Contents:

Chapter 1. Executive summary 3 Scope of the analysis 3 Our insight into the hematological malignancies market 4 Key metrics 6 Our pipeline assessment summary 10 Chapter 2. Pipeline overview and dynamics 24 Pipeline overview 24 Products in late-phase development for hematological malignancies 24 Products in Phase II development for hematological malignancies 27 Products in Phase I development for hematological malignancies 36 Pipeline by developmental phase and class 43 There are 180 different products in the clinical developmental pipeline for hematological malignancies 43 Segmentation of products by developmental phase reflects high attrition rate in oncology drug development 44 Segmentation of products by class reflects shift in oncology drug development away from cytotoxics 49 Pipeline by indication 52 Over 50% of the pipeline products are being investigated in leukemia 52 The 22 late-phase pipeline products target eight different hematological malignancies 55 Pipeline by company 57 Developmental pipeline dominated by small pharma/biotech players 57 Only 17 (12%) companies/institutes have more than two candidates in the developmental pipeline for hematological malignancies 58 Novartis has six candidates in clinical development 59 Biogen Idec draws on the success of Rituxan 61 Chapter 3. Hematological malignancies - market potential 64 A diverse range of disease subtypes 64 Genetic basis of cancer evolution 64 Tumorigenesis is the result of co-operative accumulated mutations 66 Existing pharmacotherapy approaches provide limited treatment benefit 66 Cytotoxic drugs lack specificity 67 Hormonal or endocrine therapy provides incremental benefit in selected tumors 67 Optimizing current treatment strategies is paramount 67 The emergence of targeted treatment heralds a revolution in cancer pharmacotherapy 67 Dynamic cancer market offers significant commercial opportunity 68 Ongoing sales growth drives the market 68 Intensive R&D produces a rich developmental pipeline 69 Epidemiology - Hematological Malignancies 70 Cancer epidemiology - an expanding patient base 70 Leukemia 73 Lymphoma 77 Multiple myeloma 81 Myelodysplastic syndrome 83 Disproportionate increase in prevalence results from improvements in diagnosis and treatment 86 Significant areas of unmet need persist 88 The need for more sophisticated pharmacotherapy 88 Long-term control of advanced tumors is suboptimal 88 Novel strategies required to reduce relapse rates in early-stage disease 89 Toxicity of existing treatments jeopardizes quality of life and rates of treatment uptake 89 Improvements in diagnostics and prognostic analysis will enhance cost-effectiveness of treatment 90 Enhanced preventative strategies will ease the disease burden 90 Clinical and strategic threats to the commercialization of cancer drugs 91 Progressively rising R&D costs threaten industry productivity 91 High attrition rates can be mitigated by improved strategic decision-making 92 Lengthening drug approval process - a consequence of increased regulatory demands 92 Pharmacoeconomic pressures drive payers to implement restrictive pricing and reimbursement policies 92 Therapeutic and generic competition reduces periods of market exclusivity 93 Segmentation of market will require changes in clinical trial methodology 94 Chapter 4. R&d approach 95 Classification of pipeline products 95 Molecular targeted therapies 95 Angiogenesis inhibitors 95 Single-target signal transduction inhibitors 99 Multi-targeted inhibitors 99 Cell cycle and apoptosis targeted inhibitors 101 Epigenetic modulators 103 Cytotoxic Therapies 104 Antimetabolites 104 Mitotic inhibitors 105 DNA-interactive chemotherapeutic agents 105 Immunotherapeutic agents 110 Antibody-based technologies are an effective anticancer approach 110 Active, specific immunotherapy 111 Evolution in oncology clinical trial design 112 Patient selection is increasingly significant in the era of targeted treatment 113 Clinical trials must have sufficient follow-up to establish true clinical benefit 114 Diversity of targeted treatments will require an evolution in clinical trial design 114 Most oncology clinical trials designate multiple endpoints 115 Survival 115 Quality of life 115 Tumor response rates 116 Toxicity 116 Time to tumor progression 116 Modification of accelerated approval process may impact significantly on approval times for hematologic oncology drugs 117 Chapter 5. Molecular targeted therapies analysis and forecasts 120 Overview of molecular targeted therapies for hematological malignancies 120 Pipeline summary 120 Late-phase pipeline of molecular targeted therapies 121 Phase II pipeline of molecular targeted therapies 122 Phase I pipeline of molecular targeted therapies 125 Comparative forecasts 127 Definition of current comparator therapy 130 Novartiss Gleevec/Glivec (imatinib) 130 Tasigna (Nilotinib, AMN-107 Novartis) 133 Drug overview 133 Clinical trial data 133 Tasigna enters preregistration in the US and EU for Gleevec-resistant CML 133 Promising Phase II interim data reported 134 Tasigna appears effective in CML patients who have failed or are intolerant to both Gleevec and Sprycel 138 Only one BCR-ABL mutation is insensitive to Tasigna 139 Our comments 140 Tasigna ready to challenge Bristol-Myers Squibbs already approved Sprycel 140 Novartis looking to expand its leading role in the CML therapy market 140 Forecasts to 2016 141 Our drug assessment summary 142 Ceflatonin (Myelostat ChemGenex Pharmaceuticals) 143 Drug overview 143 Clinical trial data 144 Ceflatonin receives Fast Track status for chronic myeloid leukemia 145 Ceflatonin aims to restore Gleevec sensitivity in CML patients 145 ChemGenex looking to expand Ceflatonin into the AML/APL market 147 Our comments 148 Despite convincing clinical benefit, Ceflatonin will face strong competition from Bristol-Myers Squibbs Sprycel and Novartiss Tasigna 148 Forecasts to 2016 149 Our drug assessment summary 150 Sarasar (Lonafarnib Schering-Plough) 151 Drug overview 151 Clinical trial data 152 Main focus of Sarasar development in MDS, where greatest antitumor activity is shown 152 Farnesyl transferase inhibitors predominately in hematological disorders 153 Mild toxicity in the majority of patients, although grade 3 events do occur 153 Our comments 154 Sarasars chances for approval will be delayed beyond 2007 154 Sarasar racing against Johnson & Johnsons Zarnestra as the first farnesyl transferase inhibitor to reach the market 154 Presence in oncology market will aid commercialization of Sarasar 155 Forecasts to 2016 155 Our drug assessment summary 157 Torisel (Temsirolimus Wyeth) 158 Drug overview 158 Torisel inhibits a key pathway in tumor cell proliferation 158 Clinical trial data 159 Torisel showing promise in mantle cell lymphoma 159 Torisel also making headway in other NHL subtypes 161 Our comments 163 Torisel will have to face Velcade in the MCL market 163 Prior commercialization of Mylotarg and Neumega will provide Wyeth with valuable insight into the oncology market 164 Forecasts to 2016 164 Our drug assessment summary 165 Zarnestra (Tipifarnib Janssen/Johnson & Johnson) 166 Drug overview 166 Clinical trial data 167 Following rejection of NDA, the FDA requires Phase III data for Zarnestra in AML before regulatory approval can be considered 168 Results from Phase III studies have yet to be announced 168 Zarnestra has demonstrated a favorable profile in a variety of Phase II studies 169 Single-agent Zarnestra demonstrates antitumor activity in relapsed/refractory aggressive NHL 171 Zarnestra holding promise in juvenile myelomonocytic leukemia 172 Initiation of Phase II trials in large granular lymphocyte leukemia and multiple myeloma 173 Mild toxicity is particularly significant since Zarnestras main indication is for elderly AML patients where quality of life is a major issue 173 Our comments 173 Schering-Ploughs Sarasar catching up with Zarnestra as the first farnesyl transferase inhibitor to reach the market 173 Johnson & Johnson limiting Zarnestras target population in the short term 174 Johnson & Johnsons experience will be invaluable to Zarnestra 175 Forecasts to 2016 175 Our drug assessment summary 177 Alvocidib (Flavopiridol Sanofi-Aventis) 178 Drug overview 178 Clinical trial data 179 Continuous infusion dosing schedules fail to demonstrate clinical activity 180 Modified dosing regimen drives further development in CLL 182 Our comments 183 Given alvocidibs checkered history, Sanofi-Aventis may face an uphill struggle communicating the drugs potential 183 Alvocidib may show more promise as part of a combination regimen 183 Presence in oncology field will aid commercialization of alvocidib 183 Enzastaurin (LY317615 Eli Lilly) 184 Drug overview 184 Clinical trial data 184 Enzastaurin looking to make its mark in the B-Cell Lymphoma market 185 Enzastaurin holding promise as a maintenance therapy in mantle cell lymphoma 186 Our comments 186 Eli Lilly adopt a risky stragtegy for enzastaurin in DLBCL 186 Termination of Phase III trial for enzastaurin in glioma may hamper its potential in other indications 187 Forecasts to 2016 188 Our drug assessment summary 189 Lestaurtinib (CEP-701 Cephalon) 190 Drug overview 190 Clinical trial data 191 Lestaurtinib emerging as a promising agent for AML patients harboring Flt-3 activating mutations 191 Our comments 193 Lestaurtinib may be the first in its class to reach the market 193 Cephalons recent acquisition of Trisenox will provide invaluable experience of the leukemia market 194 Forecasts to 2016 194 Our drug assessment summary 195 Genasense (Oblimersen Genta) 196 Drug overview 196 Clinical trial data 197 FDA reject Genasense for use in combination with chemotherapy in CLL 197 Early-phase benefits of Genasense in AML require confirmation in Phase III clinical trial 198 Disappointing Phase III trial results in multiple myeloma means status of further development is unclear 199 Promise shown in combination with Rituxan in NHL, but randomized trials have yet to be initiated 200 Our comments 201 Approval of Genasense is looking increasingly unlikely 201 Termination of agreement with Sanofi-Aventis is a major setback for Genta 202 Forecasts to 2016 202 Our drug assessment summary 204 Chapter 6. Cytotoxic therapies analysis and forecasts 206 Overview of cytotoxic therapies for hematological malignancies 206 Pipeline summary 206 Late-phase pipeline of cytotoxic therapies 207 Phase II pipeline of cytotoxic therapies 208 Phase I pipeline of cytotoxic therapies 210 Comparative forecasts 210 Clolar/Evoltra (Clofarabine Genzyme/Bioenvision) 212 Drug overview 212 Clinical trial data 213 FDA and EMEA approve Clolar for ALL but further data in AML are required 215 Clolar and cytarabine appears to be an active and well tolerated regimen for elderly AML patients for which a Phase III trial has recently been initiated 215 Single-agent Clolar may provide an important treatment option for AML patients with adverse cytogenetics who are unsuitable for standard chemotherapy 217 Despite further data now required for approval, Clolar demonstrates activity in pediatric AML 219 Our comments 220 While approval in AML will significantly broaden Clolars label, increased economic constraints on healthcare systems may restrict its uptake 220 Forecasts to 2016 222 Drug assessment summary 223 Dacogen (decitabine MGI Pharma) 224 Drug overview 224 Clinical trial data 225 Elderly AML is an attractive indication for horizontal expansion of Dacogen 226 Dacogen as a maintenance therapy in AML 226 Dacogen plus Zolinza may be an effective combination 227 Our comments 227 Dacogen would fulfill a high unmet need in unfavorable risk AML 227 Dacogen may face competition from Vidaza, another approved DNA demethylating agent in development for AML 228 Dacogen will compete with Mylotarg in the relapsed elderly AML market 228 Forecasts to 2016 229 Our drug assessment summary 230 Cloretazine (VNP40101M Vion Pharmaceuticals) 231 Drug overview 231 Clinical trial data 232 Cloretazine will enjoy the advantages of Orphan Drug and Fast Track status for AML 232 Cloretazine and cytarabine appears a feasible combination for second-line AML 233 Single agent Cloretazine appears effective in elderly poor risk AML 234 High-risk MDS patients may also benefit from Cloretazine monotherapy 235 Cloretazine and Temodar in hematological malignancies appears to be a rational combination 236 Vion discontinues Cloretazine development in CLL to focus on AML 237 Our comments 237 Given persistent high unmet needs and the lack of a gold-standard in relapsed/refractory AML, Cloretazine demonstrates promise 237 Vion should seek a collaborative agreement with a more experienced oncology partner 238 Forecasts to 2016 239 Drug assessment summary 240 Pixantrone (BBR-2778 Cell Therapeutics) 241 Drug overview 241 Clinical trial data 242 Use of pixantrone for aggressive NHL 243 Use of pixantrone for indolent NHL 246 Our comments 248 Problems associated with trying to replace genericized drugs must be overcome 248 Patient recruitment to trials and physician awareness may be an uphill struggle 248 Pixantrone set to benefit from co-licensing agreement with Novartis 249 Our drug assessment summary 251 Marqibo (Sphingosomal vincristine Hana Biosciences) 252 Drug overview 252 Clinical trial data 253 Despite an FDA non-approvable letter and recommendation to initiate a Phase III study in NHL, to date no such trial has been initiated 253 Relapsed aggressive NHL 254 Marqibo as a replacement for vincristine in the R-CHOP regimen for first-line NHL appears to be a promising possibility 256 Marqibo is a potential candidate for the treatment of relapsed/refractory Hodgkins disease 257 Trials in ALL may hold promise for Marqibo 258 Our comments 259 Hana Biosciences face a difficult strategic development plan for Marqibo in NHL and shifting the focus to ALL may offer a quicker route to market 259 Chapter 7. Immunotherapeutic agents analysis and forecasts 260 Overview of immunotherapeutic agents for hematological malignancies 260 Pipeline summary 260 Late-phase pipeline of immunotherapeutic agents 261 Phase II pipeline of immunotherapeutic agents 262 Phase I pipeline of immunotherapeutic agents 264 Comparative forecasts 267 Definition of current comparator therapy 270 Biogen Idec/Genentech/Roches Rituxan/MabThera (rituximab) 270 Ceplene (Histamine dihydrochloride Epicept) 272 Drug overview 272 Clinical trial data 272 Ceplene enters preregistration in Europe as a maintenance therapy in first remission in patients with AML 272 Ceplene plus IL-2 prolongs leukemia-free survival but no significant difference in overall survival observed 274 Our comments 274 FDA requests additional Phase III trial despite primary endpoints being met 274 EpiCepts lack of oncology experience may hamper Ceplenes market success 275 Forecasts to 2016 275 Our drug assessment summary 277 Galiximab (Anti-CD80 MAb Biogen Idec) 278 Drug overview 278 Clinical trial data 279 Randomized Phase III trial will compare survival of galiximab plus Rituxan with Rituxan alone in relapsed/refractory follicular NHL patients 279 Phase II results show galiximab and Rituxan can be safely combined and can produce promising response rates in follicular NHL patients 280 Our comments 281 Biogen Idec in a strong position to successfully market galiximab alone 281 Biogen-Idec will need to effectively demonstrate the value of a combination of galiximab and Rituxan to payers 281 Forecasts to 2016 282 Our drug assessment summary 283 Lumiliximab (Anti-CD23 MAb Biogen Idec) 284 Drug overview 284 Clinical trial data 285 Lumiliximab receives Fast Track and Orphan Drug designation for relapsed CLL 285 The addition of lumiliximab to the FCR regimen may produce a higher response rate without additional toxicity 286 Our comments 288 Lumiliximab on course to become an established addition to the standard treatment for CLL 288 Biogen Idec should look to investigate Lumiliximab as a maintenance therapy 289 Cluster of Differentiation (CD) drugs have become Biogen Idecs specialty 289 Forecasts to 2016 290 Our drug assessment summary 291 Ofatumumab (HuMax-CD20 Genmab/GlaxoSmithKline) 292 Drug overview 292 Clinical trial data 293 Genmab hoping ofatumumab will demonstrate a preferred efficacy profile over Rituxan in the clinic 293 Ofatumumab receives Fast Track status for CLL and enters a Phase III trial 294 Genmab initiate a pivotal Phase III trial in follicular NHL 296 Our comments 297 Ofatumumab may offer hope for Rituxan-insensitive patients 298 Approval of other MAbs being developed by Biogen Idec for NHL and CLL may restrict ofatumumabs potential even further 299 GlaxoSmithKline will offer invaluable experience to Genmab and aid commercialization of ofatumumab 299 Forecasts to 2016 300 Our drug assessment summary 302 Zanolimumab (HuMax-CD4 Merck Serono/Genmab) 303 Drug overview 303 Clinical trial data 304 Zanolimumabs Orphan Drug and Fast Track status reflects the high unmet needs in CTCL 304 Zanolimumab may also hold promise for PTCL patients 306 Our comments 307 The T-cell lymphoma market offers zanolimumab a limited commercial potential 307 Depletion of CD4+ T-cells by zanolimumab may render the patient susceptible to opportunistic infections 307 Forecasts to 2016 308 Our drug assessment summary 309 BIOVAXID (Accentia Biopharmaceuticals) 310 Drug overview 310 Clinical trial data 311 BIOVAXID inches closer to approval in the US and European markets for follicular NHL 311 Phase III trial initiated in February 2000 is ongoing and continues to show favorable survival benefits of BIOVAXID 312 Possible association between a specific negative chromasomal translocation following vaccination and disease free survival in follicular NHL 313 Phase II results of BIOVAXID in mantle cell lymphoma are promising 313 Our comments 314 BIOVAXID competing with FavId and MyVax for first-to-market status 314 BIOVAXIDs price-tag should reflect the anticipated competition and current treatment costs 314 Forecasts to 2016 315 Our drug assessment summary 316 FavId (Id-KLH Favrille) 317 Drug overview 317 Clinical trial data 318 FavId receives Fast Track status by the FDA for follicular NHL 318 Single-agent FavId demonstrates an objective response in indolent B-cell NHL 321 Favrille initiates FavId Phase III trial in DLBCL NHL 322 Our comments 323 FavId competing with BIOVAXID and MyVax to reach the market first 323 Favrilles lack of commercial experience will be a barrier to optimizing market penetration 323 Forecasts to 2016 324 Our drug assessment summary 325 MyVax (GTOP-99 Genitope) 326 Drug overview 326 Clinical trial data 327 MyVax received Fast Track status for follicular NHL while Phase III clinical trial approaches completion 328 Phase II clinical trials show greater number of immune responses among previously untreated patients 328 Genitope initiates Phase I/II trial for MyVax in chronic lymphocytic leukemia 329 Follow-up Phase II data of MyVax in mantle cell and diffuse large B-cell lymphoma warrants further investigation 329 Our comments 331 Despite competition from BIOVAXID and FavId, MyVax increases its commercial potential by targeting an earlier stage treatment 331 With trials ongoing in CLL, MyVax may ultimately emerge as the most adaptable anti-idiotype vaccine 331 Forecasts to 2016 331 Our drug assessment summary 333 Comparison of anti-idiotype vaccines 335 APPENDIX List of Tables List of Figures 348 Methodology 353