Rheumatoid Arthritis Market to 2020 - a Crowded Market Characterized by Modest Growth

THERAPY ANALYSIS

Rheumatoid Arthritis Market to 2020 - A Crowded Market Characterized by Modest Growth

Published: December 2014 Report Code: GBIHC354MR

www.gbiresearch.com

GBI Research Report Guidance

 The report begins with an executive summary detailing the key points driving the RA market in eight key developed markets: the US, the UK, Canada, France, Germany, Spain, Italy and Japan.  Chapter two provides an introduction to RA, detailing the etiology, epidemiology, diagnostic techniques, disease staging and typical prognoses for patients. An analysis of current treatment algorithms and options is also included.  Chapter three offers detailed analysis of the drugs currently marketed for this indication: MTX, Remicade, Humira, Enbrel, Rituxan, Orencia, Simponi Cimzia and Xeljanz. It includes key characteristics, covering safety and efficacy, clinical trial outcomes, tolerability, dosing, administration, historical sales, prices and overall competitive strength. These products are also compared in a comprehensive heat map.  Chapter four provides detailed analysis of the pipeline for RA, by stage of development, molecule type, program type, mechanism of action and molecular target. It also analyzes 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 five analyzes the clinical trials conducted since 2006 in this indication, by enrollment, duration and failure rate. Promising late-stage pipeline molecules are analyzed and assessed in terms of their potential competitive strength.  Chapter six supplies forecasts for the RA market, including epidemiology, treatment use patterns, pricing, and market size, for the 2013–2020 period. The markets are covered and data are presented at a country level with further analysis of key market drivers and barriers.  Chapter seven covers the major deals that have taken place in the global RA market since 2006, analyzing licensing and co-development agreements, by stage of development, year, molecule type, mechanism of action and value. Network graphs of these deals are also included, organized by location of company headquarters.  Chapter eight is the appendix and includes key definitions, a list of abbreviations, details of the methodology and a bibliography.

Executive Summary Increasingly Crowded Market for Second-Line Therapies Improving Treatment Options for Moderate-to-Severe Rheumatoid Arthritis Patients Rheumatoid Arthritis (RA) is a chronic, progressive and currently incurable autoimmune disease that primarily affects joints. It is characterized by synovial inflammation and gradual bone erosion over many years, and disease progression results in stiffness and pain, especially in the hands and feet, which hinders patient mobility. Without treatment, the disease leads to joint destruction and disability. Prior to 1998, treatment options for RA patients were limited to small-molecule disease-modifying therapies, such as Methotrexate (MTX), sulfasalazine and anti-malarials. However, while MTX is efficacious in controlling RA symptoms in a large percentage of patients, approximately XX% of all patients are unresponsive to these first-line drugs. The approval of revolutionary biological therapies, including Enbrel, Remicade and Humira, for the treatment of RA patients that are refractory to MTX triggered unparalleled growth in the market. Globally, there are at least XX biological therapies, including monoclonal antibodies (mAb), biosimilars and therapeutic proteins, all competing as second-line therapies for this sub-population. Over the past 16 years, the therapeutic market for RA has become extremely competitive as a result of the high number of new drug approvals. Competition in the market for Tumor Necrosis Factor Alpha (TNF-α) inhibitors is particularly fierce and now dominates the treatment market for RA patients who are refractory to first-line Disease Modifying Anti-Rheumatic Drugs (DMARD). In 2013, three TNF-α targeting mAbs, Humira (adalimumab), Remicade (infliximab) and Enbrel (etanercept), were ranked among the top-10 best-selling drugs in the world, with global revenues of $XX billion, $XX billion and $XX billion, respectively, reflecting their groundbreaking clinical and commercial success. Despite this, XX% of RA patients fail to achieve clinical responses when treated with TNF-α inhibitors (Rubbert-Roth and Finckh, 2009). However, patients who are unresponsive to TNF-α inhibitors can also be medicated with the cytokine modulators Rituxan and Xeljanz. Thus, the extensive range of available therapies is addressing the need for efficacious therapies for a wide spectrum of RA patients. Modest Rate of Market Growth Expected between 2013 and 2020 The market for RA disease-modifying therapeutics is expected to increase from $XX billion in 2013 to $XX billion in 2020 at a Compound Annual Growth Rate (CAGR) of XX%. First-line DMARDs are expected to remain stagnant, as the late-stage pipeline predominantly constitutes second-line therapies. Owing to the high number of clinically and commercially strong products in the current market, this represents a barrier for the market infiltration of such emerging therapies. In the EU market, the patent expiration of blockbuster drugs as early as 2015 is expected to cause a strong uptake of biosimilars. However, uncertainty over the regulatory guidelines that govern the approval pathway of biosimilars into the US, the largest RA market across the eight key territories, may not measurably affect the pricing of the currently marketed drugs.

1 Table of Contents 1 Table of Contents ...... 4 1.1 List of Tables ...... 7 1.2 List of Figures ...... 7 2 Introduction ...... 9 2.1 Disease Introduction ...... 9 2.2 Symptoms ...... 10 2.3 Etiology ...... 10 2.4 Pathophysiology ...... 10 2.5 Diagnosis ...... 11 2.5.1 Physical Examination ...... 11 2.5.2 Blood Tests ...... 11 2.5.3 1987 Rheumatoid Arthritis Classification ...... 12 2.5.4 The 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis ...... 12 2.6 Epidemiology ...... 13 2.7 Co-morbidities and Complications ...... 13 2.8 Disease Progression ...... 14 2.9 Pharmacotherapy Algorithm ...... 14 2.10 Treatment Options ...... 16 2.10.1 Pharmacological ...... 16 2.10.2 Methotrexate ...... 16 2.10.3 Plaquenil (hydroxychloroquine)...... 16 2.10.4 Arava (leflunomide) ...... 16 2.10.5 Azulfidine, Salazopyrin (sulfasalazine) ...... 17 2.10.6 Neoral (cyclosporine) ...... 17 2.10.7 Prograf (tacrolimus) ...... 17 2.10.8 Xeljanz (tofacitinib) ...... 17 2.11 Other Non-biologics ...... 17 2.11.1 Non-steroidal Anti-inflammatory Drugs ...... 17 2.11.2 Painkillers ...... 18 2.11.3 Glucocorticoids ...... 18 2.12 Biologic Disease-Modifying Anti-rheumatic Drugs ...... 18 2.12.1 Tumor Necrosis Factor Alpha Inhibitors ...... 18 2.12.2 Interleukin Inhibitors ...... 18 2.12.3 Other Biologics that Target B- and T-Cell Antigens ...... 19 2.13 Disease Scoring Methods for Measuring Treatment Efficacy ...... 19 2.13.1 Radiographic Progression ...... 19 2.13.2 Clinical Disease Activity Index and Simplified Disease Activity Index ...... 19 2.13.3 Disease Activity Score-28 ...... 19 2.13.4 American College of Rheumatology...... 20 2.13.5 Health Assessment Questionnaire ...... 20 3 Marketed Products ...... 21 3.1 Overview ...... 21 3.2 Small-Molecule Disease-Modifying Anti-rheumatic Drugs ...... 21 3.2.1 Methotrexate-Based Products...... 21 3.2.2 Xeljanz (tofacitinib) – Pfizer ...... 22 3.3 Biologic Disease-Modifying Anti-rheumatic Drugs ...... 23 3.3.1 Remicade (infliximab) – Johnson and Johnson, Merck ...... 23 3.3.2 Remsima – infliximab biosimilar ...... 24 3.3.3 Humira (adalimumab) – Abbvie ...... 25 3.3.4 Enbrel (etanercept) – Amgen, Pfizer and Takeda Pharmaceutical ...... 26

3.3.5 Rituxan (rituximab) – Genentech (Roche), Biogen IDEC ...... 27 3.3.6 Reditux (Non-comparable Biologic of Rituxan) ...... 28 3.3.7 AcellBia (rituximab biosimilar) ...... 29 3.3.8 Orencia (abatacept) – Bristol-Myers Squibb ...... 29 3.3.9 Simponi (golimumab) – Johnson and Johnson, Merck ...... 30 3.3.10 Cimzia (certolizumab pegol) – UCB ...... 31 3.3.11 Kineret (anakinra) – Swedish Orphan Biovitrum ...... 32 3.3.12 Actemra (tocilizumab) – Roche ...... 33 3.3.13 Comparative Safety and Efficacy ...... 34 3.4 Unmet Need ...... 37 4 Pipeline Landscape ...... 38 4.1 Overview ...... 38 4.2 Pipeline Distribution by Phase of Development, Molecule Type, Route of Administration and Novelty ...... 38 4.3 Pipeline Distribution by Mechanism of Action ...... 40 4.3.1 Cytokine Inhibitors ...... 41 4.3.2 B- and T-cells ...... 43 4.3.3 Intracellular kinases ...... 44 5 Clinical Trial Analysis ...... 46 5.1 Overall Attrition Rate ...... 46 5.2 Attrition Rate by Phase, Molecule Type and Method of Administration ...... 46 5.3 Average Clinical Trial Size by Molecule Type ...... 49 5.4 Average Clinical Trial Size by Mechanism of Action ...... 52 5.5 Average Clinical Trial Duration per Molecule Type by Product ...... 54 5.6 Average Clinical Trial Duration per Mechanism of Action by Product...... 56 5.7 Primary and Secondary End Points ...... 57 5.8 Summary ...... 58 5.9 Promising Pipeline Drugs ...... 58 5.9.1 Phase III Programs ...... 58 5.9.2 Phase II Programs ...... 65 5.10 Comparative Heat Map ...... 67 6 Market Forecasts to 2020 ...... 70 6.1 Geographical Markets ...... 70 6.2 Global Market ...... 70 6.2.1 Treatment Usage Patterns ...... 71 6.2.2 Market Size ...... 72 6.3 North America ...... 73 6.3.1 Treatment Usage Patterns ...... 73 6.3.2 Annual Cost of Therapy...... 73 6.3.3 Market Size ...... 75 6.4 Top-Five EU Markets ...... 76 6.4.1 Treatment Usage Patterns ...... 76 6.4.2 Annual Cost of Therapy...... 77 6.4.3 Market Size ...... 78 6.5 Japan ...... 79 6.5.1 Treatment Usage Patterns ...... 79 6.5.2 Annual Cost of Therapy...... 79 6.5.3 Market Size ...... 80 6.6 Drivers and Barriers of Rheumatoid Arthritis Therapeutic Market ...... 80 6.6.1 Drivers ...... 80 6.6.2 Barriers ...... 81 7 Deals and Strategic Consolidations ...... 82

7.1 Licensing agreements ...... 82 7.1.1 Deal Values by Therapeutic Molecule Types ...... 84 7.1.2 Deal Values by Therapeutic mechanism of administration ...... 86 7.1.3 AstraZeneca Enters into Licensing Agreement with Rigel Pharma for fostamatinib disodium ...... 88 7.1.4 Alder Biopharmaceuticals Enters into Licensing Deal with Bristol-Myers Squibb Company Alder Biopharmaceuticals for Clazakizumab ...... 88 7.1.5 Janssen Biotech enters into a licensing deal with Astellas Pharma for Peficitinib ...... 88 7.1.6 Ablynx enters into a licensing deal with Abbvie for the Nanobody ALX-006 ...... 88 7.2 Co-development ...... 89 7.2.1 Deal Values by Therapeutic Molecule Types and Phase ...... 90 7.2.2 Deal Values by Therapeutic mechanism of administration and Phase ...... 92 7.2.3 GlaxoSmithKline enters into Global Agreement with Archemix ...... 94 7.2.4 Abbott Laboratories Enters into Global Collaboration with Galapagos for filgotinib ... 94 7.2.5 Chroma Therapeutics Enters into a Co-development Agreement with GlaxoSmithKline ...... 94 8 Appendix ...... 95 8.1 All Pipeline Drugs by Phase of Development ...... 95 8.1.1 Discovery ...... 95 8.1.2 Preclinical ...... 96 8.1.3 IND-CTA Filed ...... 96 8.1.4 Phase I ...... 97 8.1.5 Phase II ...... 98 8.1.6 Phase III ...... 99 8.2 Market Forecasts to 2020 ...... 101 8.3 Abbreviations ...... 105 8.4 References ...... 106 8.4.1 References for Figure 11 ...... 118 8.4.2 References for Figure 23 ...... 120 8.5 Research Methodology ...... 121 8.5.1 Secondary Research ...... 122 8.5.2 Marketed Product Profiles ...... 122 8.5.3 Late-Stage Pipeline Candidates ...... 123 8.5.4 Comparative Efficacy and Safety Heat Map for Marketed and Pipeline Products ...... 123 8.5.5 Pipeline Analysis ...... 123 8.5.6 Forecasting Model ...... 124 8.5.7 Deals Data Analysis ...... 125 8.6 Contact Us ...... 125 8.7 Disclaimer ...... 125

1.1 List of Tables Table 1: 2010 ACR-EULAR Classification Criteria for Rheumatoid Arthritis ...... 13 Table 2: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Discovery Phase, 2014 ...... 95 Table 3: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Preclinical Phase, 2014 ...... 96 Table 4: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, IND/CTA-Filed Phase, 2014 ...... 97 Table 5: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase I, 2014 ...... 98 Table 6: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase II, 2014 ...... 99 Table 7: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase III, 2014 ...... 100 Table 8: Rheumatoid Arthritis, Therapeutics Market, Global, Market Forecast, 2013–2020 ...... 101 Table 9: Rheumatoid Arthritis, Therapeutics Market, US, Market Forecast, 2013–2020 ...... 101 Table 10: Rheumatoid Arthritis, Therapeutics Market, Canada, Market Forecast, 2013–2020 ...... 102 Table 11: Rheumatoid Arthritis, Therapeutics Market, UK, Market Forecast, 2013–2020 ...... 102 Table 12: Rheumatoid Arthritis, Therapeutics Market, Germany, Market Forecast, 2013–2020 ..... 103 Table 13: Rheumatoid Arthritis, Therapeutics Market, France, Market Forecast, 2013–2020 ...... 103 Table 14: Rheumatoid Arthritis, Therapeutics Market, Italy, Market Forecast, 2013–2020 ...... 103 Table 15: Rheumatoid Arthritis, Therapeutics Market, Spain, Market Forecast, 2013–2020 ...... 104 Table 16: Rheumatoid Arthritis, Therapeutics Market, Japan, Market Forecast, 2013–2020 ...... 104 Table 17: Abbreviations ...... 105

1.2 List of Figures Figure 1: American College of Rheumatology Treatment Guidelines, 2012...... 15 Figure 2: Rheumatoid Arthritis Market, Global, Annual Sales of Remicade ($bn), 2008–2013 ...... 24 Figure 3: Rheumatoid Arthritis Market, Global, Annual Sales of Humira ($bn), 2008–2013 ...... 26 Figure 4: Rheumatoid Arthritis Market, Global, Annual Sales of Enbrel ($bn), 2008–2013 ...... 27 Figure 5: Rheumatoid Arthritis Market, Global, Annual Sales of Rituxan ($bn), 2008–2013 ...... 28 Figure 6: Rheumatoid Arthritis Market, Global, Annual Sales of Orencia ($m), 2008–2013 ...... 30 Figure 7: Rheumatoid Arthritis Market, Global, Annual Sales of Simponi ($m), 2008–2013 ...... 31 Figure 8: Rheumatoid Arthritis Market, Global, Annual Sales of Cimzia ($m), 2008–2013 ...... 32 Figure 9: Rheumatoid Arthritis Market, Global, Annual Sales of Actemra ($m), 2008–2013 ...... 34 Figure 10: Comparative Efficacy and Safety of Marketed Products ...... 36 Figure 11: Rheumatoid Arthritis Market, Global, Pipeline, 2014 ...... 39 Figure 12: Rheumatoid Arthritis Market, Global, Pipeline by Mechanism of Action, 2014 ...... 41 Figure 13: Rheumatoid Arthritis Market, Global, Pipeline, Cytokine Inhibitors, 2014 ...... 43 Figure 14: Rheumatoid Arthritis Market, Global, Pipeline, Inhibitors of B and T cells, 2014 ...... 44 Figure 15: Rheumatoid Arthritis Market, Global, Pipeline, Intracellular Kinase Inhibitors, 2014 ...... 45 Figure 16: Rheumatoid Arthritis, Global, Clinical Trial Failure Rate, 2006–2014 ...... 46 Figure 17: Rheumatoid Arthritis, Global, Clinical Trial Failure Rate, 2006–2014...... 47 Figure 18: Rheumatoid Arthritis, Global, Clinical Trial Failure Rate, 2006–2014 ...... 48 Figure 19: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Molecule Type by Product, 2006–2014 ...... 50 Figure 20: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Molecule Type by Trial, 2006–2014...... 51 Figure 21: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Mechanism of Action by Product, 2006–2014 ...... 52 Figure 22: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Mechanism of Action by Trial, 2006–2014 ...... 53 Figure 23: Rheumatoid Arthritis Market, Global, Pipeline, Clinical Trial Duration by Molecule Type by Product (months), 2006–2014 ...... 55 Figure 24: Rheumatoid Arthritis Market, Global, Pipeline, Clinical Trial Duration by Mechanism of Action by Product (months), 2006–2014 ...... 56 Figure 25: Rheumatoid Arthritis Market, Global, Frequency of Primary End points Measured in Clinical Trials, 2006–2014 ...... 57

Figure 26: Rheumatoid Arthritis Market, Global, Sales Projection of Baricitinib, 2016–2020 ...... 59 Figure 27: Rheumatoid Arthritis Market, Global, Sales Projection of BOW-015, 2015–2020 ...... 60 Figure 28: Rheumatoid Arthritis Market, Global, Sales Projection of TuNEX, 2016–2020 ...... 61 Figure 29: Rheumatoid Arthritis Market, Global, Sales Projection of Sarilumab, 2015–2020 ...... 62 Figure 30: Rheumatoid Arthritis Market, Global, Sales Projection of Secukinumab, 2015–2020 ...... 63 Figure 31: Rheumatoid Arthritis Market, Global, Sales Projection of Sirukumab, 2017–2020 ...... 64 Figure 32: Comparative Efficacy and Safety of Pipeline Programs...... 69 Figure 33: Rheumatoid Market, Global, Market Size, 2013–2020 ...... 71 Figure 34: Rheumatoid Market, Global, Market Size, 2013–2020 ...... 72 Figure 35: Rheumatoid Market, North America, Treatment Usage Patterns, 2013–2020 ...... 73 Figure 36: Rheumatoid Market, North America, Annual Cost of Therapy, 2013–2020 ...... 74 Figure 37: Rheumatoid Market, North America, Market Size, 2013–2020 ...... 75 Figure 38: Rheumatoid Market, Five EU Countries, Treatment Usage Patterns, 2013–2020 ...... 76 Figure 39: Rheumatoid Market, Five EU Countries, Annual Cost of Therapy, 2013–2020 ...... 77 Figure 40: Rheumatoid Market, Five EU Countries, Market Size, 2013–2020 ...... 78 Figure 41: Rheumatoid Market, Japan, Treatment Usage Patterns, 2013—2020 ...... 79 Figure 42: Rheumatoid Market, Japan, Annual Cost of Therapy, 2013–2020 ...... 79 Figure 43: Rheumatoid Market, Japan, Market Size, 2013–2020 ...... 80 Figure 44: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006–2014 ...... 83 Figure 45: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006–2014 ...... 85 Figure 46: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006–2014 ...... 87 Figure 47: Rheumatoid Arthritis Market, Global, Co-development Deals, 2006–2014 ...... 89 Figure 48: Rheumatoid Arthritis Market, Global, Co-development Deals, 2006–2014 ...... 91 Figure 49: Rheumatoid Arthritis Market, Global, Co-development Deals, 2006–2014 ...... 93

2 Introduction 2.1 Disease Introduction Rheumatoid Arthritis (RA) is a chronic, progressive and currently incurable autoimmune disease that primarily affects the joints. It is characterized by synovial inflammation and gradual bone erosion over many years (Lefèvre et al., 2009). Disease progression results in stiffness and pain, especially in the hands and feet, which hinders the mobility of the patient. Without treatment, the disease leads to joint destruction and disability. RA can have a substantial impact on quality of life and place a considerable economic burden upon the patient. The prevalence of RA is high, with approximately XX million patients in the US, Japan, Germany, the UK, France, Italy and Spain. The chronic nature of the disease, which requires ongoing treatment, the large target patient population, and the relatively high annual cost of treatment, have made RA treatment a highly lucrative market. In addition, the signaling pathways targeted by the currently marketed products are relevant to many other autoimmune and oncological diseases and thus allow for significant repositioning opportunities. The therapeutic options for the treatment of RA have grown rapidly over the past two decades. Significant advances in the understanding of the disease and the identification of novel molecular targets have opened up avenues for new drug developments and resulted in sustained interest and high R&D activity in this indication. In particular, the diversification in pharmaceutical therapeutics has led to a transformation in both the clinical and commercial landscape with the advent of monoclonal antibodies (mAb). The first biologic to be approved for RA was Enbrel (etanercept), in 1998. Since then, at least XX biological therapies, including mAbs, biosimilars and therapeutic proteins, have been approved across the global market, resulting in one of the highest rates of penetration of any indication. In 2013, three Tumor Necrosis Factor Alpha (TNF-α) targeting mAbs, Humira (adalimumab), Remicade (infliximab) and Enbrel (etanercept), all of which are approved for RA treatment and many other indications, were ranked among the top-10 best-selling drugs in the world, with global revenues of $XX billion, $XX billion and $XX billion, respectively. The RA therapeutic market has become very competitive because of the high number of new drug approvals. Competition is fierce, particularly among TNF-α inhibitors, which dominate the treatment market for RA patients who are refractory to traditional Disease-Modifying Anti-rheumatic Drugs (DMARD). Despite this, XX% of RA patients fail to attain a clinical response when treated with TNF-α inhibitors (Rubbert-Roth and Finckh, 2009). However, other targeted programs, as well as newly marketed small molecule DMARDS, such as Janus Kinase (JAK) inhibitors, can replace inefficacious TNF-α inhibitors. Despite the superior efficacy of recently marketed therapies over traditional DMARD therapies, there is a need to improve safety in the therapeutic landscape. Elevated rates of infection are a frequent consequence of the immunosuppression involved in treatments, but this is required to suppress the autoimmune responses responsible for the symptoms of the condition. As a result, these biological therapies are not recommended to patients who are susceptible to infections. In addition, there is a need to create biologics that have a more convenient and less invasive drug-delivery method than the currently existing ones, all of which are administered subcutaneously or intravenously. These routes of administration are frequently associated with pain, rash, and allergic reactions at the injection or infusion site, and, in the case of infusion, flu-like illness, fever, chills, nausea, and headache. Thus, convenient and safe routes of administration without significant compromise of therapy efficacy remain unmet needs. However, the Food and Drug Administration (FDA) has approved Xeljanz (tofacitinib), an orally administered small molecule drug, as a second-line treatment of RA patients who have not shown an adequate response to Methotrexate (MTX) and a third-line therapy for patients who have not responded sufficiently to biologics. Thus, Xeljanz does address the need for safer and more convenient means of drug delivery. Another unmet need is the lack of access to affordable targeted therapies that can be used as front- line medication, especially in markets dominated by patent-protected premium drugs. These are the primary features that could provide significant differentiation for a new product and open up new commercial opportunities. Indeed, there is much hope for the validation of small-molecule pharmaceuticals that target specific signal transducers and can be administered orally. Overall, RA is a disease with a complex pathophysiology, and a new therapeutic approach and new molecular targets may open up new opportunities for disease-modifying therapeutics.

4 Pipeline Landscape 4.1 Overview Treatment algorithms for moderate-to-severe RA have been greatly diversified due to the emergence of efficacious biologics as a new class of therapy. The current market is now densely populated with targeted therapies that all compete for the same sub-population of RA patients, namely those who are refractory to first-line DMARDs such as MTX. However, in spite of the developments in recent years, there remains a significant unmet need in terms of safer drug profiles and convenience of administration route. Systemic therapies, such as biologic drugs, are often administered via IV infusion or subcutaneous injection, which is likely to cause inconvenience and a level of discomfort. More seriously, some patients may also experience injection or infusion site reactions and develop immunogenic responses to the drug product, producing anti-drug antibodies as a result of the body recognizing the drug as foreign material, ultimately reducing the effectiveness of the drug. Immunogenic responses are more common with chimeric (human-murine) biologics, although they can also occur with humanized and fully human biologics. Both biologic and non-biologic systemic drugs are associated with a substantial risk of developing severe infections and malignancies. Furthermore, an initial efficacious response to a drug agent will not always be maintained over the long term as patients often become resistant to therapies over time (Finkh et al., 2006). Therefore, new drugs entering the market will have a competitive advantage if they are able to improve upon existing drugs and meet these requirements. The following section will consider the scope of products in the current pipeline and profile the most promising systemic pipeline molecules. 4.2 Pipeline Distribution by Phase of Development, Molecule Type, Route of Administration and Novelty The current developmental pipeline for RA is highly active and consists of XX pipeline products in active development, (Figure 11A) where small molecules and biologics account for (XX%) and XX (XX%) of the pipeline with disclosed targets (Figure 11B). The strong presence of biologics throughout the pipeline reflects the commercial and clinical success of targeted drugs in the marketed products landscape and also represents a dramatic shift in the appeal from traditional small molecule therapies to biologic RA treatment. Late-stage developmental programs, is saturated with biologics (Figure 11C) and is being developed by big pharma companies, such as Eli Lilly, J&J, Abbvie and Novartis and smaller companies, such as Vertex Pharmaceuticals, Ablynx and Can-Fite. The dominance of biologics in the late-stage developmental pipeline is consistent with the favorable attrition rate for biologics compared with small molecules in clinical development, as discussed in Section 5.2. Figure 11D, which illustrates the distribution of pipeline molecules by route of administration, reveals that most of the pipeline drugs are formulated for administration through infusion or injection whereas only XX% of drugs are administered via oral, nasal or topical routes. This is consistent with the trend that biologics require a more direct and invasive route of administration whereas small molecules can be administered by oral and non-invasive means. Biologics are susceptible to metabolism in the GI tract and lack permeability, which collectively leads to poor bioavailability. In contrast, drugs administered via the intravenous route are associated with XX% bioavailability, as they pass directly into systemic circulation. Figure 11E represents the distribution of pipeline programs by program type and phase of development. The proportion of novel drug candidates currently in development in the RA pipeline is very high at XX% of the entire active pipeline. The presence of biosimilars which are neither considered as novel or generic APIs, is also substantial, occupying XX% of the pipeline. These therapeutics are very prominent in the late stage pipeline, representing XX out of XX Phase III programs. The remaining few programs are generics or repositioned drugs. Thus in terms of APIs, the overall level of innovation in the pipeline in strong.

Figure 11: Rheumatoid Arthritis Market, Global, Pipeline, 2014

A) Pipeline by phase B) Pipeline by molecule type

Pre registration Unknown Phase III Antibody Gene therapy Protein Peptide Discovery Small molecule Cell therapy Phase II Biologic

Vaccine Phase I To t a l : X X Preclinical To t a l : X X

Polysaccharide

IND/CTA- Biosimilar filed Monoclonal antibody Oligonucleotide Biologic

C) Pipeline by Molecule Type and Stage of D) Pipeline by RoA Development

Tran sderm al Intraarticular To p i c a l Subcutaneous

Intravenous Rectal, topical Number ofproducts

Intravenous, Parenteral To t a l : X X subcutaneous Phase I Phase II Phase III Unknown

Discovery Oral, Preclinical Nasal transdermal IND/CTA-filed Preregistration Polysaccharide Oligonucleotide Biologic Oral, topical Oral Gene therapy Antibody Vaccine Cell therapy Peptide Protein Monoclonal antibody Biosimilar Small molecule

E) Pipeline by program type

Repositioned

Generic

Biosimilar

Novel Number of products Phase I Phase II Phase III Unknown Discovery Preclinical IND/CTA-filed Preregistration

Source: GBI Research, Proprietary pipeline database COX: Cyclo-oxygenase; GPCR: G-Protein-Coupled Receptors; IND/CTA: Investigational New Drug/Clinical Trial Authorisation; mAb: monoclonal Antibody; MoA :Mechanism of Action

4.3 Pipeline Distribution by Mechanism of Action Trends in drug mechanisms can also provide insights into the level of innovation and development within the field. The diversity of drug mechanisms in the RA pipeline and their distribution throughout various developmental stages are captured in Figure 12A and Figure 12B respectively. Upon excluding the number of programs with undisclosed mechanisms of action or target molecules, it appears that a large number of programs are targeting cytokine and receptors, B- and T-cell antigens and intracellular kinases. The individual mechanisms that currently dominate the RA pipeline align closely with the marketed product landscape, including inhibitors of TNF-α, CD20, IL-6, and JAK. Given that there is an abundance of research highlighting the roles of intracellular- and intercellular-signaling pathways in the pathogenesis of autoimmunity, the pipeline reflects the translation of science into therapeutic products as opposed to programs that address the symptoms of disease, such as glucocorticoids and non-steroidal anti-inflammatory drugs, of which there is a substantial number in the current market. As Figure 12A&B shows, drugs which replicate mechanisms of marketed drugs well-represented throughout the pipeline (XX%), and particularly in the later phases of development. Unsurprisingly, the most clinical and commercially successful drugs in the current RA market also target specific molecules in the immune system, notably TNF-α amongst others. This reflects a strong degree of confidence in well-established targets for therapeutic intervention. Programs which target cellular subsets of the immune system, especially B and T cells, also are particularly well-represented in the clinical trial phases, and account for XX% of the disclosed pipeline. This further highlights the level of interest in blocking key mediators of immunity. Intracellular kinases are also prominent targets within the pipeline, as reflected by XX% share. This large family of enzymes play a critical role in mediating inflammation associated with RA. Many kinases such as JAKs mediate pro-inflammatory signaling cascades triggered by receptors of several key cytokines in RA (Wang et al., 2010). Despite there being only one JAK-3 inhibitor (Xeljanz) in the currently RA market, which was recently launched in 2012, these small-molecule programs are rapidly drawing investment and appeal, due to their strong efficacy profiles and marketed differentiation from biologics.

Figure 12: Rheumatoid Arthritis Market, Global, Pipeline by Mechanism of Action, 2014 A) Pipeline by MoA Nucleic acid precuros enzyme inhibitor

Other

COX inhibitor Neuromodulator

To t a l : X X

Intracellular kinase inhibitor Cytokine inhibitor

B) Pipeline by MoA and stage of development IL-23

Colony stimulating factor 1 receptor antagonist MIF

Other cytokine

Granulocyte-macrophage colony stimulating factor inhibitor IL-17

Other interleukins

Number of products Toll-like receptor

IL-1

IL-6 Phase I Phase II Phase III Unknown Discovery Preclinical Chemokine signaling IND/CTA-filed Preregistration TNF

Source: GBI Research, Proprietary pipeline database COX: Cyclo-oxygenase; IND/CTA: Investigational New Drug/Clinical Trial Authorisation; MoA :Mechanism of Action

7 Deals and Strategic Consolidations Patent expirations of blockbuster drugs, declining research and development productivity and high attrition rates throughout clinical development are prominent issues in the pharmaceutical industry today. Given the high level of risk in drug development, strategic consolidations such as co- development and licensing deals have numerous advantages for pharmaceutical companies, such as financial and technical support. Strategic alliances can also boost innovation, which is particularly important in the increasingly competitive market. As such, companies can clearly benefit from both the in-licensing and out-licensing of innovative drugs for development. Successfully identifying strategic partners, whether for licensing or co-development deals, is therefore essential for a company’s success in today’s pharmaceutical industry. Strategic consolidation trends can therefore provide useful insight into the research and development activity and commercial interest of an indication. The following section examines trends in co-development and licensing strategic consolidations relevant to RA between 2006 and 2014. 7.1 Licensing agreements Analysis of the licensing deals landscape demonstrates a high level of licensing activity involving RA therapeutics since 2006. The geographical diversity of the total XX licensing deals shows that the greatest proportion of international licensing deals involved companies headquartered in the US, acquiring product licenses from companies in overseas territories, a considerable proportion of which came from Germany and Japan (Figure 44). Additionally, a large number of therapeutic products were out-licensed by US companies to those in the UK. The total number of deals has fluctuated dramatically over the years, peaking at XX deals in 2008 and dropping to XX in 2011. The aggregate deal valuation peaked in 2009 at $XX billion, although there are a substantial number of deals with undisclosed valuations.

Figure 44: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006–2014

A) Deals by territory

Note: Node sizes, arrow sizes and edge thicknesses correspond to the volume of deals occurring, with larger nodes, larger arrows and thicker edges indicating a higher volume of deals.

B) Number and value of deals by year Number of deals Aggregate deal Aggregate values ($ bn)

2006 2007 2008 2009 2010 2011 2012 2013 Number of deals with undisclosed values Number of deals with disclosed values Total disclosed value ($billion) Total upfront value ($billion)

Source: GBI Research Proprietary Strategic Alliances Database

8 Appendix 8.1 All Pipeline Drugs by Phase of Development 8.1.1 Discovery

Table 2: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Discovery Phase, 2014 Product Company Molecule type Mechanism of action

Source: GBI Research

8.1.2 Preclinical

Table 3: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Preclinical Phase, 2014 Product Company Molecule type Mechanism of action

Source: GBI Research

8.1.3 IND-CTA Filed

Table 4: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, IND/CTA-Filed Phase, 2014 Product Company Molecule type Mechanism of action

Source: GBI Research

8.1.4 Phase I

Table 5: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase I, 2014 Product Company Molecule type Mechanism of action

Source: GBI Research

8.1.5 Phase II

Table 6: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase II, 2014 Product Company Molecule type Mechanism of action

Source: GBI Research

8.1.6 Phase III

Table 7: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase III, 2014 Product Company Molecule type Mechanism of action

Source: GBI Research

8.2 Market Forecasts to 2020

Table 8: Rheumatoid Arthritis, Therapeutics Market, Global, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 9: Rheumatoid Arthritis, Therapeutics Market, US, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 10: Rheumatoid Arthritis, Therapeutics Market, Canada, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020

Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 11: Rheumatoid Arthritis, Therapeutics Market, UK, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 12: Rheumatoid Arthritis, Therapeutics Market, Germany, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020

Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 13: Rheumatoid Arthritis, Therapeutics Market, France, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 14: Rheumatoid Arthritis, Therapeutics Market, Italy, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 15: Rheumatoid Arthritis, Therapeutics Market, Spain, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

Table 16: Rheumatoid Arthritis, Therapeutics Market, Japan, Market Forecast, 2013–2020 2013 2014 2015 2016 2017 2018 2019 2020 Prevalence population ('000) Treatment population ('000) Maximum market size ($m) Projected market size ($m) Minimum market size ($m) Source: GBI Research

8.3 Abbreviations

Table 17: Abbreviations Abbreviation Expanded term A3AR A3 Adenosine Receptor ACPA Anti-Citrullinated Protein Antibody ACR American College of Rheumatology ACoT Annual Cost of Therapy AP-1 Activator Protein-1 CAGR Compound Annual Growth Rate CC Chemokine CCR Chemokine Receptor CD Cluster of Differentiation COX-2 Cyclooxygenase-2 CHMP Committee for Medicinal Products for Human Use CRP C-Reactive Protein CTA Clinical Trial Authorization DAS-28 Disease Activity Score-28 DC Dendritic Cell DMARD Disease-Modifying Anti-rheumatic Drugs EMA European Medicines Agency ESR Erythrocyte Sedimentation Rate EULAR European League Against Rheumatism fab fragment antigen-binding Fc crystallizable fragment FDA Food and Drug Administration GM-CSF Granulocyte-Macrophage Colony-Stimulating Factor GPCR G Protein Coupled Receptor HAQ Health Assessment Questionnaire HCQ Hydroxychloroquine HDL High-Density Lipoprotein ICAM-1 Intercellular Adhesion Molecule-1 Ig Immunoglobulin IL Interleukin IL-1Ra Interleukin-1 Receptor a IL-6R IL-6 Receptor IND Investigational New Drug IV Intravenous JAK Janus Kinase JNK c-Jun N-Terminal Kinase LDL Low-Density Lipoprotein LEF Leflunomide mAb monoclonal antibody

MAPK Mitogen-Activated Protein Kinase MCSF Macrophage Colony Stimulating Factor MSC Mesenchymal Stem Cells MTX Methotrexate mTSS Modified Total Sharp Score NFκB Nuclear Factor kappa-B NHS National Health Service NICE National Institute of Clinical Excellence NOD Non-Obese Diabetic NSAID Non-Steroidal Anti-Inflammatory Drug PAD Peptidylarginine Deiminase RA Rheumatoid Arthritis RANKL Receptor Activator of Nuclear factor Kappa-B Ligand RASS Rheumatoid Arthritis Severity Scale RF Rheumatoid Factor RoA Route of Administration STAT Signal Transducers and Activators of Transcription Th T helper TLR Toll-Like Receptor TNFR TNF Receptor TB Tuberculosis TNF-α Tumor Necrosis Factor Alpha TWEAK Tumor necrosis factor-like WEAK inducer of apoptosis Treg regulatory T

Source: GBI Research

8.4 References  Abbott Laboratories (2003). Annual Report. Abbott Laboratories. Available from: http: //quicktake.morningstar.com/StockNet/SECDocuments.aspx?Symbol=ABT&Country=USA [Accessed on October 5, 2013].  Adams CP and Brantner VV (2010). Spending on New Drug Development. Health Economics; 19(2): 130–141.  Aletaha D, et al. (2010). 2010 Rheumatoid Arthritis Classification Criteria. Arthritis and Rheumatism; 62(9): 2569–2581.  Amacher DE. (1998). Serum transaminase elevations as indicators of hepatic injury following the administration of drugs. Regulatory Toxicology and Pharmacology: 27(2): 119-30.  Amgen (2002). Annual Report. Amgen. Available from: http: //quicktake.morningstar.com/StockNet/SECDocuments.aspx?Symbol=AMGN&Country=USA. [Accessed on October 5, 2013].  Arnett FC, et al. (1988). The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheumatology; 31(3): 315–324.  Arthritis Alliance of Canada (2011). The Impact of Arthritis in Canada: Today and Over the Next 30 Years. Arthritis Alliance of Canada. Available at http: //www.arthritisalliance.ca/images/PDF/eng/Initiatives/20111022_2200_impact_of_arthritis.pdf

 Huizinga et al. (2014). Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Annals of the Rheumatic Diseases; 73(9): 1626–34  Bioworld. (2013). Can-Fite’s CF101 delivers a can-do performance in RA. Available at http: //www.bioworld.com/content/can-fite%E2%80%99s-cf101-delivers-can-do-performance-ra-0 [Accessed on December 15, 2014].  News-Medical. (2012). Incyte, Lilly announce 12-week results from baricitinib Phase IIb study on RA. Available at http: //www.news-medical.net/news/20120611/Incyte-Lilly-announce-12-week- results-from-baricitinib-Phase-IIb-study-on-RA.aspx [Accessed on December 15, 2014].  Tak et al. (2011). Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial. Annals of the Rheumatic Diseases; 72(3): 337–44  Regeneron. (2013). Sanofi and Regeneron Report Positive Results with Sarilumab in First Phase 3 Rheumatoid Arthritis Registration Trial. Available at http: //investor.regeneron.com/releasedetail.cfm?ReleaseID=809088 [December 15, 2014].  Cardiel et al. (2010). A phase 2 randomized, double-blind study of AMG 108, a fully human monoclonal antibody to IL-1R, in patients with rheumatoid arthritis. Arthritis Research & Therapy; 12(5): R192  Ablynx. Anti-IL-6 Receptor Nanobody (ALX-0061) Seamless “First-in-Human” Phase I/II Proof-of- Concept Study in Patients with Active Rheumatoid Arthritis on Stable Methotrexate Treatment: Single-dose results. Available at http: //www.ablynx.com/wp-content/uploads/2012/11/ACR- 2012_Ablynx-poster-1307.pdf [Accessed on December 15, 2014].  Genovese et al. (2013). Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Annals of the Rheumatic Diseases; 72(6): 863–9  Ablynx. (2011). A Multiple Ascending Dose/Proof of Concept study of ATN-103 (ozoralizumab) in Rheumatoid Arthritis Subjects on a background of Methotrexate. Available at http: //www.ablynx.com/wp-content/uploads/2012/06/ACR-2011_POC-study-ATN-103.pdf [Accessed on December 15, 2014].  Emu et al. (2012). Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin α: results of a phase I randomized, placebo- controlled trial. Arthritis Research & Therapy; 14(1): R6.  Behrens et al. (2014). MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Annals of the Rheumatic Diseases; doi: 10.1136  Tigenix. (2014). Cx611. Available at http: //www.tigenix.com/en/page/15/cx611 [Accessed on December 15, 2014]. 8.5 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 decision- making. 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. 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 end point design, product competitiveness benchmarking and multi-scenario forecasting. 8.5.1 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 8.5.2 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.

8.5.3 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 end points, 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. 8.5.4 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 end points 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 end point, allowing us to determine the strongest performer in each end point category. A dark blue color indicates the strongest performers in that category, whereas light gray colors indicate weaker performers. 8.5.5 Pipeline Analysis 8.5.5.1 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. 8.5.5.2 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 end point analysis. Each is analyzed by clinical stage of development. 8.5.5.3 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. 8.5.5.4 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. 8.5.5.5 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. 8.5.5.6 Clinical trial End point Analysis A clinical trial end point is a measure from which a decision can be made to accept or reject the null hypothesis. The primary and secondary end points 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 end points. These data are then graphically presented to display the most prominent primary and secondary end points. Trends in primary and secondary end points are assessed by Phase of development and, when possible, over a specified timeframe to identify any changing patterns in clinical trial design. 8.5.6 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 RoA 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. 8.5.7 Deals Data Analysis This section includes analysis of GBI Research proprietary strategic deals data relevant to the indication being assessed. The two major deal types analyzed are co-development deals and licensing deals. When analyzing co-development and licensing deals data, the parameters assessed are often consistent, although there can be some variation depending on data availability. Firstly, deals are analyzed by country, value and year. Analysis by country includes the use of network charts, which visually represent links between different nations to visualize where companies involved in deals are headquartered and to identify deal hubs. The deals data are analyzed further to display the number of deals by stage of development, molecule type and mechanism of action. Qualitative analysis of the major deals within the indication is also provided. 8.6 Contact Us If you have any queries about this report or would like further information, please contact: North America: +1 646 395 5477 Europe: +44 207 406 6777 Asia Pacific: +91 40 6616 6878 E-mail: [email protected] 8.7 Disclaimer All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher, GBI Research. The facts of this report are believed to be correct at the time of publication but cannot be guaranteed. Please note that the findings, conclusions and recommendations that GBI Research delivers will be based on information gathered in good faith from both primary and secondary sources, whose accuracy we are not always in a position to guarantee. As such GBI Research can accept no liability whatever for actions taken based on any information that may subsequently prove to be incorrect.