GBI Research Report Guidance

Transcription

1 THERAPY ANALYSIS Multiple Myeloma Therapeutics in Major Developed Markets to Growth Driven by Rising Prevalence, Continued Success of Revlimid and Emerging Supplementary Treatments Published: July 2015 Report Code: GBIHC365MR

2 GBI Research Report Guidance Chapter two provides an overview of the disease, its symptoms, etiology, pathophysiology, diagnosis, classification, epidemiology, prognosis, staging and treatment options. Chapter three provides a detailed profiling and comparative heat map analysis on the safety and efficacy of the currently marketed products in the MM market. Chapter four presents a detailed pipeline analysis of the disease, including individual product profiles and a comparative efficacy and safety profile heat map analysis of the most promising pipeline products, as well as analysis on the distribution of molecule types across the MM developmental pipeline, the molecular targets of pipeline drug candidates, clinical trial failure rates, durations and sizes. Chapter five provides market forecasts for the major developed countries of the US, UK, France, Germany, Italy, Spain, Japan and Canada. The multiple scenario forecasts take into account a range of factors that are likely to vary and provide a clear perspective of the potential degree of variance in market size. Chapter six covers the major deals that have taken place in the MM market in recent years. Coverage includes co-development deals and licensing agreements, which are segmented on the basis of geography and total value. A concomitant analysis of the licensing deal values for products, by molecule type and molecular target, is also provided. Page 2

3 Executive Summary Rising Prevalence and Product Approvals to Drive Market Growth The Multiple Myeloma (MM) market is forecast to grow from a value of $XX billion in 2014 to $XX billion in 2021 at a Compound Annual Growth Rate (CAGR) of XX%. Over the forecast period, the prevalence of MM is widely expected to increase across the top eight markets. A globally aging population is driving this, given that the disease is notably more common in the elderly (Alexander et al., 2007). In addition, the approval of novel compounds over the past two decades, as well as the continued development of novel compounds, has resulted in improved clinical outcomes and survival rates. The rising prevalence population, together with improved diagnostic techniques and data registration, will lead to an increase in the diagnosis and treatment population in the developed markets, boosting demand for therapeutics and contributing to market growth over the forecast period (Renshaw et al., 2010). The market is set to be driven further by new approvals for drugs that will supplement current market leaders, such as Revlimid, and offer greater therapeutic options, mainly in the relapsed/refractory setting. Promising examples include ixazomib, ARRY-520 (filanesib), elotuzumab, and daratumumab, all of which are expected to be approved over the forecast period and demonstrated clinical benefit when used in combination with the established drugs such as Revlimid. Growing Therapeutic Options Improve Patient Outcomes Over recent decades, the MM market has undergone significant change. Although the disease remains incurable, greater understanding of its underlying cellular and molecular biology has driven the development of novel therapeutics. Consequently, clinical outcomes have improved significantly, with survival rates rising by about 50% since the introduction of novel agents into the market (Lacy et al., 2009). The spectrum of MM disease stages has benefited from novel drugs entering the market. Most notably, immunomodulatory drugs such as Thalomid (thalidomide) and its derivatives Revlimid (lenalidomide) and Pomalyst (pomalidomide) have improved outcomes in both initial stages of disease and in the relapsed or refractory disease settings. Other novel agents, including those recently approved for MM, have also benefited the market, particularly in the relapsed or refractory disease setting. For instance, Kyprolis (carfilzomib) showed superiority over market leader Velcade (bortezomib), and demonstrated efficacy in heavily pre-treated patients, which contains high unmet need. In addition, the approval of the Histone Deacetylase (HDAC) inhibitor Farydak (panobinostat), which represented another novel entry into the market, demonstrates how diversity and innovation continue to drive the MM treatment landscape. Late Stage Pipeline Set to Expand Relapsed/Refractory Treatment Options The MM pipeline contains XX products in active development, the vast majority of which are in Preclinical, Phase I, and Phase II. There is significant diversity in the molecule type and molecular target of these pipeline products, which will build on the growing diversity in the market following the introduction of immunomodulatory therapies and the HDAC inhibitor Farydak. Targeting oncogenic signaling cascades through inhibition of growth factor receptors and inducing an immune response, either directly or through tumor-associated antigens, are common features of therapies throughout the developmental pipeline, in an effort to improve targeted therapy options. The late-stage pipeline contains several products with the potential to be approved and launched during the forecast period. Most are aimed at the relapsed/refractory patient population, but some target the newly diagnosed patient population, such as daratumumab. Despite a significant presence of proteasome and HDAC inhibitors in the late-stage pipeline following the market success of therapies such as Velcade and Farydak, there is a considerable level of innovation in the treatments for relapsed/refractory patients, such as elotuzumab and daratumumab, which utilize novel mechanisms of action. Although some late-stage therapies are predicated to be low-impact, others have demonstrated promising clinical results in specific patient populations such as heavily pretreated. Consequently, they are likely to provide physicians with increased choice and complexity in the MM treatment algorithm over the forecast period. Page 3

4 1 Table of Contents 1 Table of Contents List of Tables List of Figures Introduction Disease Introduction Etiology Pathophysiology Symptoms Diagnosis and Classification Epidemiology Prognosis and Disease Staging Treatment Options Treatment Algorithm Initial Therapy for Newly Diagnosed Symptomatic Disease Maintenance Therapy Therapy for Relapsed or Refractory Myeloma Marketed Products Overview Immunomodulatory Agents Thalomid (thalidomide) Celgene Revlimid (lenalidomide) Celgene Pomalyst (pomalidomide) Celgene Proteasome Inhibitors Velcade (bortezomib) Millennium Pharmaceuticals/Takeda Kyprolis (carfilzomib) Onyx Histone Deacetylase Inhibitors Farydak (panobinostat) Novartis Chemotherapy Doxil (doxorubicin HCl liposome injection) Janssen Comparative Efficacy and Safety of Marketed Products Pipeline Products Overall Pipeline Pipeline Analysis by Molecular Target Clinical Trials Failure Rate Patient Enrolment and Clinical Trial Size Duration Competitive Clinical Trials Metrics Analysis Promising Drug Candidates in the Pipeline Ixazomib Citrate Millennium Pharmaceuticals Zolinza (vorinostat) Merck ARRY-520 (filanesib) Array Biopharma Aplidin (plitidepsin) PharmaMar Elotuzumab AbbVie and Bristol Myers Squibb Daratumumab Johnson & Johnson Heat Map for Pipeline Products Market Forecast to Geographical Markets Global Market North America Page 4

5 5.3.1 Treatment Usage Patterns Annual Cost of Therapy Market Size Top Five EU Markets Treatment Usage Patterns Annual Cost of Therapy Market Size Japan Treatment Usage Patterns Annual Cost of Therapy Market Size Drivers and Barriers for the Disease Market Drivers Barriers Deals and Strategic Consolidations Licensing Deals Genmab Enters into Licensing Agreement with Janssen Biotech for Daratumumab Genentech Enters into Licensing Agreement with Seattle Genetics Now Terminated OncoPep Enters into Licensing Agreement with Dana-Farber Cancer Institute for Cancer Vaccine Technology PharmaMar Enters into Licensing Agreement with Chugai for Aplidin Onyx Enters into Licensing Agreement with Ono Pharma for Kyprolis and Oprozomib Co-development Deals Celgene Enters into Co-development Agreement with MedImmune Acetylon Enters into Co-development Agreement with Leukemia & Lymphoma Society Boehringer Ingelheim Enters into Collaboration Agreement with Micromet Multiple Myeloma Research Foundation Enters into Co-development Agreement with Onyx Dana-Farber Cancer Institute Enters into Agreement with MannKind Nordic Nanovector Enters into Co-development Agreement with Affibody Appendix All Pipeline Drugs by Phase of Development Discovery Preclinical IND/CTA-filed Phase I Phase II Phase III Pre-registration Market Forecasts to Global US Canada UK France Germany Italy Spain Japan Page 5

6 7.3 Bibliography Abbreviations Research Methodology Secondary Research Marketed Product Profiles Late-Stage Pipeline Candidates Comparative Efficacy and Safety Heat Map for Marketed and Pipeline Products Forecasting Model Deals Data Analysis Expert Panel Validation Contact Us Disclaimer List of Tables Table 1: Multiple Myeloma Therapeutics Market, Global, Initial Screening in Suspected Myeloma Patients...12 Table 2: Multiple Myeloma Therapeutics Market, Global, Diagnostic Criteria for MGUS, Asymptomatic Myeloma and Symptomatic Myeloma...13 Table 3: Multiple Myeloma Therapeutics Market, Global, Myeloma-Related Organ or Tissue Impairment...13 Table 4: Multiple Myeloma Therapeutics Market, Global, Disease Staging, Durie-Salmon Staging System...16 Table 5: Multiple Myeloma Therapeutics Market, Global, Prognostic Factors...17 Table 6: Multiple Myeloma Therapeutics Market, Global, Prognostic Factors...18 Table 7: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Discovery, Table 8: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Preclinical, Table 9: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, IND/CTA-filed, Table 10: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Phase I, Table 11: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Phase II, Table 12: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Phase III, Table 13: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Pre-registration, Table 14: Multiple Myeloma Therapeutics Market, Global, Market Forecast, Table 15: Multiple Myeloma Therapeutics Market, US, Market Forecast, Table 16: Multiple Myeloma Therapeutics Market, Canada, Market Forecast, Table 17: Multiple Myeloma Therapeutics Market, UK, Market Forecast, Table 18: Multiple Myeloma Therapeutics Market, France, Market Forecast, Table 19: Multiple Myeloma Therapeutics Market, Germany, Market Forecast, Table 20: Multiple Myeloma Therapeutics Market, Italy, Market Forecast, Table 21: Multiple Myeloma Therapeutics Market, Spain, Market Forecast, Table 22: Multiple Myeloma Therapeutics Market, Japan, Market Forecast, Page 6

7 1.2 List of Figures Figure 1: Multiple Myeloma Therapeutics Market, Global, Average Number of New Cases per Year and Age Specific Incidence Rates, UK, Figure 2: Multiple Myeloma Therapeutics Market, Global, Treatment Algorithm for Myeloma...19 Figure 3: Multiple Myeloma Therapeutics Market, Global, Heat Map for Initial Treatment Efficacy...36 Figure 4: Multiple Myeloma Therapeutics Market, Global, Heat Map for Initial Treatment Safety.36 Figure 5: Multiple Myeloma Therapeutics Market, Global, Heat Map for Maintenance Treatment...37 Figure 6: Multiple Myeloma Therapeutics Market, Global, Heat Map for Relapsed or Refractory Multiple Myeloma Efficacy...37 Figure 7: Multiple Myeloma Therapeutics Market, Global, Heat Map for Relapsed or Refractory Multiple Myeloma Safety...38 Figure 8: Multiple Myeloma Therapeutics Market, Global, Overview of Pipeline Products...40 Figure 9: Multiple Myeloma Therapeutics Market, Global, Target Families in the Pipeline...43 Figure 10: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Overall Attrition Rate and Failure Rate by Phase, Figure 11: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Overall Attrition Rate and Failure Rate by Phase and Molecule Type, Figure 12: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Attrition Rate and Failure Rate by Phase and Molecular Target, Figure 13: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Size per Product by Molecule Type, Figure 14: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Size per Individual Trial by Molecule Type, Figure 15: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Size per Product by Molecular Target, Figure 16: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Size per Individual Trial by Molecular Target, Figure 17: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Duration by Stage of Development and Molecule Type, Figure 18: Multiple Myeloma Therapeutics Market, Global, Clinical Trial Duration by Stage of Development and Molecular Target, Figure 19: Multiple Myeloma Therapeutics Market, Global, Comparison of Average Trial Metrics by Phase and Molecule Type...53 Figure 20: Multiple Myeloma Therapeutics Market, Global, Comparison of Average Trial Metrics by Phase and Molecular Target...53 Figure 21: Multiple Myeloma Therapeutics Market, Global, Ixazomib Citrate Market Forecast, Figure 22: Multiple Myeloma Therapeutics Market, Global, Zolinza Market Forecast, Figure 23: Multiple Myeloma Therapeutics Market, Global, ARY-520 Market Forecast, Figure 24: Multiple Myeloma Therapeutics Market, Global, Elotuzumab Market Forecast, Figure 25: Multiple Myeloma Therapeutics Market, Global, Daratumumab Market Forecast, Figure 26 : Multiple Myeloma Therapeutics Market, Global, Pipeline Heat Map, Figure 27: Multiple Myeloma Therapeutics Market, Global, Treatment Patterns ( 000) and Market Size ($bn), Figure 28: Multiple Myeloma Therapeutics Market, North America, Treatment Patterns, Figure 29: Multiple Myeloma Therapeutics Market, North America, Annual Cost of Therapy ($), Figure 30: Multiple Myeloma Therapeutics Market, North America, Market Size, Figure 31: Multiple Myeloma Therapeutics Market, EU, Treatment Patterns, Figure 32: Multiple Myeloma Therapeutics Market, EU, Annual Cost of Therapy ($), Figure 33: Multiple Myeloma Therapeutics Market, EU, Market Size, Figure 34: Multiple Myeloma Market, Japan, Treatment Usage Patterns ( 000), Figure 35: Multiple Myeloma Market, Japan, Annual Cost of Therapy ($), Figure 36: Multiple Myeloma Therapeutics Market, Japan, Market Size ($m), Page 7

8 Figure 37: Multiple Myeloma Therapeutics Market, Global, Licensing Deals by Region, Figure 38: Multiple Myeloma Therapeutics Market, Global, Licensing Deals by Deal Value ($m), Figure 39: Multiple Myeloma Therapeutics Market, Global, Number of Disclosed and Undisclosed Licensing Deals by Year, Aggregate Deal Value ($m) and Aggregate Upfront Payment Value ($m), Figure 40: Multiple Myeloma Therapeutics Market, Global, Licensing Deals by Stage of Development, Deal Value ($m) and Upfront Payment Value ($m), Figure 41: Multiple Myeloma Therapeutics Market, Global, Licensing Deals by Molecule Type, Stage of Development and Aggregate Deal Value ($m), Figure 42: Multiple Myeloma Therapeutics Market, Global, Licensing Deals by Molecular Target, Figure 43: Multiple Myeloma Therapeutics Market, Global, Co-development Deals by Region, Figure 44: Multiple Myeloma Therapeutics Market, Global, Number of Disclosed and Undisclosed Co-development Deals by Year, Figure 45: Multiple Myeloma Therapeutics Market, Global, Co-development Deals by Stage of Development, Figure 46: Multiple Myeloma Therapeutics Market, Global, Co-development Deals by Molecule Type and Stage of Development, Figure 47: Multiple Myeloma Therapeutics Market, Global, Co-development Deals by Molecular Target, Page 8

9 The disease is considered incurable, although over the past decade, there have been significant improvements in therapy. 2 Introduction 2.1 Disease Introduction Multiple Myeloma (MM) is a hematological malignancy characterized by the proliferation of plasma cells in the Bone Marrow (BM). It is considered the second-most frequently diagnosed hematological malignancy, with an annual prevalence in the US of about XX (Singhal and Mehta, 2006). The majority of patients with MM evolve from the asymptomatic pre-malignant stage known as Monoclonal Gammopathy of Undetermined Significance (MGUS). This stage develops into MM at a rate of XX% per year. There is also an intermediate stage, which is asymptomatic but a more advanced pre-malignant stage than MGUS, called Smouldering (or indolent) Multiple Myeloma (SMM). Together, MM, MGUS and SMM encompass the spectrum of plasma cell disorders, with MGUS and SMM being slowly proliferative and quite stable compared with the active form of the disease (Singhal and Mehta, 2006). The disease is considered incurable, although over the past decade, there have been significant improvements in therapy, driven by a greater understanding of pathophysiology. There are now five classes of drugs used in the treatment of myeloma: immunomodulatory drugs, chemotherapy, proteasome drugs, Histone Deacetylase (HDAC) inhibitors and steroids. Many of the notable drugs in these classes were approved over the past years. Recent examples of new approvals include Farydak (panobinostat), a HDAC inhibitor approved in February 2015, and Kyprolis (carfilzomib), a proteasome inhibitor approved in July Etiology Although the exact etiology of MM has not been determined, genetic, environmental and occupational factors have been identified. There is no evidence of a hereditary basis for the disease. However, MM has been reported in identical twins and first-degree relatives (Shah, 2015). Abnormalities in some oncogenes have been associated with disease progression. For example, abnormalities in the oncogene c-myc develop early in the course of plasma cell tumors, while abnormalities in oncogenes, including K-ras and N- ras, are associated with development after BM relapse (Shah, 2015). In addition, abnormalities in tumor suppressor genes such as p53 are linked to spread to other organs. Although mutation of p53 in MM is considered rare at diagnosis (it is found in about XX% of newly diagnosed patients) the incidence is thought to increase as the disease advances, which suggests it plays a key role in disease progression (Teoh and Chng, 2014). In addition to genetic factors, potential environmental or occupational causes have also been identified. In particular, individuals significantly exposed to the food, petrochemical and agriculture industries over a long-term period. For example, elevated risk has been associated with farmers who use insecticides or herbicides (Shah, 2015). MGUS is also a risk factor for the development of MM. MGUS can be categorized as non- Immunoglobulin (Ig)M MGUS, IgM MGUS and light chain MGUS, and is found in XX% of the elderly Caucasian population. Patients with the non-igm MGUS have a risk of developing MM at a rate of 1% per year. However, patients with IgM MGUS rarely progress to MM and instead have a risk of progression to Waldenstrom macroglobulinemia or, albeit less frequently, lymphoma or Amyloid Light Chain (AL) amyloidosis. Light chain MGUS can progress to light chain MM, AL amyloidosis and light chain deposition disease (Shah, 2015). Other factors linked to MM development include radiation, chronic inflammation and infection. Although there is not a great deal of evidence to suggest these factors are strongly linked with MM, the human herpesvirus XX infection of BM dendritic cells has been identified in some patients with MM and some patients with MGUS (Shah, 2015). Age is also considered a significant risk factor. The disease is rarely diagnosed in individuals aged under XX. For those aged over XX, the incidence increases significantly up to about the age of XX, following which it declines (Alexander et al., 2007). Page 9

10 4 Pipeline Products 4.1 Overall Pipeline The MM pipeline contains XX products in active development, encompassing a range of molecule types and therapeutic targets. The innovation that has characterized the market over recent years is also clearly present in the current pipeline, with a strong presence of targeted products. For example, the PI3K/Akt pathway is frequently targeted in the pipeline and includes proteins such as Akt and PKC. In addition, therapies targeting the MAPK/ERK pathway are relatively common. The distribution of MM products by stage reveals that the vast majority of pipeline products are in the early stages of development, between Discovery and Phase I. Despite this, significant activity was found in Phase II, which accounts for XX% of pipeline therapies. However, there is a considerable drop in Phase III, which only accounts for XX% of the total pipeline. Although the small proportion of products in Phase III suggests that there will be few new market entrants over the forecast period, the large number of products in the Phase I, II, and Preclinical stages provides some security, as there will be a continued supply of products progressing through development for the foreseeable future. Small molecules are the most abundant molecule type in the pipeline, accounting for XX% of all products. With almost a third of products in the pipeline being biologics, this is the second most prominent molecule type category. Biologics primarily consist of mabs (XX%), although there are also biosimilars and peptide therapies included in this category. Other molecule type categories are present at lower frequencies, as together, small molecules and biologics occupy XX% of the pipeline. The remaining XX% comprises cell therapies, vaccines, oligonucleotides and stem cell therapies. Examination of the various molecule types by stage shows only minor deviations from the overall pipeline trend, as the most prevalent molecule type in each stage is small molecule, followed by biologics. The data show that Phase III is made up of small molecules and biologics exclusively, with the less common molecule types such as oligonucleotide and stem cell therapy found only in Phase I and Preclinical. The most frequent route of administration, in XX% of pipeline therapies, is intravenous injection, as this is thought to be one of the most efficient methods of delivering the necessary concentrations of antimyeloma therapy into the blood. Orally taken therapies also constitute a significant portion of the pipeline, with XX%. Orally available therapies have the advantage of being more convenient than other drug delivery routes for both patients and physicians, as no hospital visit is required. Therefore, oral therapies are often preferred providing the necessary drug absorption and delivery to the blood can be reached, which can be achieved by an increase in dose in most cases. The rest is made up of some less common routes of administration including parenteral, subcutaneous, intradermal and intramuscular. Page 39

11 Figure 8: Multiple Myeloma Therapeutics Market, Global, Overview of Pipeline Products A Pipeline by Stage of Development B Pipeline by RoA Phase III Preregistration Unknown Discovery Intravenous, oral Subcutaneous Intradermal Phase II Total: XX Preclinical Parenteral Total: XX Intravenous Phase I IND/CTAfiled Oral C Pipeline by Program Type D Pipeline by Molecule Type Number of products Discovery Preclinical IND/CTA-filed Phase I Phase II Phase III Pre-registration Generic Repositioned Novel Unknown Cell therapy Vaccine Biologic Other Oligonucleotide Total: XX Stem cell therapy Small molecule Includes XX pipeline products of an undisclosed molecule type E Pipeline by Stage and Molecule Type Number of products Discovery Preclinical IND/CTA-filed Phase I Phase II Phase III Pre-registration Unknown Stem cell therapy Other Oligonucleiotide Cell therapy Vaccine Biologic Small molecule, Proprietary Pipeline Products Database Abbreviations: IND/CTA: Investigational New Drug/Clinical Trial Authorization; mab: Monoclonal Antibody; RoA: Route of Administration 4.2 Pipeline Analysis by Molecular Target A multi-tiered categorization system was used to analyze the MM pipeline by the molecular target of products. With XX products and XX% of the total pipeline, the largest target family contains proteins involved in cytokine/growth factor signal transduction. The majority of these are cell surface receptors that initiate intracellular signaling pathways that often impact oncogenic processes. Cytokine/growth factor signaling is linked to the signal transduction category as many of these therapies modulate the activation of various cell surface receptors for ligands such as Fibroblast Growth Factor Receptor (FGFR) and Interleukin XX, which play a vital role in initiating the intracellular signal cascade. Therapies in this target category represent XX% of the overall pipeline, making them almost as common as therapies targeting intracellular signaling. Page 40

12 7 Appendix 7.1 All Pipeline Drugs by Phase of Development Discovery Table 7: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Discovery, 2015 Product name Company Molecule type Mechanism of action Page 94

13 7.1.2 Preclinical Table 8: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Preclinical, 2015 Product name Company Molecule type Mechanism of action Page 95

14 7.1.3 IND/CTA-filed Table 9: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, IND/CTA-filed, 2015 Product name Company Molecule type Molecular target(s) Page 96

15 7.1.4 Phase I Table 10: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Phase I, 2015 Product name Company Molecule type Molecular target(s) Page 97

16 7.1.5 Phase II Table 11: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Phase II, 2015 Product name Company Molecule type Molecular target(s) Page 98

17 7.1.6 Phase III Table 12: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Phase III, 2015 Product name Company Molecule type Molecular target(s) Page 99

18 7.1.7 Pre-registration Table 13: Multiple Myeloma Therapeutics Market, Global, Pipeline Products, Pre-registration, 2015 Product name Company Molecule type Molecular target(s) 7.2 Market Forecasts to Global Table 14: Multiple Myeloma Therapeutics Market, Global, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum market size ($bn) Projected market size ($bn) Minimum market size ($bn) Page 100

19 7.2.2 US Table 15: Multiple Myeloma Therapeutics Market, US, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($bn) Projected market size ($bn) Minimum market size ($bn) Canada Table 16: Multiple Myeloma Therapeutics Market, Canada, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Page 101

20 7.2.4 UK Table 17: Multiple Myeloma Therapeutics Market, UK, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) France Table 18: Multiple Myeloma Therapeutics Market, France, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Page 102

21 7.2.6 Germany Table 19: Multiple Myeloma Therapeutics Market, Germany, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Italy Table 20: Multiple Myeloma Therapeutics Market, Italy, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Page 103

22 7.2.8 Spain Table 21: Multiple Myeloma Therapeutics Market, Spain, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Japan Table 22: Multiple Myeloma Therapeutics Market, Japan, Market Forecast, Year Prevalence population ('000) Diagnosis population ('000) Treatment population ('000) Maximum ACoT ($) Projected ACoT ($) Minimum ACoT ($) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Page 104

23 7.3 Bibliography Abdelkefi A, et al. (2008). Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicentre randomized clinical trial. Blood; 111: Al-Quran SZ, et al. (2007). Assessment of bone marrow plasma cells infiltrates in multiple myeloma: the added value of CD138 immunohistochemistry. Human Pathology; 38: Alexander DD, et al. (2007). Multiple Myeloma: A review of the epidemiology literature. International Journal of Cancer; 12:40-61 Amgen (2015) Annual report and 10-K. Available from [Accessed on June 19, 2015] Anderson KC, et al. (2010). NCCN clinical practice guidelines in oncology: multiple myeloma. Version 2, National Comprehensive Cancer Network. Available from: Andhavarapu S and Roy V (2013). Immunomodulatory drugs in multiple myeloma. Expert Review of Hematology; 6: Atanackovic D, et al. (2007). Cancer-Testis Antigens are Commonly Expressed in Multiple Myeloma and Induce Systemic Immunity Following Allogenic Stem Cell Transplantation. Immunobiology; 109(3): Attal M, et al. (2006). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood; 108: Attal M, et al. (2012). Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. The New England Journal of Medicine; 366: Badros AZ, et al. (2010). The role of maintenance therapy in the treatment of multiple myeloma. Journal of the National Comprehensive Cancer Network; 8: S21-S27 Barlogie B, et al. (2006). Thalidomide and hematopoietic-cell transplantation for multiple myeloma. The New England Journal of Medicine; 354: Benboubker L, et al. (2014). Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. The New England Journal of Medicine; 371: Bird JM, et al. (2014). Guidelines for the diagnosis and management of multiple myeloma. British Committee for Standards in Haematology. Available from: Brenner H, et al. (2009). Expected long-term survival of patients diagnosed with multiple myeloma in Haematologica; 2: Celgene (2014) annual report. Celgene. Available from: Chari A, et al. (2013). A Phase I Study of ARRY-520 (Filanesib) with Bortezomib in Relapsed or Refractory Multiple Myeloma; ASH 2013 Annual Meeting. Abstract #1938 Detre C, et al. (2010). SLAM Family Receptors and SLAM-associated Protein (SAP) Modulate T- Cell Functions. Seminars in Immunopathology; 32(2): Dimopoulos M, et al. (2007). Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. The New England Journal of Medicine; 357: Dimopoulos M, et al. (2013). Vorinostat or Placebo in Combination with Bortezomib in Patients with Multiple Myeloma (VANTAGE 088): A Multicentre, Randomised, Double-Blind Study. Lancet Oncology; 14(11): Page 105

24 Zappasodi P, et al. (2006). Bortezomib-combination based therapy in relapsed-refractory myeloma patients. Haematologica Reports; 2(5) 7.4 Abbreviations µmol: Micromole AEs: Adverse Events Akt: Protein Kinase B AL: Amyloid Light Chain BiPN: Bortezomib-emergent Peripheral Neuropathy BM: Bone Marrow BMP: Bone Morphogenetic Protein BTD: Breakthrough Therapy Designation CAGR: Compound Annual Growth Rate CD: Cluster of Differentiation CDK: Cyclin-Dependent Kinases CEACAM5: Carcinoembryonic Antigen-related Cell Adhesion Molecule 5 ChT-L: Chymotrypsin-Like CR: Complete Response CT: Computerised Tomography CTA: Cancer Testis Antigens DACi: Deacetylase inhibitors Dex: Dexamethasone dl: decilitre ECM: Extracellular Matrix EFS: Event-Free Survival EPHA3: Ephrin A3 ERK: Extracellular Signal-Regulated Kinases ESR: Erythrocyte Sedimentation Rate FBC: Full Blood Count FDA: Food and Drug Administration FGFR: Fibroblast Growth Factor Receptor FISH: Fluorescence In Situ Hybridization gm: gram HDAC: Histone Deacetylase HGFR: Hepatocyte Growth Factor Receptor HMRN: Haematological Malignancy Research Network IAP: Inhibitor of Apoptosis Protein ICAM: Intracellular Adhesion Molecule Ig: Immunoglobulin Page 110

25 IGF: Insulin-like Growth Factor IL: Interleukin ISS: International Staging System IV: Intravenous JAK: Janus Kinase KMA: Kappa Myeloma Antigen KSP: Kinesin Spindle Protein LDH: Lactate Dehydrogenase mab: Monoclonal Antobody MAGEA3: Melanoma-Associated Antigen 3 MAGEC2: Melanoma-Associated Antigen C2 MAPK: Mitogen-Activated Protein Kinase MCL: Myeloid Cell Leukemia MDM2: Murine Double Minute 2 MGUS: Monoclonal Gammopathy of Undetermined Significance MM: Multiple Myeloma mmol: Millimole MP: Melphalan + Prednisone MPT: Melphalan + Prednisone + Thalidomide MRI: Magnetic Resonance Imaging MUC; Mucin NF-κB: Nuclear -κb factor ORR: Overall Response Rate OS: Overall Survival PAD: Velcade + Doxorubicin + Dexamethasone PD: Programmed cell Death PFS: Progression-Free Survival PI3K: Phosphoinositide 3-Kinase PIM: Proviral Insertion in Murine PR: Partial Response PTPRC: Protein-Tyrosine Phosphatase Receptor-type C RANK: Receptor Activator of NF-κB RANKL: Receptor Activator of NF-κB ROTI: Myeloma-Related Organ Impairment Ligand RVP: RVD: Revlimid + Velcade + Dexamethasone SAE: Serious Adverse Events SFLC: Serum Free Light Chain SLAM: Signaling Lymphocytic Activation Molecule Page 111

26 SMM: Smouldering (or indolent) Multiple Myeloma STAT: Signal Transducers and Activators of Transcription TNF: Tumor Necrosis Factor TRAIL: TNF-Related Apoptosis Inducing Ligand TTF: Time to Treatment Failure TTP: Time to Disease Progression TTR: Time to Response UL: Units/Litre VAD: Vincristine + Doxorubicin + Dexamethasone VEGF: Vascular Endothelial Growth Factor VMP: Velcade + melphalan + prednisone VMPT: Velcade + Melphalan + Prednisone + Thalidomide VTD: Velcade + Thalomid +Dexamethasone β2-m: beta 2 -Microglobulin 7.5 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 methodologies to extract meaningful and innovative data sets and provide insightful analyses. Page 112

27 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 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. Page 113

28 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. 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 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 in 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 Clinical trial size assesses the mean and median subject recruitment size of clinical trials by Phase and compares the respective indications against the wider therapy area or industry benchmarks. This is commonly analyzed further by molecule type and mechanism of action Clinical Trial Duration Like clinical trial size, clinical trial duration analyzed and disclosed the mean and median duration (in months) of clinical trials by Phase and molecule type/mechanism of action Clinical trial Endpoint Analysis A clinical trial endpoint is a measure from which a decision can be made to accept or reject the null hypothesis. The primary and secondary endpoints used in clinical trials can be used to provide insight into the patient outcomes driving drug development. The analysis is designed to extract the primary and secondary outcome measures used across all clinical trials in the indication, whether different safety, efficacy or pharmacokinetic endpoints. These data are then graphically presented to display the most prominent primary and secondary endpoints. Trends in primary and secondary endpoints are assessed by Phase of development and, when possible, over a specified timeframe to identify any changing patterns in clinical trial design. Page 114

29 7.5.5 Forecasting Model This GBI Research report covers the following major developed markets: the US; Canada; the top five countries in Europe: the UK, Germany, France, Spain, Italy; and Japan. The total market size for each country is provided, which is the sum value of the market sizes of all the indications for that particular country. Our forecasting model uses an epidemiology-based approach, in which sales for each product are calculated based on the cost of the drug, and the number of patients using it. Initially, based on peer-reviewed literature, the disease prevalence is calculated and extrapolated with historic trends and any other relevant inputs gathered from the literature. In the same way, the proportion of prevalent patients that are diagnosed and the proportion of diagnosed patients that are ultimately treated are also calculated. If relevant, the treatment population is then divided into segments using any available inputs from scientific literature. For example, in oncology indications it is common for us to divide the patient population based on the stage of disease. Each drug may appear in more than one segment within this model and, if used as part of a combination of products, revenues are calculated on single product levels across all segments and combinations. The use of each drug within each segment (as a percentage) is estimated as accurately as possible, primarily using treatment guidelines, primary research and any other relevant peer-reviewed data inputs for each indication. The market penetration of pipeline products in their first few years after approval is estimated based primarily on published clinical trial data, with the safety and efficacy profiles of each pipeline drug being compared against any other competitors in their patient segment(s). Pipeline products that are expected to fulfill an unmet need and perform better than marketed products are typically given higher distributions than those that are not. While efficacy and safety data are usually the most important criteria for making these estimates, other characteristics such as the route of administration and dosing convenience are weighted more strongly in relevant indications. The cost of each drug is estimated based on its cost per gram (cost of one unit divided by the size of each unit in grams) and the number of grams taken by each patient in a single year (or a course of therapy). For the purposes of this model, different formulations for a single drug with different dosages (for example, a pediatric and adult formulation) are treated as separate entities. For pipeline drugs, the cost is estimated based on a benchmark of existing marketed products (typically within the indication). Based on their ability to fulfill unmet needs and compete effectively with marketed products, a percentage markup (or occasionally a markdown) versus its benchmark is assigned. This benchmark may be an individual product (such as a direct competitor) or an average of existing products. The cost is adjusted to take into account inflation of pharmaceutical products and any estimated effects of patent expiries (with biologics having a slower and weaker price erosion than small molecules following patent expiry). Finally, based on percentage distributions, a weighted average cost of each drug is estimated for all patients treated for the disease. This can then be multiplied by the treatment population to arrive at a sales estimate for that drug, and the total sales of all drugs is then the overall market size. From this primary forecast, peak and low market sizes and drug sales are estimated based on potential variations and uncertainties in price inflation, patent expiry, distribution shifts, pipeline product market penetration, and drug pricing for pipeline products. Inherently unpredictable events such as policy changes are not modeled directly in the scenarios, but are accounted for in the numeric inputs. These multiple scenarios aim to supplement the primary forecast with an accurate, transparent picture of the inherent uncertainty of the future market, and the likely range of outcomes. Page 115