Contents:

Chapter 1 Executive summary Insight into the acute leukemia market 3 The acute luekemias comprise a heterogeneous group of diseases 3 Cytogenetic classification provides the most compelling prognostic information 4 Current treatment options fail to offer sustained remission 4 Integration of targeted therapy into treatment protocols provides potential for sustained remission 5 Pending FDA approval of Gleevec in ALL marks first targeted therapy approval in this indication 6 Future therapies will fragment the acute leukemia market 7 Heterogeneity of disease means developers must aim for more homogenous trial groups 8 Chapter 2 Disease overview Pathobiology of acute leukemias 17 Blood cells are formed through a process of hematopoiesis 17 Hematopoiesis is comprised of a series of lineage commitment steps 18 Leukemia is a consequence of imbalances in the maturation and differentiation process 19 Immunophenotyping may be required to differentiate between lymphoid and myeloid lineages 20 Leukemia subtypes each have their own distinctive epidemiological profile 20 AML is predominantly a disease of the elderly while ALL incidence peaks in childhood 21 Acute myeloid leukemia holds the greatest commercial opportunity in adult acute leukemias 26 Acute Myeloid Leukemia 26 Acute myeloid leukemia etiology and risk factors 26 The clonal origin of AML is suggested by non-random chromosomal abnormalities 28 Cytogenetics offer valuable prognostic information in AML 28 Staging and classification of AML 29 New WHO classification system updates the French-American-British classification system 31 The need for greater molecular monitoring in AML evidenced by lack of prognostic indicators for patients with normal karyotype disease 38 Aberrant signal transduction pathways provide opportunities for the developers of targeted treatments 38 Acute lymphoblastic leukemia 39 ALL contrasts to AML with fewer definitive risk factors 40 Morphologic classification of ALL has evolved to incorporate immunogenic and cytogenetic features 40 Precursor B-cell ALL is associated with the Philadelphia positive gene 42 Incidence of mature B-cell ALL increasing concurrent with rise in immunodeficiency 43 Cytogenetic features helps predict ALL prognosis 43 Chapter 3 Unmet needs High rate of accelerated approval for drugs to treat hematological malignancies 46 Drugs targeting acute leukemia are likely to benefit from Fast Track or Orphan drug status 46 An increase in understanding of molecular and biochemical changes in acute leukemias has not yet translated into improved survival 48 The development of agents which address the heterogeneity of acute leukemia are pivotal to improving treatment outcomes 49 Sustained periods of remission remain elusive for patients with acute leukemia 49 Improved second-line treatments needed to overcome multi-drug resistance 50 Less toxic therapy and improved quality of life required for elderly patients with acute leukemia 50 Chapter 4 Current treatment controversies Disease specific factors influence prognosis and therapy options 54 Patient specific factors influence prognosis and therapy options 54 The frequency of high-risk karyotypes increases with age 55 Proteonomic conseqeuences of recurring genetic abnormalities provide potential drug targets 58 The presence of high risk karyotypes reduces the probablity of remission and long term survival 58 Developers must be aware of the prognostic significance of cytogenetics when designing clinical trials 61 Despite heterogeneity in disease, developers should aim for homogenous trial group 61 Overview of AML treatment 62 Cytarabine-anthracycline combination regimens form the cornerstone of induction therapy for AML 62 Consolidation therapy is crucial to preventing early relapse 63 Hematopoeitic Stem Cell Transplantation in first remission is the most aggressive form of consolidation treatment 63 Despite success of induction and consolidation treatment, high relapse rates prevail among AML patients 64 Efforts to treat refractory AML rely on experimental strategies 64 Treatment of AML in patients less than 60 years age 65 Cytarabine-anthracycline regimens dominate induction therapy in younger AML patients 65 Agents which prolong remission can expect significant uptake 69 Treatment of AML in patients greater than 60 years age 75 Cytarabine containing regimes remain central to induction therapy in elderly AML 76 Increasing the intensity of chemotherapy in induction therapy does not increase over all survival 76 Clinical trial design should encompass cytogenetic stratification for patients with elderly AML 79 No accepted treatment strategy for elderly-AML in the post remission setting. 80 The benefits of intensive conditioning and autologous HSCT are offset by the higher treatment related mortality in elderly AML 81 Opinion leaders optimistic about increasing use of the ‘mini transplant’ in elderly AML 82 Treatment tree for elderly-AML 83 Treatment of relapsed AML in elderly patients 85 Treatment of relapsed AML in elderly patients with Mylotarg 85 Treatment of Acute Promyelocytic leukemia (APL) 86 The introduction of all-trans retinoic acid (ATRA) for treatment of APL represents a significant advance 87 ATRA therapy is associated with retinoic acid syndrome 88 ATRA combined with an anthracycline firmly grounded in first-line therapy 88 Consolidation therapy for APL 88 Trisonex induces remission in refractory APL 89 Trisenox as first-line consolidation therapy in APL 89 Hematopoeitic stem cell transplantation is recommended for APL patients in CR2 90 Potential role for Mylotarg in relapsed APL 90 High unmet needs prevail in the treatment of adult ALL 93 Patient-specific factors effecting treatment of elderly ALL 93 First-line treatment for ALL 95 Consolidation therapy for ALL 97 Maintenance therapy 99 Management of Philadelphia-positive ALL 100 Targeted therapy is already integrated into treatment regimes for ALL 100 Philadelphia-positive ALL patients remain a population with significant unmet needs 102 Opinion leaders are disappointed in ALL progress 103 Chapter 5 Drugs in ongoing clinical development Key opinion leaders express optimism over Zarnestra 105 Marqibo, Phase III trials likely to be initiated following partnership with Hana Biosciences. 108 Ceplene, pending EMEA submission for maintenance therapy in AML 110 Arranon (nelarabine 506U78), GlaxoSmithKline garners FDA approval based in pivotal Phase II trial 112 Mylotarg may have potential to change first-line treatment for AML 114 Key opinion leaders divided on their opinion on Troxatyl 117 Genasense’s troubled route to commercialization may obscure key opinion leader opinion 119 Genasense’s troubled route to commercialization may hinder Genta’s ability to find marketing partner 120 Cloretazine (VNP-40101M), Vion Pharmaceuticals 121 Clolar/Evoltra uptake may be restricted by current pharamacoeconomic constraints 124 FDA approval of Clolar in pediatric ALL 124 Bioenvision receive positive opinion in Europe for pediatric ALL 125 Clolar demonstrates activity in pediatric AML but not approved by the FDA 126 First-line-extension anticipated 2006 126 Two Phase III studies planned in AML following FDA request for additional data 127 Approval in AML will ensure maximum commercial returns 127 Increase economic constraints on healthcare systems may restrict uptake 128 PROMISING PHASE II DRUGS Flt-3 inhibition promsing for AML 131 Lestaurtinib (CEP-701), Celphalon, most clinically advanced flt-3 inhibitor 131 Targeting multiple pathways, Midostaurin (PKC-412), Novartis 134 Next generation Bcr-Abl tyrosine kinase inhibitors eagerly awaited, Nilotinib (AMN107), Novartis 136 Bristol-Myers Squibb’s Dasatinib (BMS-354825) generates excitement in key opinion leaders 137 Cytotoxics will remain at the cornerstone of acute leukemia treatment 140 Chapter 6 Opinion leader transcripts Contributing experts 142 US Opinion leader 143 US Opinion leader 153 European opinion leader 164 European opinion leader 173 APPENDIX List of Tables Table 1: Immunophenotyping markers used in AML 4 Table 2: Leukemia incidence in the seven major markets, 2006-2016 4 Table 3: Frequency of leukemia subtypes in the seven major 4 Table 4: Crude incidence rates of leukemia (per 100,000) 4 Table 5: Leukemia sub-type incidence in the seven major markets 2000-2016 4 Table 3: Prognosis conferred by cytogenetic abnormalities in AML 4 Table 4: The French American British Classification system of AML 4 Table 5: WHO classification of acute myeloid leukemia 4 Table 6: Two distinct classes of t-MDS/AML can be related to alkylating agents and topoisomearase II inhibitors 4 Table 7: Molecular abnormalities associated with AML and their corresponding prognosis 4 Table 8: The French American British Classification system of ALL 4 Table 9: Morphological, immunogenic and cytogenetic classification of ALL 4 Table 10: Three year survival related to cytogenetics in ALL 4 Table 11: Recently approved acute leukemia drugs receiving accelerated approval. 4 Table 12: Elderly AML patients spend significant percentage of life in hospital 4 Table 13: ECOG performance status 4 Table 14: Cytogenetic patterns by age in patients with AML 4 Table 15: Commonly used agents in AML 4 Table 16: Standard induction therapy for AML 4 Table 17: High dose cytarabine versus standard cytarabine in AML 4 Table 18: High dose cytarabine benefits patients with poor prognosis 4 Table 19: Responsiveness to induction therapy declines with age 4 Table 20: High dose cytarabine in consolidation therapy only benefits younger patients 4 Table 21: Post-induction therapy does not offer improved survival in elderly-AML 4 Table 22: Berlin- Frank- Muster regimes and Larson regime for ALL 4 Table 23: Linker regime 4 Table 24: Marketed and developmental drugs in acute leukemia 4 Table 25: Pivotal Phase II trials for Arranon approval 4 Table 26: Cloretazine demonstrates activity in untreated elderly AML 4 Table 27: Clolar demonstrates activity in pediatric ALL 4 Table 28: Clolar activity in elderly ALL 4 Table 29: Phase II acute leukemia drugs 4 Table 30: Trial results of lestaurtinib in relapsed AML 4 Table 31: Midostaurin in combination with chemotherapy in patients with AML 4 Table 32: Comparison of AMN107 and dasatinib List of Figures Figure 1: Schematic diagram of hematopoiesis 18 Figure 2: Age related incidence of AML and ALL 22 Figure 3: Leukemia sub-type incidence in the seven major markets, 2006-16 25 Figure 4: Unmet needs in acute leukemia 45 Figure 5: Cytogenetic risk groups by age group 56 Figure 6: Cytogenetic patterns by age in patients with AML 57 Figure 7: Probability of continuous complete remission according to karyotypes 59 Figure 8: Overall survival for patients with AML according to karyotype 60 Figure 9: Basic principles in the treatment of AML in younger patients (<60 years) 75 Figure 10: No overall survival advantage conferred by any one particular anthracycline/anthracenedione in elderly AML 77 Figure 11: CR and median survival according to karyotype in elderly-AML 79 Figure 12: Treatment pathway for elderly AML 84 Figure 13: Treatment pathway for patients with APL 92 Figure 14: Incidence of Ph+ve cases of ALL increases with age 95 Figure 15: SWOG Mylotarg trial in newly diagnosed AML 115