Introduction
Unmet needs across the hematological malignancies remain high, with most traditional therapies conferring low levels of specificity and high toxicity. Pipeline candidates classified as molecular targeted therapies, cytotoxic therapies and immunotherapeutic agents, may offer attractive therapeutic additions and Datamonitor's insight into their clinical and commercial potential is provided.
Scope
Research and analysis of the hematological malignancies pipeline with in-depth clinical and commercial assessment of Phase III candidates Seven major pharmaceutical market sales forecasts to 2016 for key pipeline candidates incorporating product specific assumptions and events Segmentation and examination of product pipeline by developmental phase, class, indication and developer Insight and analysis of the hematological malignancies market potential including commercial opportunity and disease epidemiology
Highlights
180 different pipeline candidates have been identified of which 22 are in late-phase development. These existing candidates have a forecast sales potential of up to $3.61 billion in the seven major pharmaceutical markets by 2016. Agents holding strong commercial potential include Novartis' Gleevec-follow-on, Tasigna (nilotinib), and Genzyme's already approved purine analog Clolar (clofarabine) which is in development for acute myeloid leukemia. Other notable candidates include the anti-idiotype therapeutic vaccines and Biogen Idec's anti-CD23 MAb, lumiliximab. Over 50% of the products are being investigated in acute and/or chronic leukemia. However, as an individual hematological subtype, NHL attracts the greatest attention from developers with 53 (29%) products in the pipeline despite the malignancy being comparatively well served by existing treatment regimens.
Reasons to Purchase
Acquire a detailed appreciation and impartial perspective of the entire hematological malignancies developmental pipeline Identify the key products in late-phase development based on sales forecasts to 2016 and Datamonitor's drug assessment methodology Consider, assess and react to opportunities and risks influencing the future potential of products in the hematological malignancies pipeline
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the hematological malignancies market 4
Key metrics 6
Datamonitor 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
Novartis's 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
Datamonitor comments 140
Tasigna ready to challenge Bristol-Myers Squibb's already approved Sprycel 140
Novartis looking to expand its leading role in the CML therapy market 140
Forecasts to 2016 141
Datamonitor 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
Datamonitor comments 148
Despite convincing clinical benefit, Ceflatonin will face strong competition from Bristol-Myers Squibb's Sprycel and Novartis's Tasigna 148
Forecasts to 2016 149
Datamonitor 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
Datamonitor comments 154
Sarasar's chances for approval will be delayed beyond 2007 154
Sarasar racing against Johnson & Johnson's 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
Datamonitor 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
Datamonitor 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
Datamonitor 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 Zarnestra's main indication is for elderly AML patients where quality of life is a major issue 173
Datamonitor comments 173
Schering-Plough's Sarasar catching up with Zarnestra as the first farnesyl transferase inhibitor to reach the market 173
Johnson & Johnson limiting Zarnestra's target population in the short term 174
Johnson & Johnson's experience will be invaluable to Zarnestra 175
Forecasts to 2016 175
Datamonitor 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
Datamonitor comments 183
Given alvocidib's checkered history, Sanofi-Aventis may face an uphill struggle communicating the drug's 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
Datamonitor 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
Datamonitor 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
Datamonitor comments 193
Lestaurtinib may be the first in its class to reach the market 193
Cephalon's recent acquisition of Trisenox will provide invaluable experience of the leukemia market 194
Forecasts to 2016 194
Datamonitor 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
Datamonitor 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
Datamonitor 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
Datamonitor comments 220
While approval in AML will significantly broaden Clolar's label, increased economic constraints on healthcare systems may restrict its uptake 220
Forecasts to 2016 222
Datamonitor 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
Datamonitor 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
Datamonitor 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
Datamonitor 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
Datamonitor 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
Datamonitor 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
Forecasts to 2016 250
Datamonitor 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 Hodgkin's disease 257
Trials in ALL may hold promise for Marqibo 258
Datamonitor 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/Roche's 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
Datamonitor comments 274
FDA requests additional Phase III trial despite primary endpoints being met 274
EpiCept's lack of oncology experience may hamper Ceplene's market success 275
Forecasts to 2016 275
Datamonitor 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
Datamonitor 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
Datamonitor 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
Datamonitor 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 Idec's specialty 289
Forecasts to 2016 290
Datamonitor 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
Datamonitor 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 ofatumumab's potential even further 299
GlaxoSmithKline will offer invaluable experience to Genmab and aid commercialization of ofatumumab 299
Forecasts to 2016 300
Datamonitor drug assessment summary 302
Zanolimumab (HuMax-CD4; Merck Serono/Genmab) 303
Drug overview 303
Clinical trial data 304
Zanolimumab's Orphan Drug and Fast Track status reflects the high unmet needs in CTCL 304
Zanolimumab may also hold promise for PTCL patients 306
Datamonitor 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
Datamonitor 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
Datamonitor comments 314
BIOVAXID competing with FavId and MyVax for first-to-market status 314
BIOVAXID's price-tag should reflect the anticipated competition and current treatment costs 314
Forecasts to 2016 315
Datamonitor 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
Datamonitor comments 323
FavId competing with BIOVAXID and MyVax to reach the market first 323
Favrille's lack of commercial experience will be a barrier to optimizing market penetration 323
Forecasts to 2016 324
Datamonitor 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
Datamonitor 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
Datamonitor drug assessment summary 333
Comparison of anti-idiotype vaccines 335
APPENDIX 338
List of tables 338
List of figures 348
Methodology 353
Datamonitor forecast methodology 353
Datamonitor drug assessment summary 354
Abbreviations 356
Contributing experts 358
Key opinion leader interview transcripts 358
Bibliography 359
About Datamonitor 371
About Datamonitor Healthcare 371
Datamonitor Healthcare's therapy area capabilities 372
About the Disease analysis team 372
Disclaimer 374