Pipeline Insight: Disease Modification In Rheumatoid Arthritis - Pipeline Uptake Inhibited By Anti-TNFs

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