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 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 33% 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 has triggered unparalleled growth in the market. Globally, there are at least 12 biological therapies, including monoclonal antibodies (mAb), biosimilars and therapeutic proteins, 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 for Tumor Necrosis Factor Alpha (TNF-a) 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-a 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 $11.1 billion, $9.9 billion and $8.9 billion respectively, reflecting their groundbreaking clinical and commercial success. Despite this, 30% of RA patients fail to achieve clinical responses when treated with TNF-a inhibitors (Rubbert-Roth and Finckh, 2009). However, patients who are unresponsive to TNF-a 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 broad spectrum of RA patients.

Modest Rate of Market Growth Expected between 2013 and 2020

The market for disease-modifying RA therapeutics is expected to increase from $56.6 billion in 2013 to $80.7 billion in 2020, at a Compound Annual Growth Rate (CAGR) of 5.2%. First-line DMARDs are expected to remain stagnant, as the late-stage pipeline predominantly constitutes second-line therapies. The high number of clinically and commercially strong products in the current market represents a barrier for the market infiltration of such emerging therapies. In the EU market, the patent expiration of blockbuster drugs from 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.

Scope

The report covers and includes –

• A brief introduction to RA, including symptoms, pathophysiology, and an overview of pharmacotherapy and treatment algorithms
• Detailed analysis of the drugs currently marketed for this indication: MTX, Remicade, Humira, Enbrel, Rituxan, Orencia, Simponi, Cimzia and Xeljanz, including key characteristics such as safety and efficacy, clinical trial outcomes, tolerability, dosing, administration, historical sales, price, and overall competitive strength, as well as a comprehensive heat map comparison
• Detailed analysis of the pipeline for RA by stage of development, molecule type, program type, mechanism of action, and molecular target, as well as analysis of recent clinical trials by enrollment, duration, failure rate, and promising late-stage pipeline molecules
• Forecasts for the RA market, including epidemiology, treatment usage pattern, pricing, and market size for the 2013-2020 period, for which data are presented at country level with further analysis of key market drivers and barriers
• 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

Reasons to buy

Primarily, the report will allow clients to gain a strong understanding of RA, helping to identify and clarify market opportunities and the competitive environment. It will also allow you to –

• Understand the RA pipeline and the key trends in the current product development landscape
• Observe detailed profiles for the promising pipeline products, including revenue forecasts, and gain an insight into how they are likely to compete in the market, and what their main competitors will be
• Follow the trends in RA clinical trial size and duration in relation to industry averages and assess the potential risk of future developmental programs for RA therapeutics, depending on the mechanism of action, by considering the recorded clinical trial failure rates
• Observe the potential growth patterns expected for the RA market over the forecast period, and identify which countries are expected to make the biggest contribution to this growth

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 24
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) 28
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 45
5.1 Overall Attrition Rate 45
5.2 Attrition Rate by Phase, Molecule Type and Method of Administration 45
5.3 Average Clinical Trial Size by Molecule Type 48
5.4 Average Clinical Trial Size by Mechanism of Action 51
5.5 Average Clinical Trial Duration per Molecule Type by Product 53
5.6 Average Clinical Trial Duration per Mechanism of Action by Product 55
5.7 Primary and Secondary End Points 56
5.8 Summary 57
5.9 Promising Pipeline Drugs 57
5.9.1 Phase III Programs 57
5.9.2 Phase II Programs 64
5.10 Comparative Heat Map 66

6 Market Forecasts to 2020 69
6.1 Geographical Markets 69
6.2 Global Market 69
6.2.1 Treatment Usage Patterns 70
6.2.2 Market Size 71
6.3 North America 72
6.3.1 Treatment Usage Patterns 72
6.3.2 Annual Cost of Therapy 72
6.3.3 Market Size 74
6.4 Top-Five EU Markets 75
6.4.1 Treatment Usage Patterns 75
6.4.2 Annual Cost of Therapy 76
6.4.3 Market Size 77
6.5 Japan 78
6.5.1 Treatment Usage Patterns 78
6.5.2 Annual Cost of Therapy 78
6.5.3 Market Size 79
6.6 Drivers and Barriers of Rheumatoid Arthritis Therapeutic Market 79
6.6.1 Drivers 79
6.6.2 Barriers 80

7 Deals and Strategic Consolidations 81
7.1 Licensing agreements 81
7.1.1 Deal Values by Therapeutic Molecule Types 83
7.1.2 Deal Values by Therapeutic mechanism of administration 85
7.1.3 AstraZeneca Enters into Licensing Agreement with Rigel Pharma for fostamatinib disodium 87
7.1.4 Alder Biopharmaceuticals Enters into Licensing Deal with Bristol-Myers Squibb Company Alder Biopharmaceuticals for Clazakizumab 87
7.1.5 Janssen Biotech enters into a licensing deal with Astellas Pharma for Peficitinib 87
7.1.6 Ablynx enters into a licensing deal with Abbvie for the Nanobody ALX-006 87
7.2 Co-development 88
7.2.1 Deal Values by Therapeutic Molecule Types and Phase 89
7.2.2 Deal Values by Therapeutic mechanism of administration and Phase 91
7.2.3 GlaxoSmithKline enters into Global Agreement with Archemix 93
7.2.4 Abbott Laboratories Enters into Global Collaboration with Galapagos for filgotinib 93
7.2.5 Chroma Therapeutics Enters into a Co-development Agreement with GlaxoSmithKline 93

8 Appendix 94
8.1 All Pipeline Drugs by Phase of Development 94
8.1.1 Discovery 94
8.1.2 Preclinical 98
8.1.3 IND-CTA Filed 108
8.1.4 Phase I 109
8.1.5 Phase II 111
8.1.6 Phase III 113
8.2 Market Forecasts to 2020 115
8.3 Abbreviations 119
8.4 References 120
8.4.1 References for Error! Reference source not found. 132
8.4.2 References for Figure 32 134
8.5 Research Methodology 135
8.5.1 Secondary Research 136
8.5.2 Marketed Product Profiles 136
8.5.3 Late-Stage Pipeline Candidates 136
8.5.4 Comparative Efficacy and Safety Heat Map for Marketed and Pipeline Products 137
8.5.5 Pipeline Analysis 137
8.5.6 Forecasting Model 138
8.5.7 Deals Data Analysis 139
8.6 Contact Us 139
8.7 Disclaimer 139

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 94
Table 3: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Preclinical Phase, 2014 98
Table 4: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, IND/CTA-Filed Phase, 2014 108
Table 5: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase I, 2014 109
Table 6: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase II, 2014 111
Table 7: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase III, 2014 113
Table 8: Rheumatoid Arthritis, Therapeutics Market, Global, Market Forecast, 2013-2020 115
Table 9: Rheumatoid Arthritis, Therapeutics Market, US, Market Forecast, 2013-2020 115
Table 10: Rheumatoid Arthritis, Therapeutics Market, Canada, Market Forecast, 2013-2020 116
Table 11: Rheumatoid Arthritis, Therapeutics Market, UK, Market Forecast, 2013-2020 116
Table 12: Rheumatoid Arthritis, Therapeutics Market, Germany, Market Forecast, 2013-2020 117
Table 13: Rheumatoid Arthritis, Therapeutics Market, France, Market Forecast, 2013-2020 117
Table 14: Rheumatoid Arthritis, Therapeutics Market, Italy, Market Forecast, 2013-2020 118
Table 15: Rheumatoid Arthritis, Therapeutics Market, Spain, Market Forecast, 2013-2020 118
Table 16: Rheumatoid Arthritis, Therapeutics Market, Japan, Market Forecast, 2013-2020 118
Table 17: Abbreviations 119

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 42
Figure 14: Rheumatoid Arthritis Market, Global, Pipeline, Inhibitors of B and T cells, 2014 43
Figure 15: Rheumatoid Arthritis Market, Global, Pipeline, Intracellular Kinase Inhibitors, 2014 44
Figure 16: Rheumatoid Arthritis, Global, Clinical Trial Failure Rate, 2006-2014 45
Figure 17: Rheumatoid Arthritis, Global, Clinical Trial Failure Rate, 2006-2014 46
Figure 18: Rheumatoid Arthritis, Global, Clinical Trial Failure Rate, 2006-2014 47
Figure 19: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Molecule Type by Product, 2006-2014 49
Figure 20: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Molecule Type by Trial, 2006-2014 50
Figure 21: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Mechanism of Action by Product, 2006-2014 51
Figure 22: Rheumatoid Arthritis Market, Global, Pipeline, Recruitment Size by Mechanism of Action by Trial, 2006-2014 52
Figure 23: Rheumatoid Arthritis Market, Global, Pipeline, Clinical Trial Duration by Molecule Type by Product (months), 2006-2014 54
Figure 24: Rheumatoid Arthritis Market, Global, Pipeline, Clinical Trial Duration by Mechanism of Action by Product (months), 2006-2014 55
Figure 25: Rheumatoid Arthritis Market, Global, Frequency of Primary End points Measured in Clinical Trials, 2006-2014 56
Figure 26: Rheumatoid Arthritis Market, Global, Sales Projection of Baricitinib, 2016-2020 58
Figure 27: Rheumatoid Arthritis Market, Global, Sales Projection of BOW-015, 2015-2020 59
Figure 28: Rheumatoid Arthritis Market, Global, Sales Projection of TuNEX, 2016-2020 60
Figure 29: Rheumatoid Arthritis Market, Global, Sales Projection of Sarilumab, 2015-2020 61
Figure 30: Rheumatoid Arthritis Market, Global, Sales Projection of Secukinumab, 2015-2020 62
Figure 31: Rheumatoid Arthritis Market, Global, Sales Projection of Sirukumab, 2017-2020 63
Figure 32: Comparative Efficacy and Safety of Pipeline Programs 68
Figure 33: Rheumatoid Market, Global, Market Size, 2013-2020 70
Figure 34: Rheumatoid Market, Global, Market Size, 2013-2020 71
Figure 35: Rheumatoid Market, North America, Treatment Usage Patterns, 2013-2020 72
Figure 36: Rheumatoid Market, North America, Annual Cost of Therapy, 2013-2020 73
Figure 37: Rheumatoid Market, North America, Market Size, 2013-2020 74
Figure 38: Rheumatoid Market, Five EU Countries, Treatment Usage Patterns, 2013-2020 75
Figure 39: Rheumatoid Market, Five EU Countries, Annual Cost of Therapy, 2013-2020 76
Figure 40: Rheumatoid Market, Five EU Countries, Market Size, 2013-2020 77
Figure 41: Rheumatoid Market, Japan, Treatment Usage Patterns, 2013—2020 78
Figure 42: Rheumatoid Market, Japan, Annual Cost of Therapy, 2013-2020 78
Figure 43: Rheumatoid Market, Japan, Market Size, 2013-2020 79
Figure 44: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006-2014 82
Figure 45: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006-2014 84
Figure 46: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006-2014 86
Figure 47: Rheumatoid Arthritis Market, Global, Co-development Deals, 2006-2014 88
Figure 48: Rheumatoid Arthritis Market, Global, Co-development Deals, 2006-2014 90
Figure 49: Rheumatoid Arthritis Market, Global, Co-development Deals, 2006-2014 92