ABOUT DATAMONITOR HEALTHCARE 2
About the Oncology pharmaceutical analysis team 2
Nish Saini - Director of Oncology 2

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Datamonitor insight into the targeted therapies market 3

CHAPTER 2 PIPELINE OVERVIEW 22
Pipeline overview 22
Pipeline by developmental phase and class of drug 25
The cell cycle and apoptosis targeted agents make up the largest number of MTTs in the pipeline 25
Segmentation of drugs by developmental phase reflects attrition rate of drug development in the oncology market 28
Targeted therapy remains a promising anticancer drug development strategy 28
Developmental agents by phase for each class 28
Pipeline by indication 32
MTTs are being investigated in 29 different cancers 32
The 'big four' tumor types are the most popular indications for development 34
Pipeline by mode of action 35
Pipeline MTTs are being directed against a huge variety and combination of molecular targets 35
The VEGF/VEGFR family remains the focus of development for MTTs 37
Pipeline by company 39
There are over 150 different companies developing targeted therapies 39
Top three companies in terms of number of pipeline MTT products are Pfizer, Novartis and GlaxoSmithKline 40
Pfizer 41
Novartis 43
GlaxoSmithKline 45
Key metrics 48
Datamonitor pipeline assessment summary 55

CHAPTER 3 PIPELINE DYNAMICS 62
A diverse range of disease subtypes 62
Genetic basis of cancer evolution 62
Tumorigenesis is the result of co-operative accumulated mutations 64
Existing pharmacotherapy approaches provide limited treatment benefit 64
Cytotoxic drugs lack specificity 65
Hormonal or endocrine therapy provides incremental benefit in selected tumors 65
Optimizing current treatment strategies is paramount 65
The emergence of targeted treatment heralds a revolution in cancer pharmacotherapy 65
Dynamic cancer market offers significant commercial opportunity 66
Ongoing sales growth drives the market 66
Intensive R&D produces a rich developmental pipeline 67
Growing patient population and significant unmet needs propel innovation in the cancer market 68
Cancer epidemiology - an expanding patient base 68
Significant areas of unmet need persist 73
Clinical and strategic threats to the commercialization of cancer drugs 77
Progressively rising R&D costs threaten industry productivity 77
High attrition rates can be mitigated by improved strategic decision-making 78
Lengthening drug approval process - a consequence of increased regulatory demands 78
Pharmacoeconomic pressures drive payers to implement restrictive pricing and reimbursement policies 79
Therapeutic and generic competition reduces periods of market exclusivity 79
Segmentation of market will require changes in clinical trial methodology 80

CHAPTER 4 MARKET DEFINITION & PIPELINE CLASSIFICATION 81
Targeted therapies overview 81
The development of molecular targeted therapies 81
Current therapies are less cancer cell-specific 81
The strategy is to target the specific survival factors of a tumor 81
Key issue is the identification of targets unique to cancer cells 82
Market definition 82
L1X3 - Antineoplastic monoclonal antibodies 82
L1X9 - All other antineoplastics 83
Classification of pipeline products 84
Angiogenesis inhibitors 84
Angiogenesis as a normal biological process 84
Angiogenesis is known to be abberant in tumor cell proliferation 85
Angiogenesis inhibitors as viable antitumor agents can target a number of pathways 86
At present, only one angiogenesis inhibitor exists in the market 87
Single-target signal transduction inhibitors 87
A plethora of potential targets exist along the signaling cascade 87
Several signal transduction inhibitors have reached the market, bringing with them their own sets of issues for consideration 88
Multi-targeted inhibitors 89
Multi-targeted inhibitors have certain advantages over single targeted agents 89
Approval of three multi-targeted inhibitors 90
Cell cycle and apoptosis targeted inhibitors 91
Only one cell cycle inhibitor has entered Phase III 91
Cell death can be induced via a number of different pathways 91
To date, only one apoptosis stimulator has reached the market 92
Epigenetic modulators 92
Despite relative immaturity of development in this class of drugs, the potential to enhance current therapies exists 93
Immunomodulatory and immunoconjugated therapeutics 93
Antibody-based technologies are an effective anticancer approach 93
Pipeline comparator 94
Current market situation 95

CHAPTER 5 MARKETED PRODUCTS FORECAST ANALYSIS 98
Country-specific assumptions and effects 98
Effect of Medicare Modernization Act in the US 98
Biennial price cuts in Japan 98
National Institute of Clinical Excellence in the UK 98
Generic erosion assumptions 99
Product assumptions and effects 100
Angiogenesis inhibitors 100
Genentech/Roche's Avastin (bevacizumab) 100
Single-target signal transduction inhibitors 103
ImClone/Bristol-Myers Squibb/Merck KGaA's Erbitux (cetuximab) 103
Novartis's Gleevec/Glivec (imatinib) 106
Genentech/Roche's Herceptin (trastuzumab) 108
AstraZeneca's Iressa (gefitinib) 110
OSI Pharmaceuticals/Genentech/Roche's Tarceva (erlotinib) 112
Eisai's Targretin (bexarotene) 114
Multi-targeted inhibitors 116
Onyx Pharmaceuticals/Bayer AG's Nexavar (sorafenib) 116
Bristol-Myers Squibb's Sprycel (dasatinib) 119
Pfizer's Sutent (sunitinib) 121
Cell cycle and apoptosis targeted agents 124
Ortho Biotech/Millennium Pharmaceuticals' Velcade (bortezomib) 124
Immunomodulatory and immunoconjugated therapeutics 126
GlakoSmithKline's Bexxar (tositumomab) 126
Schering AG/Berlex's Campath (MabCampath; alemtuzumab) 127
Wyeth's Mylotarg (gemtuzumab) 128
Biogen IDEC/Genentech/Roche's Rituxan/MabThera (rituximab) 129
Biogen Idec/Schering AG's Zevalin (ibritumomab) 131
Eisai's Ontak (Onzar; denileukin) 131
Forecasts 132

CHAPTER 6 PIPELINE ANGIOGENESIS INHIBITORS ANALYSIS & FORECASTS 133
Pipeline overview 133
AstraZeneca's AZD2171 136
Drug Profile 136
Clinical Trial Data 137
AZD2171 as a monotherapeutic agent 139
AZD2171 in combination with chemotherapy appears to be a promising approach 139
AZD2171 has potential in NSCLC in combination with standard chemotherapy regimens and with Iressa 140
Datamonitor Comments 141
As a potentially more potent inhibitor of angiogenesis, and given its formulation, AZD2171's future may be very promising 141
AstraZeneca's strength in the oncology market will be key in AZD2171's success 141
GlaxoSmithKline's Pazopanib (GW 786034) 142
Drug Profile 142
Clinical Trial Data 142
Pazopanib as a possible second-line monotherapy treatment for metastatic RCC 143
Co-administration with Tykerb may alter the pharmacokinetics of pazopanib 144
Other Indications 144
Datamonitor Comments 145
Initial approval in RCC will force pazopanib to compete against the already approved Sutent and Nexavar 145
Tykerb may well enhance the success of pazopanib but at what price? 146
Novartis/Schering AG's Vatalanib (PTK-787) 146
Drug Profile 146
Clinical Trial Data 146
Anticipated regulatory filing for vatalanib in CRC is becoming increasingly unlikely following disappointing CONFIRM-1 and CONFIRM-2 interim results 148
Recent update of vatalanib in Gleevec-resistant GIST patients 149
Recent update of the Phase II GOAL Study in NSCLC 149
Novartis/Schering AG adopt an aggressive approach, investigating vatalanib in a number of indications 150
Datamonitor Comments 150
Vatalanib unlikely to compete with Avastin in the metastatic CRC market 150
Schering AG's and particularly Novartis's prior oncology experience will be invaluable to vatalanib 151
Novartis and Schering AG are determined to exploit any commercial potential vatalanib may have 151
Sanofi Aventis/Regeneron's VEGF-Trap 152
Drug Profile 152
Clinical Trial Data 152
VEGF-Trap enters Phase III for ovarian cancer 153
VEGF-Trap in Phase II for NSCLC and RCC 154
Selecetd Phase I clinical studies in solid tumors 154
VEGF-Trap demonstrates similar side effects to Avastin 156
Datamonitor Comments 156
Fierce competition with Avastin in the ovarian cancer market 156
Presence in oncology field will aid commercialisation of VEGF-Trap 158
Forecasts 158
Datamonitor drug assessment summary 160

CHAPTER 7 PIPELINE SINGLE-TARGET SIGNAL TRANSDUCTION INHIBITORS ANALYSIS & FORECASTS 163
Pipeline overview 163
Amgen's Vectibix (panitumumab; ABX-EGF) 166
Drug Profile 166
Overexpression of EGFR makes an ideal target for Vectibix development 166
Clinical Trial Data 166
Vectibix is approved for metastatic CRC and showing promise in a range of other treatment settings 168
Addition of Vectibix does not enhance standard chemotherapy in NSCLC 169
Vectibix fails as a single agent in RCC 170
Main side effect is a potential indicator of Vectibix activity 170
Datamonitor Comments 170
Humanized nature of Vectibix will challenge its competitor EGFR inhibitors 170
Vectibix versus Erbitux 171
Third-line setting for metastatic CRC is a good place to start 172
Amgen should focus on combination regimens while considering the intellectual property issues 173
Potential development of a biomarker for Vectibix 173
Amgen's presence will ensure success with profitability increasing by targeting earlier lines of therapy 174
Schering-Plough's Sarasar (Lonafarnib) 174
Drug Profile 174
Clinical Trial Data 174
Main focus of Sarasar development in MDS, where greatest antitumor activity is shown 175
Farnesyl transferase inhibitors predominately in hematological disorders 176
Lack of efficacy has led to termination of pivotal Phase III trial in NSCLC 176
Lack of clinical data makes it difficult to judge Sarasar's potential in breast cancer 177
Initiation of a Phase II trial in Ovarian Cancer 177
Benefit shown in advanced head and neck cancer, although no further trials have been announced 177
Currently no further trials planned for pancreatic cancer, urothelial carcinoma and colorectal cancer 178
Mild toxicity in the majority of patients, although grade 3 events do occur 178
Datamonitor Comments 178
Sarasar's chances for approval will be delayed beyond 2007 178
Sarasar racing against Johnson & Johnson's Zarnestra as the first farnesyl transferase inhibitor to reach the market 179
Presence in oncology market will aid commercialization of Sarasar 180
Abbott Laboratories' Xinlay (atrasentan) 180
Drug Profile 180
Xinlay's target receptor plays a key role in cancer cell proliferation 180
Clinical Trial Data 181
FDA do not approve Xinlay for prostate cancer 181
Other trials 183
Datamonitor Comments 184
Despite its rejection by the FDA, Xinlay's future may still be promising 184
Abbott's favorable position in the prostate cancer market will be invaluable 184
Wyeth's Torisel (Temsirolimus; CCI-779) 185
Drug Profile 185
Temsirolimus inhibits a key pathway in tumor cell proliferation 185
Clinical Trial Data 185
Promising Phase III results in RCC reported at ASCO 2006 186
Torisel showing promise in mantle cell lymphoma 187
Torisel trial in breast cancer is discontinued 188
Combination studies with Torisel initiated in malignant melanoma 188
Combination studies with Torisel initiated in glioblastome multiforme 188
Torisel as a monotherapy 189
Mild toxicity means Torisel is well tolerated 189
Datamonitor Comments 189
Targeting poor prognosis patients may eventually accelerate Torisel's expansion within RCC 189
Torisel will have to face Velcade in the MCL market 190
Prior commercialization of Mylotarg and Neumega will provide Wyeth with valuable insight into the oncology market 190
Janssen/Johnson & Johnson's Zarnestra (tipifarnib) 191
Drug Profile 191
Clinical Trial Data 191
Following rejection of NDA, the FDA requires Phase III data for Zarnestra in AML before regulatory approval can be considered 193
Zarnestra shows activity in MDS 195
Zarnestra development in breast cancer remains in Phase II trials 195
Following modest activity in brain cancer, further trials have been initiated 195
Initiation of Phase II trials in large granular lymphocyte leukemia and malignant melanoma 197
Negative Phase III trial results caused termination of development in solid tumors 198
Phase I trial is ongoing for Zarnestra in combination with chemotherapy in advanced NSCLC 199
Mild toxicity is particularly significant since Zarnestra's main indication is for elderly AML patients where quality of life is a major issue 199
Datamonitor Comments 199
Schering-Plough's Sarasar catching up with Zarnestra as the first farnesyl transferase inhibitor to reach the market 199
Johnson & Johnson limiting Zarnestra's target population in the short term 200
Johnson & Johnson's experience will be invaluable to Zarnestra 201
YM Bioscience's TheraCIM (Theraloc; Nimotuzumab) 201
Drug Profile 201
Clinical Trial Data 202
Phase III for pediatric pontine (brain stem) glioma 202
Phase II pediatric trial demonstrated activity 202
Positive efficacy and favorable toxicity data for Phase II trial results of TheraCIM 203
Datamonitor Comments 203
Phase III trial results required to verify the efficacy of this agent 203
Forecasts 204
Datamonitor drug assessment summary 207

CHAPTER 8 PIPELINE MULTI-TARGETED INHIBITORS ANALYSIS & FORECASTS 210
Pipeline overview 210
GlaxoSmithKline's Tykerb/Tycerb (Lapatinib) 214
Drug Profile 214
Tykerb is unique among the EGFR inhibitors, targeting two receptor tyrosine kinases 214
Clinical Trial Data 214
Tykerb set to penetrate the breast cancer market 216
Tykerb did not meet the primary endpoint in mRCC Phase III study 222
Tykerb monotherapy shows no activity in BTC but shows promise in HCC 223
Tykerb appears to have little activity in SCCHN 223
Other clinical trials 224
Datamonitor Comments 224
Tykerb's dual ErbB targeting mechanism will lead to a significant patient potential 224
Tykerb and capecitabine combination looking to become the gold-standard for second-line metastatic beast cancer 224
Tykerb's ability to threaten Herceptin still hangs in the balance 225
GSK also looks to secure a future for Tykerb as part of combination regimens 226
GSK's limited oncology portfolio will be bolstered by the arrival of Tykerb 226
ChemGenex Pharmaceuticals' Ceflatonin (CGX-635, Myelostat) 227
Drug Profile 227
Clinical Trial Data 227