抗リウマチ薬（DMARD）動向

Overview

Introduction

The treatment of Rheumatoid Arthritis (RA) has been rapidly evolving over the last decade. Currently, the newer targeted biologic therapies against specific molecules involved in the pathogenesis of RA reduce side-effects, but cheaper traditional therapies are still used in the majority of patients. DMARDs are a rapidly changing growth area of the RA market showing high innovation and competition.

Scope

• Detailed pipeline analysis for key products in a specific RA indication, plus drug sales forecasts to 201
• Overview of patient potential, segmentation by indication and unmet needs in RA across the seven major markets
• Benchmarking of key clinical and company attractiveness of the late-Phase pipeline products
• Detailed clinical trial information and opinion from key thought leaders

Report Highlights

If biologic products continue their exponential uptake the market could reach over US$11 billion by 2014. However, this would put an incredible strain on the financial resources of the key markets, as most growth is driven by high biologic pricing and it is likely that restrictions will be put in place to reduce the cost to payers.

Competition will be fierce between the next DMARDs to be launched, Rituxan/MabThera (rituximab) and Orencia (abatacept). Rituximabs promising dosing and use in cancer indications gives it an advantage over abatacepts novel co-stimulatory modulator. Both will initially be competing for anti-TNF failure patients.

The Roche, Biogen Idec and Genentech partnership looks set to dominate future biologic treatments in RA. Roches financial clout and Japanese partnership with Chugai compliments Biogen Idecs immunology innovation and Genentechs protein-based specialist knowledge to place the products from this group at an immediate advantage.

Reasons to Purchase

• Understand why pricing restraint is necessary for the continued exponential uptake and commercial growth of the biologic DMARDs
• Quantify the future size and potential of the market for novel treatments in the RA indication in each of the seven major markets
• Use analysis of the key molecular targets under investigation to find gaps in the market for your product

Table of Contents

ABOUT DATAMONITOR HEALTHCARE

• About the CNS, Arthritis and Pain pharmaceutical analysisteam

CHAPTER 1 EXECUTIVE SUMMARY

• Scope of the analysis
• Datamonitor insight into the RA market
  • Summary

CHAPTER 2 PATIENT POTENTIAL

• Definition of the disease
• Segmentation of RA
  • US and northern Europe show a higher prevalence of RAacross the seven major markets
  • Average RA clinical trial participant is over 50 andfemale
  • Decrease in RA severity due to better treatment butepidemiology research continues
• Key epidemiology studies in RA in the US, EU and Japan
  • 2005 studies are coming from France and Canada but keyJapanese studies need updating
    • US
    • Europe
    • Japan
  • Statistical caveats
    • Prevalence versus incidence
    • Diagnosed versus undiagnosed prevalence
    • Different methods of gathering prevalence data
    • Data ranges
• Unmet need in RA is still headed by efficacy
  • Clinical unmet needs
    • Efficacy
    • Side effects
    • Administration and patient compliance
    • Cytokine assays a key challenge for treatment development
  • Environmental unmet needs
    • Cost

CHAPTER 3 R&D APPROACH

• The current treatment approach puts biologic therapy afterdifferent combinations of traditional DMARD treatments
• Current market definition includes the most commonbiologic and traditional DMARDs
  • The Japanese market
  • The market value is calculated using IMS diagnosis value
• Classification of pipeline products
  • Cytokines
  • Interleukins
  • TNF inhibitors
  • Cell adhesion molecule inhibitors
  • MAP kinase
  • Immunomodulators
  • Other chemokines
• Clinical trial design
• Clinical trial endpoints in RA
  • American College of Rheumatology (ACR) measures are themost common endpoints
  • Disease Activity Scale
  • Tender Joint Count and Swollen Joint Count
  • Quality of Life Questionnaires
    • HAQ
    • Medical Outcome Short Form 36 (SF-36) Health Survey
  • Blood testing
    • Erythrocyte sedimentation rate (ESR)
    • C-reactive proteins (CRP)
  • Disease progression

CHAPTER 4 RA PIPELINE ANALYSIS

• Pipeline overview
  • Pre-registration and Phase III
  • Phase II
• Key companies involved in the RA pipeline
  • Roche dominates the late-stage pipeline
  • Sanofi-Aventis is a key player in traditional DMARDs buthas not broken into the biologic arena
• Strategies for success
  • Improved dosing and administration methods will drivesales
    • Patient preference or marketing strategies?
    • Flexibility in dosing will be key
  • Is a humanized Mab better than a chimeric one?
    • Therapeutic antibody types
    • The antibody misconception
    • Mabs vs. therapeutic proteins vs. small molecules
  • Biologic combinations should continue to be tested, butnot in the near future

CHAPTER 5 TRADITIONAL DMARDS IN LATE STAGE DEVELOPMENT

• Overview for traditional DMARDs
  • Pipeline summary
  • Methotrexate is key comparator but Arava shows mostinnovation and highest sales in the traditional DMARD class
• Comparison of key compounds in the traditional DMARD class
• Prograf (tacrolimus)
  • Drug overview
    • Clinical trial data
    • Tacrolimus will compete with cyclosporine and methotrexatebut only possibility of modified release give it any advantage
    • RA is just one more indication for Astellass alreadytop-selling drug
    • Prograf competes in terms of cost and its oraladministration, but side effects and comparative efficacy to biologics aremajor drawbacks
  • Forecasts to 2014
    • US
    • EU
    • Japan
• T-614 (iguratimod)
  • Drug overview
    • Clinical trial data
    • A broad action for T-614 raises side-effect concerns
    • Launch in Japan is more likely than in the US or EU
    • ACR50 scores lacking in the latest data making clinicalefficacy difficult to compare
  • Forecasts to 2014
    • US
    • EU
    • Japan
• Other traditional DMARDs
  • Teriflunomide
  • Rosaglitazone

CHAPTER 6 BIOLOGIC DMARDS IN LATE-STAGE DEVELOPMENT

• Overview for biologic therapies
  • Pipeline summary
  • Current biologic comparator therapy is Enbrel
• Comparison of key compounds in biologic DMARD class
• Actemra (tocilizumab/MRA)
  • Drug overview
    • Clinical trial data
    • IL-6 inhibition has potential in many immune disorders
    • Chugais new "Strategic Marketing Units" addconsiderable competitive strength to Actemra
    • Actemras IV dosing may prove more popular in Japan, whichwill be this products key market
  • Forecasts to 2014
    • US
    • EU
    • Japan
• Rituxan/MabThera (rituximab)
  • Drug overview
    • Clinical trial data
    • Rituximabs considerable use in the cancer market dispelsany fears over side effects
    • The Rituxan/MabThera brand has a strong marketinginfrastructure behind it
    • A minimal dosing frequency offers a considerable advantagefor rituximab
  • Forecasts to 2014
    • US
    • EU
    • Japan
• Orencia (abatacept, CTLA4-Ig)
  • Drug overview
    • Clinical trial data
    • Orencias novel mechanism shows great promise inTNF-failures
    • BMS may lack experience in the RA market, but its proposedpharmacovigilance program is well received by the FDA
    • Orencia competes well in most clinical aspects
  • Forecasts to 2014
    • US
    • EU
    • Japan
• Cimzia (CDP 870)
  • Drug overview
    • Clinical trial data
    • Crohns disease is the primary indication for Cimzia
    • A lack of recent data in RA may be losing physician faithin Cimzia, but ACR 2005 meeting data may save it
    • Cost advantage needs to follow through for Cimzia tosucceed
  • Forecasts to 2014
    • US
    • EU
    • Japan
• AMG-714 (HuMax Il-15)
  • Drug overview
    • Clinical trial data
    • AMG-714 shows promise in many indications, includingincrease in BMD for osteoporosis
    • Amgens experience will be an advantage, but AMG-714 mayreach the market too late
    • AMG-714 offers yet another TNF-failure alternative
  • Forecasts to 2014
    • US
    • EU
• LymphoStat-B (belimumab)
  • Drug overview
    • Clinical trial data
    • BLyS shows promise in Lupus, which is expected to be thenext major indication for biologic therapies
    • HGS should seek a partner to bring this product to the RAmarket
    • Initial ACR20 values not promising, but mechanism is sound
  • Forecasts to 2014
• Other drugs in DMARD class
  • RGN-303 (IL-1 Trap)
  • SCIO-469
  • MLN 1202
  • VX-702
  • CNTO-148
  • AZD-9056
  • AT-001 (dnaJp1)
  • AMG-162
  • Eculizumab (Mab C5)
  • INCB-3284
  • AD 452
• Recently discontinued late-stage development compounds
  • CDP-484
  • ABT-874
  • ISIS-104838
  • Doramapimod (BIRB-796)
  • AGIX 4207

CHAPTER 7 INNOVATIVE EARLY-STAGE PROJECTS

• Key Phase I and preclinical compounds in RA
  • Phase I
  • Preclinical
• CD20 directed therapy
  • The candidates so far?
    • HuMax-CD20
    • TRU 015
    • PR070769
  • Will they succeed?
• BLyS inhibitor BR3-FC
  • Less concern exists about long-term safety of BLySantagonists
  • Preliminary data from a similar pipeline product,LymphoStat-B, appear sub-par

• APPENDIX A - METHODOLOGY, BIBLIOGRAPHY AND CONTRIBUTINGEXPERTS
  • Methodology
    • Datamonitor forecast methodology
      • Assumptions
    • Company and product assessments
      • Company factors and score definitions
      • Product factors and score definitions
  • Report methodology
  • Definitions
    • Standard units
    • Japanese market data
    • Derivation of sales forecasts and pricing trends
    • Regional launch dates for new products
    • Generic erosion and pricing assumptions
  • Contributing experts
  • Bibliography
    • Websites
• APPENDIX B - FORECAST DATA TABLES
  • US
  • Japan
  • France
  • Germany
  • Italy
  • Spain
  • UK
  • 5 EU
  • Global
• APPENDIX C - ABOUT DATAMONITOR
  • About Datamonitor
    • About Datamonitor Healthcare
  • Datamonitor Healthcares therapy area capabilities
    • About the CNS, Arthritis and Pain analysis team
  • Disclaimer

List of Tables

• Table 1: Global RA forecast, US$m, 2004-2014
• Table 2: RA population by country, 2005
• Table 3: Point prevalence of RA, by age and sex, per 100patients in Norfolk UK study, 2002
• Table 4: RA prevalence, by gender and country
• Table 5: Key American RA epidemiology studies
• Table 6: Key European RA epidemiology studies
• Table 7: Japan age-adjusted point prevalence of RA innine consecutive surveys of the Kamitonda population, %, 1965-96
• Table 8: Annual costs for biologic and traditionalDMARDs, UK, 2000
• Table 9: NICE incremental cost effectiveness ratio perQALY
• Table 10: Key interleukin targeted products in R&Dpipeline, 2005
• Table 11: TNF products in the pipeline, 2005
• Table 12: Approved biologic TNF inhibitors
• Table 13: p38 MAP kinase targets in the RA pipeline
• Table 14: Immunosuppressant in the RA pipeline
• Table 15: Breakdown of other chemokine-targetedinhibitors in the pipeline, 2005
• Table 16: Key trial data presented in prescribinginformation and used for approval of Enbrel and Remicade
• Table 17: DMARD pipeline breakdown, 2005
• Table 18: Pre-registration and Phase III DMARDs in thepipeline, 2005
• Table 19: Phase II DMARD pipeline, 2005
• Table 20: Products undergoing human clinical trials inRA in collaboration with Roche
• Table 21: Advantages and disadvantages of IV and scadministration methods
• Table 22: Key traditional DMARDs on the market
• Table 23: Overview of late Phase traditional DMARDs
• Table 24: Results of trial to find optimal dosing oftacrolimus in refractory RA, %, 2004
• Table 25: Tacrolimus Phase II trial results
• Table 26: Prograf Phase III trial results
• Table 27: Global franchise and clinical trial phasesummary for Prograf, 2005
• Table 28: Tacrolimus RA forecast by country, $m, 2005-14
• Table 29: Iguratimod RA forecast, $m, 2005-2014
• Table 30: Overview of late phase biologic DMARDs
• Table 31: Enbrel: key facts
• Table 32: MRA RA forecast by country, $m, 2005-2014
• Table 33: Primary and secondary endpoints in rituximabsPhase IIb DANCER trial, 2005
• Table 34: Clinical response over two years following asingle treatment course of rituximab
• Table 35: Rituximab RA forecast by country, $m,2005-2014
• Table 36: Change from baseline in structural damage andprogression, AIM trial
• Table 37: Infections seen in each treatment arm, %
• Table 38: Etanercept plus anakinra serious infectionrates, %
• Table 39: Comparative one and two year trial results, %of patients achieving ACR20, 50 and 70
• Table 40: Abatacept RA forecast by country, $m,2005-2014
• Table 41: CDP 870 Phase IIb trial results, 2001
• Table 42: CDP 870 RA forecast by country, 2005-2014
• Table 43: AMG-714 Phase II results
• Table 44: AMG 714 RA forecast by country, $m, 2005-2014
• Table 45: LymphoStat-B Phase II RA trial results, 2005
• Table 46: IL-1 Trap Phase II trial results, 2003
• Table 47: Recently discontinued projects, 2005
• Table 48: Phase I and preclinical targets, 2005
• Table 49: Phase I DMARD pipeline, 2005
• Table 50: Preclinical pipeline DMARDs, 2005
• Table 51: CD20 directed therapies in the pipeline
• Table 52: ICD10 codes used to define an RA diagnosis
• Table 53: Company factors
• Table 54: Product factors
• Table 55: US RA forecast, US$, m, 2004-2014
• Table 56: Japan RA forecast, US$m, 2004-2014
• Table 57: France RA forecast, US$m, 2004-2014
• Table 58: German RA forecasts, US$m, 2004-2014
• Table 59: Italy RA forecast, US$m, 2004-2014
• Table 60: Spain RA forecast, US$m, 2004-2014
• Table 61: UK RA forecast, US$m, 2004-2014
• Table 62: Five major EU countries RA forecast, US$m,2004-2014
• Table 63: Global RA forecast, US$m, 2004-2014

List of Figures

• Figure 1: The future RA market
• Figure 2: Normal and rheumatoid joint comparison
• Figure 3: Main cause of disability of civiliannon-institutionalized people age 18 and over, %, 1999
• Figure 4: Likely sites of action of the major noveldrugs on the RA market
• Figure 5: RA prevalence, by gender and country
• Figure 6: Unmet needs in RA cited by physicians inDatamonitor primary research, 2003
• Figure 7: Treatment algorithm for RA
• Figure 8: Historical sales for IL-1 inhibitor Kineret,Q3 2001-Q4 2004
• Figure 9: Overview of Interleukin targets in thepipeline
• Figure 10: Mechanism of action of tacrolimus (FK506) andcyclosporine (CsA)
• Figure 11: Swollen and tender joint count assessment
• Figure 12: DMARD pipeline breakdown by mechanism orstructure, Phase I to Pre-registration, 2005
• Figure 13: Roche portfolio breakdown
• Figure 14: Biologic vs. traditional DMARD sales for RAin the US, 2004
• Figure 15: Breakdown of late-stage projects byadministration method, 2005
• Figure 16: Improved self-administration syringe
• Figure 17: Enbrel retail vs. hospital sales, for allindications, Q2 2003 to Q1 2005
• Figure 18: Patient preference for administration methods
• Figure 19: Definitions of antibody sections
• Figure 20: Illustration of Mab types
• Figure 21: Volume and value comparison of traditionalDMARDs for RA, 2001-04
• Figure 22: Traditional DMARDs company and productprofiles
• Figure 23: Prograf comparative clinical profile
• Figure 24: T-614 comparative clinical profile
• Figure 25: Biologic DMARDs company and productcomparison
• Figure 26: MRA ACR responses at 12 and 16 weeks
• Figure 27: MRA comparative clinical profile
• Figure 28: Primary Phase IIb DANCER results forrituximab, 2005
• Figure 29: Prospective MabThera, and B-cell depiction,for rituximab in RA
• Figure 30: Rituximab comparative clinical profile
• Figure 31: AIM and ATTAIN trial results
• Figure 32: Abatacept comparative clinical profile
• Figure 33: Cimzia comparative clinical profile
• Figure 34: Comparison of German biologic uptake in RA,$m, 2001-04
• Figure 35: AMG-714 comparative clinical profile
• Figure 36: LymphoStat-B comparative clinical profile