Acute Myeloid Leukemia Therapeutics Market to Novel Therapies to Offer Clinical Benefit in Small Patient Cohorts

Transcription

1 Acute Myeloid Leukemia Therapeutics Market to 2020 Novel Therapies to Offer Clinical Benefit in Small Patient Cohorts

2 GBI Research Report Guidance GBI Research Report Guidance The report begins with an executive summary detailing the key points that are driving the AML market. Chapter two provides an introduction to AML, detailing the etiology, epidemiology, disease staging and typical prognoses for patients. An analysis of current treatment algorithms is also included. Chapter three outlines the current treatment algorithm for AML, detailing the drug monotherapies and combinations used for the treatment of this disease. Key characteristics include treatment efficacy and safety, as well as drug administration and dosing. The results for each monotherapy or combination therapy are outlined in a comprehensive heat map. Chapter four offers detailed analysis of the drugs currently marketed for this indication. Detailing the key characteristics of these drugs, including, but not limited to, patent data and mechanism of action. The section also outlines the current performance of each drug within the market, and how this may change throughout the forecast period. Chapter five provides detailed analysis of the pipeline for AML, by stage of development, molecule type, program type and Mechanism of Action (MoA). It also analyses recent clinical trials in this indication by enrollment, duration and failure rate. Finally, promising late-stage pipeline molecules are analyzed and assessed in terms of their potential competitive strength. Chapter six offers market forecasts for the AML market, including: epidemiology, treatment usage patterns, pricing and market size for the period. Eight major markets (the US, Canada, Germany, the UK, France, Italy, Spain and Japan) are covered, and data are presented on a country-by-country level, with further analysis of key market drivers and barriers. Chapter seven outlines the key drivers and barriers facing the AML market, both at present and throughout the forecast period. Chapter eight describes the major deals that have taken place in the global AML market in recent years. This coverage analyzes licensing and co-development agreements, segmented by stage of development, year, molecule type, MoA and value. Network graphs for these deals are also included, organized by location of company headquarters. Page 2

3 Executive Summary Executive Summary Minimal but Positive Increases in Incidence Rate and New Drug Approvals to Drive Market Growth Acute Myeloid Leukemia (AML) is classed as an orphan disease, with a global incidence rate of approximately XX diagnoses per 100,000 of the population per year. This is a clear limitation to market revenues, in comparison with major indications in oncology, such as breast and lung cancer. AML is a disease primarily of the elderly, with an average age of diagnosis of approximately 66 (American Cancer Society, 2014). Throughout the forecast period, the proportion of the population aged 65 and over is expected to increase significantly, as members of the baby boom generation of the s reach retirement age, coupled with low, or declining current birth rates across each territory analyzed in this report. The result of this shift in population demographics is an increase in the rate of AML across the entire population, increasing the prevalence population of those diagnosed with AML. This increase in prevalence is expected to be somewhat negated by an increase in patient cure rates, but overall the number of patients is expected to grow at a rate higher than that of general population growth throughout the forecast period. Although prevalence rates are expected to remain low, any increase in rate will have a noticeable impact on market revenues. Furthermore, from the current developmental pipeline, five late-stage drugs have demonstrated particularly encouraging efficacy and safety results and are expected to be approved within the forecast period. These drugs (CPX-351, midostaurin, quizartinib, StemEx and treosulfan) are expected to make a moderate impact on the market, outcompeting inferior drugs and increasing treatment rates. However, the efficacy of each drug is restricted to small patient cohorts. Nevertheless, the approval of novel, premium-priced drugs in this market, which is heavily dominated by generics, will result in an increase in the Annual Cost of Therapy (ACoT) and therefore market revenues. Lack of Targeted Therapies Addressed by Current Developmental Pipeline There is a complete lack of targeted therapies in the current AML treatment landscape. Their development and introduction in this indication is significantly lacking, especially considering the relatively strong understanding of the cytogenetic and molecular genetic abnormalities that cause the initiation and propagation of AML. Treatment is dominated by generic chemotherapeutic agents, predominantly cytarabine and daunorubicin, which have been the treatment of choice for the past four decades. The dynamics of the current developmental pipeline do, however, suggest a strong focus on the introduction of targeted therapy, with a wide range of novel targets specific to AML, growth and progression under development. These are predominately Small Molecule (SM) inhibitors of serine threonine proteins kinases, immunological agents against tumor associated antigens/genes, and antagonists against cell-surface receptors. Targeting Leukemic Stem Cell Transplants may be Crucial in AML Treatment Initial remission induction treatment of AML can be considered moderately successful, with response rates of XX% in young patients and on average 50% in elderly patients. Hematopoietic Stem Cell Transplants (HSCT) offer a chance for long-term survival in applicable patients, but most patients ultimately relapse. Relapse is thought to be a consequence of the presence of a population(s) of leukemic stem cells which are resistant to chemotherapy. They ultimately resist treatment, and propagate to stimulate relapse. It can be speculated therefore that to effectively cure disease in the majority of patients, these populations of leukemic stem cells must be targeted. Efforts are being made to develop a targeted therapy, with immunotherapies against Cluster of Differentiation (CD) 35, a known cell surface marker of leukemic stem cells, under development. It can be hoped that an effective drug against leukemic stem cells will be introduced beyond the forecast period that will effectively increase the chance of obtaining a long-term remission. Page 3

4 Table of Contents 1 Table of Contents 1 Table of Contents List of Tables List of Figures Introduction Disease Introduction Epidemiology Symptoms Risk Factors Age Gender Smoking Chemotherapy or Radiation Therapy Benzene Previous Myelodysplastic Syndrome Chromosomal Disorders or Genetic Mutations Diagnostic Techniques Blood Tests and Immunophenotyping Flow-Cytometry Cytogenetic Analysis Molecular Diagnostics Pathophysiology Diagnostic Criteria Prognosis and Survival Treatment Algorithm Treatment of Acute Promyelocytic (M3) Leukemia is Effective, with High Cure Rates Clinical Trial Response Criteria Remission Induction Therapy Intensive Remission Induction Therapy Non-intensive Remission Induction Therapy Consolidation Therapy High- or Low-dose Cytarabine-based Therapy Stem Cell Transplantation Remission Re-induction in Relapsed Disease Salvage Chemotherapy HSCT in Relapsed Disease Commercial and Clinical Prospects of Marketed Products Cytarabine...47 Page 4

5 Table of Contents 4.2 Daunorubicin Idarubicin Vidaza Dacogen Mitoxantrone Etoposide Fludarabine Busulfan Cyclophosphamide Conclusion Pipeline for Acute Myeloid Leukemia Therapeutics Overview by Phase and Route of Administration Overview by Molecule Type and Molecular Target Key Molecular Targets in the Developmental Pipeline DNA Machinery Targets Targeted Therapies CD CD Wilm s Tumor Fms-Like Tyrosine Kinase 3 and its Downstream Pathway Components Discussion Clinical Trials Clinical Trial Duration Clinical Trial Size Clinical Trial Failure Rates Discussion Promising Drugs in AML Developmental Pipeline New Formulations Nucleoside analogues Stem Cell Therapy Conclusions Market Forecasts Global Treatment Usage Patterns Market Forecasts North America US Canada Page 5

6 Table of Contents 6.3 Top Five European Markets Epidemiology and Treatment Usage Patterns Annual Cost of Therapy Market Revenues Japan Epidemiology and Treatment Usage Patterns Annual Cost of Therapy Market Forecast Drivers and Barriers Market Drivers High Level of Understanding of Genetic and Epigenetic Factors Underlying AML High Number of Candidates in Drug Development Aging Population Orphan Designation High Degree of Clinical Trial Participation Market Barriers Increasing Rates of Stem Cell Transplant High Heterogeneity of the Disease Lack of Standardized Treatment Market Heavily Dominated by Generics Strategic Consolidations Co-development Deals Ambit Biosciences Enters Co-development Agreement with Astellas Equity Financing of BioTheryX by Leukemia and Lymphoma Society Leukemia and Lymphoma Society Provide Funding for Celator s CPX Ascenta Therapeutics Enter Agreement with Leukemia and Lymphoma Society Stemline Therapeutics and MD Anderson Cancer Centre Enter Collaboration Licensing Deals EpiCept Sells European Rights of Ceplene to Meda Biokine Therapeutics Out-License Development of BL-8040 to BioLineRx Tolero In-License alvocidib from Sanofi Bristol-Myers Squibb Enter Licensing Agreement with Innate Pharma for Lirilumab Cell Therapeutics Enters Licensing Agreement with Chroma Erytech Pharma Enters Licensing Agreement with Orphan Europe for Graspa Appendix All Pipeline Drugs by Phase Discovery Preclinical Page 6

7 Table of Contents IND/CTA-Filed Phase I Phase II Phase III Market Forecasts to Global The US Canada The UK France Germany Italy Spain Japan References Abbreviations Research Methodology Secondary Research Marketed Product Profiles Late-Stage Pipeline Candidates Comparative Efficacy and Safety Heat Map for Marketed and Pipeline Products Product Competitiveness Framework Pipeline Analysis Forecasting Model Deals Data Analysis Contact Us Disclaimer Page 7

8 Table of Contents 1.1 List of Tables Table 1: Acute Myeloid Leukemia Therapeutics, French-American-British Classification, Incidence (%) and Prognosis, Table 2: Acute Myeloid Leukemia Therapeutics, World Health Organization Classification, Table 3: Table 4: Table 5: Table 6: Table 7: Table 8: Table 9: Acute Myeloid Leukemia Therapeutics, Cytogenetic and Molecular Genetic Alterations and their Implications in Disease Prognosis...19 Acute Myeloid Leukemia Therapeutics, Response Criteria (Remission or Treatment Failure)...23 Acute Myeloid Leukemia Therapeutics, Survival and Relapse Rates by Risk Category, Prognosis...28 Acute Myeloid Leukemia Therapeutics, Dosing Regimens of Conventional Care Regimes of Comparator Arm of One Phase III Clinical Trial of Vidaza, Acute Myeloid Leukemia Therapeutics, Hazard Ratio for Allogeneic Stem Cell Transplants vs Chemotherapy and Autologous Stem Cell Transplant in Patients in First Remission, Acute Myeloid Leukemia Therapeutics, Therapies Targeting CD123 in the Developmental Pipeline, Acute Myeloid Leukemia Therapeutics, Therapies Targeting CD33 in the Developmental Pipeline, Table 10: Acute Myeloid Leukemia Therapeutics, Therapies Targeting Wilm s Tumor 1 in Developmental Pipeline, Table 11: Acute Myeloid Leukemia Therapeutics, Upstream and Downstream Pathway Components of FLT3, Table 12: Acute Myeloid Leukemia Therapeutics, Therapies Targeting FLT3 in Developmental Pipeline, Table 13: AML Therapeutics, Combination Therapies* in Current Developmental Pipeline...68 Table 14: Acute Myeloid Leukemia Therapeutics, Dosing Schedules in One Phase II Trial of Qinprezo, Table 15: Acute Myeloid Leukemia Therapeutics, Results of a Phase II Clinical Trial of Midostaurin, Table 16: Acute Myeloid Leukemia Therapeutics, Therapies Targeting CD123 in the Developmental Pipeline, Table 17: Acute Myeloid Leukemia Therapeutics, Top Five European Markets, Annual Cost of Therapy, ($), Table 18: Market for AML, Global, Developmental Pipeline, Discovery, Table 19: Market for AML, Global, Developmental Pipeline, Preclinical, Table 20: Market for AML, Global, Developmental Pipeline, IND/CTA-Filed, Table 21: Market for AML, Global, Developmental Pipeline, Phase I, Table 22: Market for AML, Global, Developmental Pipeline, Phase II, Table 23: Market for AML, Global, Developmental Pipeline, Phase III, Table 24: Acute Myeloid Leukemia Market, Global, Market Forecasts, Table 25: Acute Myeloid Leukemia Market, US, Market Forecasts, Table 26: Acute Myeloid Leukemia Market, Canada, Market Forecasts, Page 8

9 Table of Contents Table 27: Acute Myeloid Leukemia Market, UK, Market Forecasts, Table 28: Acute Myeloid Leukemia Market, France, Market Forecasts, Table 29: Acute Myeloid Leukemia Market, Germany, Market Forecasts, Table 30: Acute Myeloid Leukemia Market, Italy, Market Forecasts, Table 31: Acute Myeloid Leukemia Market, Spain, Market Forecasts, Table 32: Acute Myeloid Leukemia Market, Japan, Market Forecasts, List of Figures Figure 1: Acute Myeloid Leukemia Therapeutics, Efficacy Results for Key Parameters Marketed Products, Intensive Remission Induction Therapy Figure 2: Acute Myeloid Leukemia Therapeutics, Efficacy Results for Key Parameters Marketed Products, Non-Intensive Remission Induction Therapy Figure 3: Acute Myeloid Leukemia Therapeutics, Efficacy Results for Key Parameters Marketed Products, Salvage Therapy in Relapsed Disease Figure 4: Acute Myeloid Leukemia Therapeutics, Treatment Algorithm Figure 5: Acute Myeloid Leukemia Therapeutics, Global, Pipeline Distribution by Stage, Program Type and Route of Administration, Figure 6: Acute Myeloid Leukemia Therapeutics, Global, Pipeline by Molecule Type and Molecular Target, Figure 7: Acute Myeloid Leukemia Therapeutics, Global, Molecular Targets of Developmental Pipeline, Figure 8: Acute Myeloid Leukemia Therapeutics, Global, Clinical Trial Duration (Months), Figure 9: AML Therapeutics, Global, Clinical Trial Size (Participants), Figure 10: AML Therapeutics, Global, Clinical Trial Failure Rate and Reasons for Failure, Figure 11: Acute Myeloid Leukemia Therapeutics, Clinical Trial Heat Map Figure 12: Acute Myeloid Leukemia Therapeutics, Global, Forecast Revenues of CPX-351 ($m), Figure 13: Acute Myeloid Leukemia Therapeutics, Global, Forecast Revenues of Midostaurin ($m), Figure 14: Acute Myeloid Leukemia Therapeutics, Global, Forecast Revenues of Quizartinib ($m), Figure 15: Acute Myeloid Leukemia Therapeutics, Global, Forecast Revenues of StemEx ($m), Figure 16: Acute Myeloid Leukemia Therapeutics, Efficacy Results for Key Parameters Pipeline (Blue) and Marketed Products Comparison. Intensive Remission Induction Figure 17: Acute Myeloid Leukemia Therapeutics, Efficacy Results for Key Parameters Pipeline (Blue) and Marketed Products Comparison. Non-Intensive Remission Induction Figure 18: Acute Myeloid Leukemia Therapeutics, Efficacy Results for Key Parameters Pipeline (Blue) and Marketed Products Comparison. Salvage Therapy for Relapsed Disease Figure 19: Acute Myeloid Leukemia Therapeutics, Global, Treatment Usage Patterns ( 000) and Market Revenues ($m), Page 9

10 Table of Contents Figure 20: Acute Myeloid Leukemia Therapeutics, US, Treatment Usage Patterns ( 000) and Annual Cost of Therapy ($), Figure 21: Acute Myeloid Leukemia Therapeutics, US, Market Revenues ($m), Figure 22: Acute Myeloid Leukemia Therapeutics, Canada, Treatment Usage Patterns and ACoT ( 000; $), Figure 23: Acute Myeloid Leukemia Therapeutics, Canada, Market Revenues ($m), Figure 24: Acute Myeloid Leukemia Therapeutics, Top Five European Markets, Treatment Usage Patterns ( 000), Figure 25: Acute Myeloid Leukemia Therapeutics, Top Five European Markets, Annual Cost of Therapy ($), Figure 26: Acute Myeloid Leukemia Therapeutics,Top Five European Markets, Market Revenues ($m), Figure 27: Acute Myeloid Leukemia Therapeutics, Japan, Treatment Usage Patterns and Annual Cost of Therapy ( 000; $), Figure 28: Acute Myeloid Leukemia Therapeutics, Japan, Market Revenues ($m), Figure 29: Acute Myeloid Leukemia Therapeutics, Global, Co-development Deals, Figure 30: Acute Myeloid Leukemia Therapeutics, Global, Co-development Deals (Molecule Type and Mechanism of Action), Figure 31: Acute Myeloid Leukemia Therapeutics, Global, Licensing Deals by Region, Figure 32: Acute Myeloid Leukemia Therapeutics, Global, Licensing Deals by Value and Year, Figure 33: Acute Myeloid Leukemia Therapeutics, Global, Licensing Deals by Molecule Type and Mechanism of Action, Page 10

11 Introduction 2 Introduction Leukemias are a heterogeneous group of cancers which affect the White Blood Cells (WBC) and bone marrow. All leukemias are characterized by the proliferation of abnormal progenitor blood cells or blasts, which result in a decline in the numbers of normal, healthy, fully differentiated blood cells, leading to the classical symptoms of anemia, bleeding and increased risk of infection. Leukemia can develop along either the lymphoid or myeloid stem cell lines, depending on the effect of genetic and epigenetic mutations on the progression of pluripotent stem cells to the various lines of mature cells which pass into the blood. The effected line, combined with the rate of onset and progression of disease reflects the four main classifications: chronic lymphoblastic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, and Acute Myeloid Leukemia (AML). The latter is the focus of this report. AML is a rare but serious disease, being the most common leukemia suffered by adults. Whilst it can affect anyone at any age, the average age at first diagnosis is approximately 66 (American Cancer Society, 2014). The disease is clinically heterogeneous, characterized by chromosomal and genetic aberrations which accrue with age (Döhner et al., 2008). If not treated, AML develops very quickly, typically over the course of a few weeks and patients quickly become severely ill. Due to its rapid onset and acute nature, there is no standard staging system of AML: the disease is described as either untreated, in remission, or recurrent, with prognosis being heavily dependent on age, molecular profile and cytogenetic profile, the latter being well understood in AML in comparison with other cancers. Despite the variations in cytogenetic profile and prognosis in AML, first-line treatment in eligible patients is almost always intensive chemotherapy with cytarabine and daunorubicin (referred to as remission induction therapy). This treatment has changed little in the last 40 years, with initial rates of remission being XX% in young patients and XX% in elderly patients. Despite these initial remission rates, survival is relatively poor, with AML having the lowest survival rate of all leukemias, being XX% at five years (Roboz et al., 2011). These lack of changes to treatment have resulted in a market heavily dominated by generics. The only patented drugs being Vidaza and Dacogen, approved in 2009 and 2012, respectively, in the EU alone, for the treatment of elderly patients with AML. This is disappointing, given the relatively advanced understanding of the genetic, particularly cytogenetic, mutations which cause AML. Efforts have been made to introduce novel therapies to the AML market. However, drug approval in AML is notoriously difficult. Several drugs have been rejected by the US Food and Drug Administration (FDA), including Dacogen, Laromustine and Tipitarnib. This can be attributed to several factors, including a lack of clear guidelines for endpoint selection and a market with no treatment of choice beyond initial intensive chemotherapy (in eligible patients). Therefore, there is no clear hierarchy for the selection of comparator drugs, making the effectiveness of pipeline drugs, and their place in the market, difficult to determine. However, this lack of a clear treatment algorithm can also work in favor of drugs seeking approval, with at least two of the drugs forecast to be approved for AML in the forecast period being indicated for patient cohorts in which no specific therapy currently exists. Page 11

12 Introduction It is estimated that approximately XX adults die each year of AML in the US (Deschler and Lübbert 2006). 2.8 Prognosis and Survival Although AML is a rare disease, it accounts for a disproportionately large number of cancer deaths. It is estimated that approximately XX adults die each year of AML in the US (Deschler and Lübbert 2006). Without treatment the disease is fatal with only supportive care offering median durations of Overall Survival (OS) between 11 and 20 weeks (Deschler and Lübbert, 2006). Even with the use of chemotherapy, survival rates are still low, with only XX% of all adults diagnosed with AML living for more than five years. In those patients that obtain a CR, consolidation of remission is attempted in order to maintain a reduction of leukemic cells and to prevent their propagation. Durations of remission are, however, often short, with long-term survival often only observed in patients with the best cytogenetics or those who have received allogeneic stem cell transplants (see Section 3.4.2). In the majority of patients which develop relapsed disease, treatment options are limited. Remission re-induction with cytarabine and daunorubicin is an option; however, due to drug resistance, re-induction therapies are more usually a combination of alternative cytotoxic agents. Commonly employed drugs include cladribine, mitoxantrone, fludarabine, idarubicin and etoposide, with or without cytarabine and/or daunoribicin. Remission of relapsed AML is much harder to induce and is associated with a poorer prognosis compared to induction of, and prognosis with first remission. Page 18

13 Treatment Algorithm Cytarabine plus Anthracycline (Daunorubicin or Idarubicin) Treatment in Young Patients Cytarabine in combination with an anthracycline has long been established as the treatment of choice for intensive remission induction in AML. Daunorubicin and idarubicin are almost exclusively the anthracyclines of choice, with both drugs interacting with DNA intercalation and the function of topoisomerase II, to prevent effective DNA division and therefore cell division and tumor growth Efficacy Profile In typical comparison studies of daunorubicin and idarubicin in combination with cytarabine, patients are randomized to receive induction therapy with cytarabine (100mg/m²/day) for seven days plus either daunorubicin (45mg/m²/day) or idarubicin (13mg/m²/day) on the first three days of treatment. Post-remission therapy typically consists of continued treatment courses of cytarabine and the anthracycline administered, but for a reduced number of days (for example 5+2). The results indicate that treatment with cytarabine/idarubicin frequently produces a significant improvement in both CRR and median OS over daunorubicin. However, this has not resulted in the drug becoming the anthracycline of choice in the treatment of AML in young patients. This may be due to the inconsistency of these results, with some trials demonstrating equivalency between the two drugs. It may also be due to the evidence of increased toxicity with idarubicin, as will be discussed in the following section. Page 24

14 Treatment Algorithm Safety Profile Toxicity has been found to be similar between idarubicin and daunorubicin in the aforementioned comparative clinical trials. In the trial by Wiernik et al. (1992) vomiting occurred more frequently with cytarabine/daunorubicin treatment than comparison with cytarabine/idarubicin (XX% and XX% of patients respectively), as did anorexia (XX% v XX%). Nausea (XX%), stomatitis (XX%), esophagitis (XX%), hemorrhage (XX%) and diarrhea (XX%) were also common, occurring at equal frequencies in both arms, and were generally mild in severity. Infection was diagnosed in XX% of patients treated with cytarabine/idarubicin compared with XX% in those treated with cytarabine/daunorubicin (Wiernik et al., 1992). The induction death rates and the number of days of hospitalization were equivalent between the two arms in the Wiernik et al. (1992) trial, but significant increases in the rate of sepsis and 60-day mortality were found in a more recent, equivalent trial with 60-day mortality of XX% with idarubicin compared with XX% with daunorubicin (Ohtake et al., 2011) Discussion Daunorubicin or idarubicin in combination with cytarabine has long been established as standard of care in the treatment of younger patients. Numerous individual studies have established that idarubicin treatment commonly results in higher CRRs and increased median OS, but at the risk of higher myelosuppression, longer recovery times, and increased induction mortality rates, particularly after consolidation therapy with this regimen. As such there is no consensus on which induction drug combination is superior, with use depending strongly on country and clinician preference. It is estimated therefore that global use of the XX drug combinations is equivalent. Page 25

15 Commercial and Clinical Prospects of Marketed Products 4.4 Vidaza Vidaza (azacitidine) was approved for the treatment of MDS and AML with XX% blasts in both the US and the EU in 2004 and 2008 respectively. The approval was based on the results of trials conducted by Silverman et al. (2006) and Fenaux et al. (2010), in the US and EU, respectively, as discussed in Section 2. The US patent of Vidaza expired in 2011 but is not due to expire in Europe until Vidaza, as a non-intensive therapy, is primarily reserved for elderly patients who are ineligible for intensive chemotherapy. This typically constitutes patients with poor cytogenetic risk, and poor performance status, estimated to account for XX% of patients diagnosed aged 65 or older. Current treatment options in this patient cohort are very limited, with treatment typically limited to Vidaza, Dacogen or LDAC monotherapy. In clinical trials, Dacogen has shown significantly higher ORR, comparable AEs, and a non-significant increase in OS, in comparison with treatment with LDAC (Kantarjian et al., 2012). With patents of both Dacogen and Vidaza expired in the US, but maintained in EU, differences in drug cost are not expected to have any additional effect on the competition between these two drugs. Overall, in line with the literature and data collected from KOLs, it is estimated that of the XX% of elderly patients eligible, a minimal XX% of patients are treated with Dacogen, depending on territory. Page 50

16 Pipeline for Acute Myeloid Leukemia Therapeutics Clinical Trial Failure Rates The overall attrition rate in the development of pharmacotherapies for AML is XX%, with failure rates of XX%, XX% and XX% at Phase I, II and III respectively. These figures are higher than those observed across the entire industry with an estimated attrition rate of XX%, based on failure rates reported by Adams and Brantner (2010) of XX% for Phase I, XX% for Phase II, and XX% for Phase III. Failure rates in AML and across the entire industry are high, contributing to the lack of new drug approvals in AML over the past decade. Figure 10: AML Therapeutics, Global, Clinical Trial Failure Rate and Reasons for Failure, A) Clinical Trial Failure Rate XX XX Failure rate (%) XX XX XX XX XX XX Phase I Phase II Phase III Attrition rate Overall SM B) Reasons for Failure XX% XX% XX% n=xx Business Efficacy Safety Accrual XX% Source: GBI Research, Proprietary Clinical Trial Database Page 73

17 Market Forecasts 6 Market Forecasts Over the forecast period, the AML market is expected to exhibit moderate growth for an orphan indication. This will be driven by multiple factors. Firstly, the approval of several pipeline drugs indicated to improve the treatment of specific cohorts of AML patients in which current treatment options are unsatisfactory. These include quizartinib and midostaurin, indicated in FLT3 mutated patients. As targeted therapies, these represent a significant milestone in the treatment of this heterogeneous disease, in which targeted therapies are currently not available. This also includes CPX-351, indicated in newly diagnosed elderly patients with secondary AML. Despite the small market penetration of these drugs, their premium price and higher inflation rates will contribute to a growth in market revenues. 6.1 Global Treatment Usage Patterns AML is a relatively rare cancer with a worldwide incidence rate of XX per XX people (Maynadié et al., 2011). This equates to a current estimate for the global prevalence population (initial plus relapsed disease) of XX. However, incidence of the disease is expected to increase throughout the forecast period, a result of a significant shift in epidemiology towards an aged population across all territories, as the baby boom generation of the 1940s and later reach 65 or older. As a consequence, the percentage of the population above XX in each territory will steadily rise. As a disease primarily of the elderly, this will result in an increase in the rate of AML across the entire population. This, combined with the general population growth expected across most territories analyzed in this report, will result in an increase in the overall prevalence population of AML throughout the forecast period. By 2020, the global prevalence population is forecast to be XX. Page 99

18 Market Forecasts Overall, the increased responses to salvage chemotherapy and improved viability of transplant in relapsed patients will have a positive effect on the number of relapsed patients offered treatment for their disease. In a disease where relapse is high, this will have a significant effect on the overall treatment population for AML. The global treatment population for AML is expected to grow from XX in 2013 to XX in 2020 at a CAGR of XX%. However, it is key to note that the growth in the use of HSCTs will increase the cure rate among both newly-diagnosed and relapsed patients. This will ultimately dampen the positive effect of the increase in incidence rate on the growth in the prevalence and treatment population in AML, as exemplified by smaller growth rates of prevalence population in the latter stages of the forecast across all markets. Page 100

19 Appendix 9 Appendix 9.1 All Pipeline Drugs by Phase Discovery Table 18: Market for AML, Global, Developmental Pipeline, Discovery, Product name Company Alias name Mechanism of action Source: GBI Research Page 129

20 Appendix Preclinical Table 19: Market for AML, Global, Developmental Pipeline, Preclinical, Product name Company Alias name Mechanism of action Source: GBI Research Page 130

21 Appendix IND/CTA-Filed Table 20: Market for AML, Global, Developmental Pipeline, IND/CTA-Filed, Product name Company Alias name Mechanism of action Source: GBI Research Phase I Table 21: Market for AML, Global, Developmental Pipeline, Phase I, Product name Company Alias name Mechanism of action Source: GBI Research Page 131

22 Appendix Phase II Table 22: Market for AML, Global, Developmental Pipeline, Phase II, Product name Company Alias name Mechanism of action Source: GBI Research Page 132

23 Appendix Phase III Table 23: Market for AML, Global, Developmental Pipeline, Phase III, Product name Company Alias name Mechanism of action Source: GBI Research 9.2 Market Forecasts to Global Table 24: Acute Myeloid Leukemia Market, Global, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research Page 133

24 Appendix The US Table 25: Acute Myeloid Leukemia Market, US, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research Canada Table 26: Acute Myeloid Leukemia Market, Canada, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research Page 134

25 Appendix The UK Table 27: Acute Myeloid Leukemia Market, UK, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research France Table 28: Acute Myeloid Leukemia Market, France, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research Germany Table 29: Acute Myeloid Leukemia Market, Germany, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research Page 135

26 Appendix Italy Table 30: Acute Myeloid Leukemia Market, Italy, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) ACoT ($) Maximum market Size ($m) Projected market Size ($m) Minimum market Size ($m) Source: GBI Research Spain Table 31: Acute Myeloid Leukemia Market, Spain, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ('000) ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research Japan Table 32: Acute Myeloid Leukemia Market, Japan, Market Forecasts, Prevalence population ( 000) Diagnosis population ( 000) Treatment population ( 000) ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research Page 136

27 Appendix 9.3 References Adams C and Brantner W (2010). Spending on new drug development. Health Economics; 19(2): Al achkar W, et al. (2013). A de novo acute myeloid leukemia (AML M4) with a complex karyotype and yet unreported breakpoints. Molecular Cytogenetics; 6:18 Amadori S, et al. (1991). Mitoxantrone, etoposide, and intermediate dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. Journal of Clinical Oncology; 9(7): American Cancer Society (2013). What are the key statistics about acute myeloid leukemia? American Cancer Society. Available at: acutemyeloidaml/detailedguide/leukemia acute myeloid myelogenous key statistics [Accessed December 2, 2013] American Cancer Society (2013b). What are the risk factors for acute myeloid leukemia? American Cancer Society. Available at: acutemyeloidaml/detailedguide/leukemia acute myeloid myelogenous risk factors [Accessed December 2, 1990] American Cancer Society (2014a). Leukemia Acute Myeloid (Myelogenous). American Cancer Society. Available at: acutemyeloidaml/detailedguide/leukemia acute myeloid myelogenous treating bone marrow stem cell transplant [Accessed June 9, 2014] American Cancer Society (2014b). Stem cell transplant (peripheral blood, bone marrow, and cord blood transplants). American Cancer Society. Available at: pheralbloodstemcelltransplant/stem cell transplant allogeneic transplant?docselected=stem cell transplant donor experience [Accessed June 9, 2014] American Cancer Society. (2014c). Treatment of acute promyelocytic (M3) leukemia. American Cancer Society. Available at: acutemyeloidaml/detailedguide/leukemia acute myeloid myelogenous treating m3 leukemia?docselected=leukemia acute myeloid myelogenous treating typical treatment of aml [Accessed July 15, 2014] AML Collaborative Group (1998). A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukemia. British Journal of Hematology; 103(1): Anderson J, et al. (2002). Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared with cytarabine and daunorubicin: a southwest oncology group study. Blood; 100: Antin J and Ferrera J (1992), Cytokine dysregulation and acute graft versus host disease. Blood; 80(12): Arup Laboratories (2014). Acute myelogenous leukemia 9AML) panel by FISH. Arup Laboratories. Available at: Baldwin E and Osheroff N (2005). Etoposide, topoisomerase II and cancer. Current Medicinal Chemistry Anti--Cancer Agents; 5(4): Barriga F, et al., Prof. Taner Demirer (Ed.), (2013). Hematopoietic Stem Cell Transplantation, Innovations in Stem Cell Transplantation, InTech, DOI: / Available from: [Accessed August 26, 2014] Bellosillo B, et al. (1998). Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B chronic lymphocytic leukemia cells. British Journal of Hematology; 100(1): Page 137

28 Appendix 9.4 Abbreviations µl: microliter ACoT: Annual Cost of Therapy AE: Adverse Event AKT: Protein Kinase B ALL: Acute Lymphocytic Leukemia AML: Acute Myeloid Leukemia APL: Acute Promyelocytic Leukemia ATP: Adenosine triphosphate ATRA: All-Trans-Retinoic Acid CAGR: Compound Annual Growth Rate CAR: Chimeric Antigen Receptor CBF: Core-Binding Factor CD: Cluster of Differentiation CDK: Cyclin Dependent Kinase CEBPA: CCAAT/Enhancer-Binding Protein Alpha CIAP1/2: Cytoplasm Inhibitor of Apoptosis CLAG-M: cladribine, cytarabine, G-CSF and mitoxantrone CML: Chronic Myeloid Leukemia COX: Cyclooxygenase CR: Complete Remission CRc: Cytogenetic Complete Response Rate CRi: Incomplete Recovery CRp: Incomplete Platelet Recovery CRR: Complete Response Rate CSF1R: Colony Stimulating Factor 1 Receptor CT: Cell Therapy CTA: Clinical Trial Application ECOG: Eastern Cooperative Oncology Group EPHA2: Ephrin Type A Receptor 2 EMA: European Medicines Agency EVI1: Ectropic Viral Integration site-1 FAB: French-American-British FAK: Focal Adhesive Kinase FBC: Full Blood Count FDA: US Food and Drug Administration FGF: Fibroblast Growth Factor FISH: Fluorescent In-Situ Hybridization Page 148

29 Appendix FLAG: fludarabine, cytarabine and G-CSF FLAG-IDA: fludarabine, cytarabine, G-CSF and idarubicin FLT3: FMS-Like Tyrosine Kinase 3 G-CSF: Granulocyte-Colony Stimulating Factor GI: Gastrointestinal GM-CSF: Granulocyte Macrophage Colony-Stimulating Factor GVHD: Graft-Versus-Host Disease HLA: Human Leukocyte Antigen HSC: Hematopoietic Stem Cells HSCT: Hematopoietic Stem Cell Transplant IAP: Inhibitor of Apoptosis Proteins IND: Investigational New Drug ITD: Internal Tandem Duplication IV: Intravenous JAK: JAnus Kinase KOL: Key Opinion Leaders LDAC: Low-Dose Cytarabine LLS: Leukemia and Lymphoma Society mab: monoclonal antibody MACE: amascrine, cytarabine and etoposide MDS: Myelodysplastic Syndrome MEC: mitoxantrone, etoposide and cytarabine MiDAC: mitoxantrone and etoposide NCCN: National Comprehensive Cancer Network NCI: National Cancer Institute NPM1: Nucleophosmin 1 OB: Other Biologics OS: Overall Survival RD: Resistant Disease PDGFR: Platelet Derived Growth Factor Receptor PI3K: Phosphoinositol 3 Kinase PKC: Protein Kinase C PLK1: Polo-Like Kinase 1 PML: Promyelocytic Leukemia PR: Partial Remission Pr: Protein RARα: Retinoic Acid Receptor-α RPN1: Ribophorin 1 Page 149

30 Appendix RUNX1: Runt related transcription factor 1 SAE: SEER: SM: SOD: TAP: TEPA: TK: TKD: Serious Adverse Event Survival, Epidemiology, and End Results Small Molecule Stage of Development Therapy Acceleration Program Tetraethylenepentamine Tyrosine Kinase Tyrosine Kinase Domain U: Unknown/Undisclosed V: Vaccine VEGFR: WBC: WHO: Vascular Endothelial Growth Factor Receptor White Blood Cell World Health Organization WT1: Wilm s Tumor Research Methodology GBI Research aims to help clients within the life sciences industries to better understand their business environment, compete successfully within it, and achieve growth. Our goal is to be the business intelligence partner of choice for companies in the life sciences arena that are looking for meaningful, innovative and evidence-based analysis to inform their key decisionmaking. Our coverage extends to the major indications across all therapy areas with a particular focus on oncology, CNS and immunology and a weighting towards indications demonstrating significant innovation in early-stage development. Our complex proprietary data methodologies drive our specialisms in indications with clearly established therapeutic landscapes, significant pipeline activity and a high proportion of approved products with market exclusivity. Everything we do at GBI Research is rooted in extensive data validation, interrogation and analysis. Our R&A teams are constantly looking for ways to evolve our products in order to provide ever more understanding and transparency around what is really happening in the market. There are a number of key themes running through all of our product offerings that serve to define our proposition and position in a crowded market: Data integrity: GBI Research has full access to comprehensive, market-leading proprietary databases covering marketed and pipeline products, clinical trials, and licensing and co-development deals. In addition to the daily database updates made by that specific team, GBI Research validates all data used in research reports, ensuring an exceptionally high degree of data accuracy. Data are refreshed immediately prior to publication to ensure the final report reflects any changes that took place during the authoring effort. Innovative and meaningful analytical techniques and frameworks: GBI Research recognizes the value of highly accurate raw data, but this is simply the platform. The entire proposition is built around understanding clients needs related to business intelligence, and the ambition to develop novel proprietary data interrogation Page 150

31 Appendix methodologies to extract meaningful and innovative data sets and provide insightful analyses. Evidence based analysis and insight: Proprietary data interrogation methodologies are applied to provide visibility over such vital and tangible data parameters as clinical trial attrition rates versus industry averages, clinical trial endpoint design, product competitiveness benchmarking and multi-scenario forecasting Secondary Research The research process begins with extensive secondary research utilizing proprietary databases and external sources, including qualitative and quantitative information relating to each market. The secondary research sources that are typically referred to include, but are not limited to: Company websites, annual reports, financial reports, broker reports, investor presentations and US Securities and Exchanges Commission (SEC) filings Industry trade journals, scientific journals and other technical literature Internal and external databases Relevant patent and regulatory databases National government documents, statistical databases and market reports Procedure registries News articles, press releases and web-casts specific to the companies operating in the market Marketed Product Profiles The marketed products section provides an overview of the market landscape and gives qualitative profiles of the leading marketed therapies. These profiles describe molecule type, mechanism of action, companies involved in development and marketing, overall clinical and commercial strength, and future prospects. Emphasis is placed on analyzing efficacy and safety data in order to comparatively determine the strongest products available for treatment and assess the clinical and commercial positioning in the current market. In addition, our marketed product profiles assess the clinical and commercial threats and opportunities in the context of late-stage pipeline products in order to provide an evidence-based outlook and perspective for product performance during the forecast period. Where available, historical revenue data are also provided Late-Stage Pipeline Candidates This section consists of qualitative profiles of drugs in the late stages of the developmental pipeline. The focus here is predominantly on Phase III drugs and, depending on clinical and commercial potential, Phase II drugs. The profiles cover areas including, but not limited to, a drug s molecule type and mechanism of action, companies involved in its development, performance in clinical trials specifically relating to efficacy and safety endpoints, and overall clinical and commercial potential. Typically, a revenue forecast for the drug candidate in the covered indication is also provided. This includes peak, medium and low-variance ranges throughout the forecast period, which take into consideration variable factors with a high degree of inherent unpredictability such as marketing approval of pipeline products, clinical uptake and potential competition, drug price inflation rates and many more Comparative Efficacy and Safety Heat Map for Marketed and Pipeline Products The comparative efficacy and safety heat map provides a visual representation of the comparative clinical profile of each marketed product based on available clinical trial data. GBI Research aims to Page 151

32 Appendix aggregate and integrate all available clinical trial efficacy and safety data, organized by the respective endpoints into heat maps to assist in direct performance benchmarking of each drug. The heat map uses conditional formatting to color-code the performance of each marketed drug from strongest to weakest. This is applied to each clinical trial endpoint, allowing us to determine the strongest performer in each endpoint category. A dark blue color indicates the strongest performers in that category, whereas light gray colors indicate weaker performers Product Competitiveness Framework The product competitiveness frameworks translate the clinical trial data in heat maps into performance benchmarks that express the comparative efficacy and safety performance as a ratio. The safety and efficacy data by endpoint are aggregated and compared with the strongest marketed product in each parameter. The baseline, as defined by the strongest marketed product on each endpoint, is defined as 1. The performance of all other marketed and pipeline products is expressed as a comparative ratio in comparison with the strongest performing product on that endpoint. Dark blue values indicate strong performers in that category and lighter gray values indicate weaker performers. This includes qualitative assessment of product features that offer meaningful differentiation from competitor s products, such as route of administration and dosage/administration frequency. Overall, this type of analysis helps to determine the potential impact of a specific new drug on the market, as well as the future competitive landscape Pipeline Analysis Overall Pipeline This section analyzes proprietary pipeline data and provides a thorough overview of the current pipeline landscape for the indication in question. Using proprietary data analysis techniques, the pipeline is broken down by stage of development, molecule type, mechanism of action and/or molecular target. Each of these categories is subject to further granulation depending on the level of data available and any observed trends or findings. It is broken down by program type to determine the degree of novelty within the pipeline. Each drug development program is defined as being novel, generic, a biosimilar, or repositioned using methodologies and processes and drawing upon multiple databases, including market and pipeline datasets. Repositioned drugs are defined as those that are already marketed for another indication and that are now in development for the indication being assessed. Novel products are defined as containing active pharmaceutical ingredients that are currently not approved in the market, whereas generic products include approved compounds that are no longer under patent. The accuracy of the data is validated using external sources such as company websites. Like all sections within the report, the data analysis provides the basis for in-depth written discussion, which determines the broader implications of the results obtained Clinical Trials The clinical trial landscape for each indication is comprehensively profiled using proprietary clinical trial data. The factors assessed include, but are not limited to, clinical trial failure rate, size and duration and endpoint analysis. Each is analyzed by clinical stage of development Failure Rate Failure rate analysis helps to determine the risk profile associated with drug development for the indication in question. The failure rate is defined as the percentage of products that fail to progress to the next stage of clinical development or reach marketing approval, as is the case for products in Phase III. Inactive development programs are defined as those for which no progress has been made and for which no further updates have been disclosed for over four years. This analysis is typically subject to further granulation, such as failure rate by Phase, mechanism of action and molecule type, to provide further insight into the risks associated with the development of certain classes of drugs and product technology Clinical Trial Size Page 152