................................................45
2.5.1 Definition................................................................................................................................................................45
2.5.2 Types of Neuropathy............................................................................................................................................46
2.5.3 Epidemiology .........................................................................................................................................................47
2.5.4 Etiology ...................................................................................................................................................................47
2.5.5 Pathophysiology.....................................................................................................................................................48
2.5.6 Diagnosis.................................................................................................................................................................48
2.5.7 Conventional Treatment ......................................................................................................................................49
2.6 DIABETIC NEPHROPATHY......................................................................................................................................50
2.6.1 Definition................................................................................................................................................................51
2.6.2 Genetics of Nephropathy ....................................................................................................................................52
2.6.3 Epidemiology .........................................................................................................................................................52
2.6.4 Etiology ...................................................................................................................................................................53

2.6.5 Pathophysiology.....................................................................................................................................................53
2.6.6 Modification of Cardiovascular Risk..................................................................................................................55
2.6.7 Diagnosis.................................................................................................................................................................55
2.6.8 Conventional Treatment ......................................................................................................................................55
2.7 TYPE I DIABETES (IDDM): THE DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT)
56
2.7.1 Earlier Trials Involving Insulin Therapy ...........................................................................................................57
2.7.2 Diabetes Control and Complications Trial Design .........................................................................................58
2.7.3 Diabetes Control and Complications Trial Results.........................................................................................59
2.7.4 Making Use of DCCT Data.................................................................................................................................62
2.7.5 Costs of Tight Glycemic Control in IDDM.....................................................................................................63
2.8 TYPE II DIABETES (NIDDM) TRIALS...................................................................................................................63
2.8.1 Current Recommendations for Treatment of NIDDM.................................................................................63
2.8.2 Costs of Therapy for NIDDM...........................................................................................................................63
2.8.3 Can Tight Control be Implemented in the Real World?................................................................................64
2.8.4 PORT Trials ...........................................................................................................................................................64
2.8.5 The United Kingdom Prospective Diabetes Study (UKPDS) ......................................................................66
SECTION 3 PRODUCT TECHNOLOGIES IMPACTING DIABETES THERAPEUTICS ......................... 71
3.1 INTRODUCTION TO PRODUCT TECHNOLOGIES IMPACTING DIABETES THERAPEUTICS .71
3.2 ANGIOGENISIS INHIBITORS..................................................................................................................................72
3.3 ANTIHYPERTENSIVE AGENTS..............................................................................................................................73
3.3.1 ACE inhibitors.......................................................................................................................................................73
3.3.2 Angiotensin II Antagonists..................................................................................................................................74
3.4 CELL THERAPY .............................................................................................................................................................75
3.5 ENZYME INHIBITORS................................................................................................................................................77
3.5.1 Pancreatic Lipase ...................................................................................................................................................77
3.5.2 Hormone-Sensitive Lipase...................................................................................................................................78
3.5.3 Alpha Glucosidase Inhibitors..............................................................................................................................78
3.5.4 Glycogen Phosphorylase......................................................................................................................................79
3.5.5 CPT-1 (carnitine palmytoyl transferase I) .........................................................................................................79
3.6 GROWTH FACTORS.....................................................................................................................................................80
3.6.1 Insulin-like Growth Factor (IGF-1)...................................................................................................................80
3.6.2 Neurotrophic Growth Factors............................................................................................................................81
3.7 GLYCATION ALTERING AGENTS........................................................................................................................82
3.7.1 Aldose Reductase Inhibitors (ARI)....................................................................................................................83
3.7.2 Advanced Glycation End Product (AGE) Inhibitors.....................................................................................83
3.8 HORMONES ....................................................................................................................................................................85
3.8.1 Leptin.......................................................................................................................................................................85
3.8.2 Amylin .....................................................................................................................................................................85
3.8.3 Steroid Hormones .................................................................................................................................................86
3.8.4 Glucagon.................................................................................................................................................................86
3.8.5 Glucagon Antagonists ..........................................................................................................................................86
3.9 IMMUNOTHERAPY......................................................................................................................................................87
3.9.1 Immunomodulators ..............................................................................................................................................87
3.9.2 Adhesion Molecules..............................................................................................................................................88
3.9.3 Vaccines ..................................................................................................................................................................88
3.10 INSULIN AND INSULIN ANALOGS......................................................................................................................89
3.10.1 Insulin Analogues and Agonists .........................................................................................................................89
3.10.2 Leading Development Programs........................................................................................................................90
3.11 INSULIN DELIVERY SYSTEMS ...............................................................................................................................91
3.11.1 Inhaled Insulin .......................................................................................................................................................91
3.11.2 Oral Insulin.............................................................................................................................................................93
3.12 INSULIN SECRETAGOGUES....................................................................................................................................93
3.12.1 Sulfonylureas ..........................................................................................................................................................94
3.12.2 Insulinotropic Agents ...........................................................................................................................................94
3.12.3 GLP-1......................................................................................................................................................................94

3.13 INSULIN SENSITIZERS...............................................................................................................................................96
3.13.1 Biguanides...............................................................................................................................................................96
3.13.2 Glucose Uptake Mediators ..................................................................................................................................97
3.13.3 Oxadiazole ..............................................................................................................................................................98
3.14 MOLECULAR...................................................................................................................................................................98
3.14.1 Gene therapy ..........................................................................................................................................................98
3.14.2 Antisense Technology ....................................................................................................................................... 100
3.14.3 Genomics............................................................................................................................................................. 100
3.15 NEUROTRANSMITTER MODULATORS........................................................................................................... 101
3.15.1 Adrenergic Agents.............................................................................................................................................. 101
3.15.2 Dopamine ............................................................................................................................................................ 102
3.16 SIGNAL TRANSDUCTION MODULATORS..................................................................................................... 103
3.16.1 Protein Kinase C (PKC) Inhibitors................................................................................................................. 103
3.16.2 Phosphodiesterase (PDE) Inhibitors.............................................................................................................. 104
3.16.3 Insulin Signaling, Tyrosine kinase/phosphatase........................................................................................... 105
3.17 THIAZOLIDINES, PPAR AGONISTS AND RXR AGONISTS..................................................................... 105
3.17.1 Thiazolidines ....................................................................................................................................................... 107
3.17.2 PPAR Agonists ................................................................................................................................................... 107
3.17.3 RXR Agonists ..................................................................................................................................................... 108
3.18 OTHER TECHNOLOGIES ...................................................................................................................................... 108
SECTION 4 MARKET ANALYSIS AND FORECAST OF THE DIABETES MARKET ............................. 109
4.1 DIABETES CATEGORY SUMMARY ANALYSIS AND FORECAST ......................................................... 109
4.1.1 Introduction to the analysis .............................................................................................................................. 109
4.1.2 Product Technology Analysis and Forecast .................................................................................................. 111
4.1.3 Market Sales Analysis and Forecast................................................................................................................. 113
4.2 DIABETES TYPE I...................................................................................................................................................... 116
4.2.1 Introduction to the Analysis............................................................................................................................. 116
4.2.2 Recent Events in Diabetes Type I................................................................................................................... 117
4.2.3 Product Technology Analysis and Forecast .................................................................................................. 120
4.2.4 Market Sales Analysis and Forecast................................................................................................................. 124
4.3 DIABETES TYPE II .................................................................................................................................................... 129
4.3.1 Introduction to the Analysis............................................................................................................................. 129
4.3.2 Recent Events in Diabetes Type II ................................................................................................................. 131
4.3.3 Product Technology Analysis and Forecast .................................................................................................. 138
4.3.4 Market Sales Analysis and Forecast................................................................................................................. 146
4.4 DIABETIC COMPLICATIONS................................................................................................................................ 152
4.4.1 Introduction to the Analysis............................................................................................................................. 152
4.4.2 Diabetic Neuropathy ......................................................................................................................................... 154
4.4.3 Diabetic Nephropathy ....................................................................................................................................... 154
4.4.4 Diabetic retinopathy........................................................................................................................................... 154
4.4.5 Recent Events in Diabetes Complication ...................................................................................................... 155
4.4.6 Product Technology Analysis and Forecast .................................................................................................. 156
4.4.7 Market Sales Analysis and Forecast................................................................................................................. 163
SECTION 5 ANALYSIS OF THE DIABETES MARKET COMPETITIVE ENVIRONMENT ................. 169
5.1 INTRODUCTION TO COMPETITIVE ENVIRONMENT AND ANALYSIS PROCESS..................... 169
5.2 TECHNOLOGY EXPERTISE DETERMINES SUCCESS............................................................................... 172
5.3 MARKETING SKILL AND STRENGTH DETERMINES SUCCESS .......................................................... 173
5.4 PORTFOLIO COMMITMENT DETERMINES SUCCESS.............................................................................. 174
5.5 ABILITY TO FUND DIABETES DEVELOPMENT PROGRAMS DETERMINES SUCCESS............ 175
5.6 SUMMARY ANALYSIS OF “DETERMINANTS OF SUCCESS” .................................................................. 176
SECTION 6 PROFILES OF MAJOR PHARMACEUTICAL MANUFACTURERS WITH INTEREST IN
THE MARKETPLACE FOR DIABETICS THERAPEUTICS ........................................... 179
6.1 ABBOTT LABORATORIES...................................................................................................................................... 179
6.2 AMERICAN HOME PRODUCTS ........................................................................................................................... 181

6.3 ASTA MEDICA............................................................................................................................................................. 183
6.4 ASTRAZENECA........................................................................................................................................................... 184
6.5 AVENTIS ........................................................................................................................................................................ 186
6.6 BAYER............................................................................................................................................................................. 189
6.7 BRISTOL-MYERS SQUIBB....................................................................................................................................... 191
6.8 ELI LILLY....................................................................................................................................................................... 193
6.9 GLAXOSMITHKLINE............................................................................................................................................... 196
6.10 MSD (MERCK & CO).................................................................................................................................................. 199
6.11 MERCK KGAA............................................................................................................................................................. 201
6.12 NOVARTIS..................................................................................................................................................................... 203
6.13 NOVO NORDISK........................................................................................................................................................ 205
6.14 PFIZER............................................................................................................................................................................ 209
6.15 PHARMACIA................................................................................................................................................................. 211
6.16 ROCHE............................................................................................................................................................................ 212
6.17 SANOFI-SYNTHÉLABO........................................................................................................................................... 214
6.18 SERVIER......................................................................................................................................................................... 216
SECTION 7 PROFILES OF BIOTECHNOLOGY COMPANIES WITH INTEREST IN THE
MARKETPLACE FOR DIABETICS THERAPEUTICS..................................................... 217
7.1 ALEXION....................................................................................................................................................................... 217
7.2 ALTEON......................................................................................................................................................................... 217
7.3 AMYLIN.......................................................................................................................................................................... 219
7.4 ANDRX ........................................................................................................................................................................... 220
7.5 ARADIGM...................................................................................................................................................................... 221
7.6 AUTOIMMUNE............................................................................................................................................................ 222
7.7 CELL THERAPEUTICS ............................................................................................................................................. 223
7.8 CYTOTHERAPEUTICS ............................................................................................................................................. 224
7.9 DURA PHARMACEUCTICALS............................................................................................................................... 224
7.10 ENTREMED.................................................................................................................................................................. 225
7.11 EXOCELL....................................................................................................................................................................... 226
7.12 FUJISAWA...................................................................................................................................................................... 226
7.13 GENENTECH............................................................................................................................................................... 227
7.14 GENEREX ..................................................................................................................................................................... 228
7.15 INHALE THERAPEUTICS ....................................................................................................................................... 229
7.16 INSMED.......................................................................................................................................................................... 230
7.17 LIGAND.......................................................................................................................................................................... 231
7.18 METABOLEX................................................................................................................................................................ 232
7.19 POWDERJECT.............................................................................................................................................................. 234
7.20 ONTOGENY................................................................................................................................................................. 234
7.21 PROVALIS (FORMERLY CORTECS).................................................................................................................... 235
7.22 SENSUS ........................................................................................................................................................................... 236
7.23 TAKEDA......................................................................................................................................................................... 236

Figure 4.1 Diabetes Type I Technology Forecast Map.................................................................. 122
Figure 4.2 Diabetes Type II Technology Forecast Map ................................................................. 142
Figure 4.3 Diabetes ComplicationsTechnology Forecast Map ...................................................... 160

Table ES- 1 Diabetes Market Forecast by Demographics...................................................................III
Table ES- 2 Diabetes Market Forecast by Indication........................................................................... IV
Table ES- 3 Diabetes Programs in Development by Indication and Technology........................... VI
Table ES- 4 Diabetes Programs in Development by Indication and Phase of Development ..... VII
Table ES- 5 Diabetes Therapeutics Market Forecast by Technology.............................................. VII
Table ES- 6 Diabetes Therapeutics Market Forecast by Company....................................................IX
Table ES- 7 Selected Companies Diabetes Rating Scale........................................................................X

Table 2.1 Secondary Causes of Diabetes ........................................................................................... 10
Table 2.2 Drugs That Can Induce Hyperglycemia........................................................................... 11
Table 4.1 Diabetes Forecast Sales by Indication............................................................................. 111
Table 4.2 Diabetes Product Development Number of Programs by Indication by
Technology.......................................................................................................................... 112
Table 4.3 Diabetes Development Programs – Number of Programs in Development by
Indication and Phase of Development ........................................................................... 112
Table 4.4 Diabetes Market Forecast Sales by Technology............................................................ 114
Table 4.5 Diabetes Market Forecast by Company ......................................................................... 115
Table 4.6 Diabetes Type I Demographic Trends ........................................................................... 116
Table 4.7 Diabetes Type I Historic European Sales by Manufacturer and Brand – 1996 to
1999 ($ Millions)................................................................................................................. 117
Table 4.8 Number of Programs in Development by Technology and Phase of
Development – Diabetes Type I ..................................................................................... 121
Table 4.9 Number of Programs in Development by Company and Phase of Development
– Diabetes Type I............................................................................................................... 121
Table 4.10 Number of Development Programs by Company and Technology – Diabetes
Type I................................................................................................................................... 123
Table 4.11 Diabetes Type I Market Forecast Sales by Technology .............................................. 124
Table 4.12 Diabetes Type I Market Forecast Sales by Company................................................... 125
Table 4.13 Diabetes Type I Launched and Development Programs ........................................... 126
Table 4.14 Diabetes Type II Market Demographics........................................................................ 130
Table 4.15 Diabetes Type II Historic Sales by Manufacturer and Brand .................................... 131
Table 4.16 Number of Programs in Development by Technology and Phase of
Development ...................................................................................................................... 139
Table 4.17 Number of Programs in Development by Company and Technology .................... 140
Table 4.18 Number of Programs in Development by Company and Phase of Development.. 141
Table 4.19 Diabetes Type II Market Forecast Sales by Technology.............................................. 143
Table 4.20 Diabetes Type II Market Forecast by Company ........................................................... 147
Table 4.21 Diabetes Type II Launched and Development Programs........................................... 148
Table 4.22 Diabetic Complications Population Forecast ................................................................ 152
Table 4.23 Number of Programs in Development by Technology and Phase of
Development – Diabetic Complications ........................................................................ 157
Table 4.24 Number of Programs in Development by Company and Phase of Development
– Diabetic Complications ................................................................................................. 158

Table 4.25 Number of Programs in Development by Company and Technology – Diabetic
Complications..................................................................................................................... 159
Table 4.26 Diabetic Nephropathy Historic Sales by Manufacturer and Brand............................ 160
Table 4.27 Diabetic Nephropathy Market Forecast Sales by Technology.................................... 161
Table 4.28 Diabetic Neuropathy Market Forecast Sales by Technology ...................................... 162
Table 4.29 Diabetic Retinopathy Market Forecast Sales by Technology ...................................... 163
Table 4.30 Market Forecast Sales by Company – Diabetic Nephropathy .................................... 164
Table 4.31 Market Forecast Sales by Company – Diabetic Neuropathy....................................... 164
Table 4.32 Market Forecast Sales by Company – Diabetic Retinopathy ...................................... 165
Table 4.33 Diabetes Complications Launched and Development Programs............................... 165
Table 5.1 Diabetes Pharmaceutical Companies Rank by European 0Sales and by Market
Segment – 1999 Factory Sales.......................................................................................... 171
Table 5.2 Diabetes Programs in Development by Major Pharmaceutical Company by
Indication ............................................................................................................................ 171
Table 5.3 Diabetes Programs in Development by Major Pharmaceutical Company by
Phase of Development...................................................................................................... 172
Table 5.4 Major Pharmaceutical Companies’ Partnered Diabetes Programs in Development 172
Table 5.5 Selected Pharmaceutical Companies – Diabetes Technology Expertise ................... 173
Table 5.6 Selected Pharmaceutical Companies – Diabetes Marketing Skill and Strength........ 174
Table 5.7 Selected Pharmaceutical Companies – Diabetes Portfolio Commitment ................. 175
Table 5.8 Selected Pharmaceutical Companies – Ability to Fund Diabetes Programs............. 176
Table 5.9 Selected Pharmaceutical Companies – Diabetes Summary Ratings ........................... 177
Table 5.10 Selected Pharmaceutical Companies – Diabetes Rating Scale..................................... 178
Table 6.1 Abbott Diabetes Programs in Development ................................................................. 180
Table 6.2 American Home Products Diabetes Programs in Development................................ 183
Table 6.3 Asta Medica Diabetes Programs in Development ........................................................ 184
Table 6.4 AstraZeneca Diabetes Programs in Development........................................................ 185
Table 6.5 Aventis Diabetes Programs in Development ................................................................ 188
Table 6.6 Bayer Diabetes Programs in Development.................................................................... 190
Table 6.7 Bristol-Myers Squibb Diabetes Programs in Development......................................... 192
Table 6.8 Eli Lilly Diabetes Programs in Development................................................................ 195
Table 6.9 Glaxo Wellcome’s Diabetes Programs in Development.............................................. 197
Table 6.10 MSD (Merck & Co) Diabetes Programs in Development........................................... 200
Table 6.11 Merck KGaA Diabetes Programs in Development...................................................... 202
Table 6.12 Novartis Diabetes Programs in Development .............................................................. 204
Table 6.13 Novo Nordisk Diabetes Programs in Development.................................................... 207
Table 6.14 Pfizer Diabetes Programs in Development ................................................................... 210
Table 6.15 Pharmacia Diabetes Programs in Development ........................................................... 212
Table 6.16 Roche Diabetes Programs in Development................................................................... 214
Table 6.17 Sanofi-Synthélabo Diabetes Programs in Development.............................................. 215
Table 6.18 Servier Diabetes Programs in Development................................................................. 216
Table 7.1 Alexion Diabetes Programs in Development ................................................................ 217
Table 7.2 Alteon Diabetes Programs in Development.................................................................. 218
Table 7.3 Amylin Diabetes Programs in Development................................................................. 220
Table 7.4 Andrx Diabetes Programs in Development................................................................... 221
Table 7.5 Aradigm Diabetes Programs in Development............................................................... 222
Table 7.6 Autoimmune Diabetes Programs in Development ...................................................... 223
Table 7.7 Cell Therapeutics Diabetes Programs in Development ............................................... 223

Table 7.8 CytoTherapeutics Diabetes Programs in Development.............................................. 224
Table 7.9 Dura Diabetes Programs in Development..................................................................... 225
Table 7.10 EntreMed Diabetes Programs in Development............................................................ 225
Table 7.11 Exocell Diabetes Programs in Development................................................................. 226
Table 7.12 Fujisawa Diabetes Programs in Development............................................................... 227
Table 7.13 Genentech Diabetes Programs in Development .......................................................... 228
Table 7.14 Generex Diabetes Programs in Development............................................................... 229
Table 7.15 Inhale Therapeutics Diabetes Programs in Development........................................... 230
Table 7.16 Insmed Diabetes Programs in Development................................................................. 231
Table 7.17 Ligand Diabetes Programs in Development.................................................................. 232
Table 7.18 Metabolex Diabetes Programs in Development ........................................................... 233
Table 7.19 PowderJect Diabetes Programs in Development.......................................................... 234
Table 7.20 Ontogeny Diabetes Programs in Development ............................................................ 235
Table 7.21 Provalis Diabetes Programs in Development................................................................ 236
Table 7.22 Sensus Diabetes Programs in Development.................................................................. 236
Table 7.23 Takeda Diabetes Programs in Development ................................................................. 237