Rheumatoid Arthritis Market to 2020 - A Crowded Market Characterized by Modest Growth - THERAPY ANALYSIS - MarketResearch.com
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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.
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 2Executive 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.
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 31 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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 43.3.5 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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 57.1 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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 61.1 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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 7Figure 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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 82 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.
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 94 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.
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 38Figure 11: Rheumatoid Arthritis Market, Global, Pipeline, 2014
A) Pipeline by phase B) Pipeline by molecule type
Pre
registration
Phase III Unknown Gene therapy
Antibody
Protein Peptide
Discovery Small molecule
Cell therapy
Phase II Biologic
Vaccine
Phase I Total: XX
Total: XX Preclinical
Polysaccharide
IND/CTA- Biosimilar
filed Monoclonal
antibody
Oligonucleotide Biologic
C) Pipeline by Molecule Type and Stage of D) Pipeline by RoA
Development
Number of products
Transdermal Intraarticular
Topical
Subcutaneous
Intravenous
Rectal, topical
Total: XX Intravenous,
Parenteral
Unknown
Preclinical
Phase I
IND/CTA-filed
Phase II
Discovery
Phase III
Preregistration
subcutaneous
Oral, Nasal
transdermal
Polysaccharide Oligonucleotide Biologic Oral, topical Oral
Gene therapy Antibody Vaccine
Cell therapy Peptide Protein
Monoclonal antibody Biosimilar Small molecule
E) Pipeline by program type
Number of products
Repositioned
Generic
Biosimilar
Novel
Unknown
Preclinical
Phase I
IND/CTA-filed
Phase II
Discovery
Phase III
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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 394.3 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.
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 40Figure 12: Rheumatoid Arthritis Market, Global, Pipeline by Mechanism of Action, 2014
A) Pipeline by MoA
Nucleic acid
precuros enzyme
inhibitor
Other
COX inhibitor
Neuromodulator
Total: XX
Intracellular
kinase inhibitor
Cytokine inhibitor
B) Pipeline by MoA and stage of development
IL-23
Colony stimulating factor 1 receptor
antagonist
MIF
Other cytokine
Number of products
Granulocyte-macrophage colony
stimulating factor inhibitor
IL-17
Other interleukins
Toll-like receptor
IL-1
Unknown
Preclinical
Phase I
Phase II
IND/CTA-filed
Discovery
Phase III
Preregistration
IL-6
Chemokine signaling
TNF
Source: GBI Research, Proprietary pipeline database
COX: Cyclo-oxygenase; IND/CTA: Investigational New Drug/Clinical Trial Authorisation; MoA :Mechanism of Action
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 417 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 $XX billion, although
there are a substantial number of deals with undisclosed valuations.
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 82Figure 44: Rheumatoid Arthritis Market, Global, Licensing Deals, 2006–2014
A) Deals by territory
Note: Node sizes, arrow sizes and edge thicknesses correspond to the volume
of deals occurring, with larger nodes, larger arrows and thicker edges indicating
a higher volume of deals.
B) Number and value of deals by year
Aggregate deal values ($ bn)
Number of deals
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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 838 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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 958.1.2 Preclinical
Table 3: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Preclinical
Phase, 2014
Product Company Molecule type Mechanism of action
Source: GBI Research
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 968.1.3 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
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 978.1.4 Phase I
Table 5: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase I, 2014
Product Company Molecule type Mechanism of action
Source: GBI Research
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
photocopied Page 988.1.5 Phase II
Table 6: Rheumatoid Arthritis, Therapeutics, Global, All Pipeline Products, Phase II, 2014
Product Company Molecule type Mechanism of action
Source: GBI Research
© GBI Research. This is a licensed product and is not to be GBIHC354MR / Published DEC 2014
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