Pipeline and Commercial Insight: Alzheimer's Disease - Beta treatments on the horizon

Table of Contents

• ABOUT DATAMONITOR HEALTHCARE
  • About the CNS pharmaceutical analysis team
• CHAPTER 1 EXECUTIVE SUMMARY
  • Objective of the analysis
  • Datamonitor insight into the AD market
  • Key opinion leaders
  • Key metrics
• CHAPTER 2 PATIENT POTENTIAL
  • Definition of Alzheimers disease
  • Segmentation of Alzheimers disease
    • Mild AD affects memory, language and reasoning
    • Moderate AD demonstrates more pronounced symptoms
    • Severe AD leaves patients completely dependent
    • Mild cognitive impairment (MCI) may be a precursor to AD
  • Comorbidities or symptoms?
    • Treatments for comorbidities
      • Treating depression improves quality of life andbehavior
      • Treatment of agitation, aggression and psychoticsymptoms is limited by side effects
      • Anxiety is treated using antidepressants andbenzodiazepines
      • Treatment of sleep disturbances is a difficult balanceof sedation
    • Broad symptomatology provides commercial opportunity
  • Diagnosis of Alzheimers disease is generally byexclusion
    • Diagnostic guidelines for AD are provided by multiplesources
      • Severity of AD is often assessed using symptomaticsubscales
    • An holistic view of AD progression is lacking
    • Diagnosis and treatment rates restrict commercialpotential
  • Epidemiology of Alzheimers disease
• CHAPTER 3 MARKET OVERVIEW
  • Market definition for this report
  • The current AD market
    • The major AD market players and franchises
      • Acetylcholinesterase Inhibitors (AChEIs) dominate themarket
      • Pfizer/Eisais Aricept (donepezil)
      • J&Js Razadyne (galantamine) franchise
      • Novartiss Exelon (rivastigmine)
      • NMDA receptor antagonists
      • Forests Namenda (memantine)
  • Unmet needs in Alzheimers disease
    • Disease modification
    • Improved efficacy
    • Fewer side effects
    • Reducing numbers of treatment unresponsive patients
    • Patient compliance
• CHAPTER 4 COUNTRY MARKET ASSESSMENT
  • Global opportunities and threats
    • Opportunities
      • Demographics will continue to expand the market size
      • Increased use of combination therapy as the diseaseprogresses
      • Clinical unmet needs ensure pipeline drugs will drivefuture growth
      • Improvements in diagnosis will increase treatment rates
      • New EU legislation will increase data exclusivityperiod, providing increased return on investment for new products
      • Efficacy in other indications could expand the market
    • Threats
      • Introduction of generic competitors will increase focuson cost
      • The economic cost of geriatric healthcare puts drugswithout clear benefits at risk
      • Parallel imports; EU expansion is likely to drive downprice
  • US
    • Market overview
    • Opportunities
      • High public awareness driven by advocacy & DTCcampaigns
      • Direct access to specialist physicians helps patientsreceive optimal treatment quicker
    • Threats
      • Generic entrants increase competition and impact price
      • Although providing drug benefit for the elderly, thefuture implications of the Medicare Modernization Act (MMA) areuncertain
      • FDA self-regulation will lead to stricter safetyevaluations
  • Japan
    • Market overview
    • Opportunities
      • Under-developed market with room for expansion
      • Improvements in diagnosis and increased awareness wouldincrease drug sales
      • Pricing process slows generic incursion
      • Separation of manufacturing and marketing entities opensmarket to overseas companies
      • Faster product approval accelerates the time to market
    • Threats
      • Biennial price cuts restrict profit
      • Healthcare reforms focus on severe reductions inpharmaceutical expenditure
      • Genericization is slowly taking off
  • France
    • Market overview
    • Opportunities
      • Approval in other AD subgroups would improve the targetpatient pool
      • Innovative drug development encouraged by price premiumand high-level reimbursement
    • Threats
      • Healthcare reforms limit patient access to specialists
      • Price reductions restrict return on investment
      • Re-evaluation of cost-effectiveness and safety datathreatens reimbursement status
      • Drives to promote generic substitution
  • Germany
    • Market overview
    • Opportunities
      • Promotion and education could realize the EUs greatestpatient potential
      • Loophole in 2004 reform exploited for price increases
      • ePharmacy and mail-order legalization increases accessto drugs and information
    • Threats
      • Focus on prescriber overspend in addition to patientco-payments support lower-priced therapies
  • Italy
    • Market overview
    • Opportunities
      • Low treatment rates suggest scope for expansion
      • Innovative drug development rewarded with premium priceand 100% reimbursement
      • UVAs increasing AD treatment efforts
    • Threats
      • Legislation enforces cost-containment in a marketalready characterized by low pricing
      • Pricing can disqualify products from reimbursement
  • Spain
    • Market overview
    • Opportunities
      • Drive to improve Alzheimers care
      • Regional differences provide localized opportunities
      • Drug innovation encouraged by enhanced financing
    • Threats
      • Regulatory and financial barriers to reimbursement
      • A complex pricing system compounded by regular changesand regional variation is a barrier to usual pricing strategies
      • Generic penetration still low but expected to increase
  • UK
    • Market overview
    • Opportunities
      • Severe AD may offer an undertreated population
    • Threats
      • NICE guidance threatens the reimbursement status of ADdrugs
      • Health Select Committee report clamps down onpharmaceutical promotion
      • Pharmaceutical Price Regulation Scheme (PPRS) curbsprice increases
      • Cost-containment measures encourage continued high useof generics
      • The UK is the top importer for parallel trade
• CHAPTER 5 R&D APPROACH
  • Classification of pipeline products
    • ACh modulators are the foundation of current treatment
    • NMDA receptor antagonists lead the way in moderate tosevere AD
    • Neuroprotective and neurotrophic drugs are developingfrom a variety of approaches
    • Beta-amyloid modulators reduce plaque deposition
    • Other compounds in development
      • Statins - the potential in AD is still unclear
      • Anti-inflammatory drugs - future hampered by safetyconcerns
      • Antioxidants may reduce cell death
      • Insulins role in AD is being defined
  • Clinical trial characteristics in Alzheimers disease
    • Gold standard
    • Patient population should be assessed for severity andpotential responders
    • Trial duration must reflect chronic nature of AD
    • Trial endpoints should include more than cognitivefunction
  • Measurement scales in Alzheimers disease
    • Alzheimers disease assessment scale (ADAS)
    • Mini-Mental Status Exam
    • Clinicians Interview-Based Impression of Change
    • Severe Impairment Battery
    • Alzheimers Disease Cooperative Study: Activities ofDaily Living
    • Neuropsychiatic Inventory
    • Clinical Dementia Rating
• CHAPTER 6 DRUG PIPELINE ANALYSIS
  • Pipeline overview
    • Phase III overview
    • Phase II overview
    • Phase I overview
  • Key companies involved in the AD pipeline
    • Eli Lilly
    • Sanofi-Aventis
  • Key companies specializing in Alzheimers disease
    • Axonyx
    • Mindset
  • Strategies for success
    • High risk, high profit versus low risk, low return
    • Diagnosis of Alzheimers disease
• CHAPTER 7 BETA-AMYLOID MODULATORS - LATE-STAGE PIPELINEANALYSIS & FORECASTS
  • Overview for beta-amyloid modulators
    • Pipeline summary
    • Definition of current comparator therapy
  • Alzhemed
    • Drug overview
    • Clinical trial data
      • Phase I
      • Phase II
      • Phase III
    • Patient potential
    • Marketing factors
    • Satisfaction of unmet need
      • Efficacy
      • Disease modification
      • Safety
      • Treatment response
    • Forecasts to 2014
    • Datamonitor comments
  • Flurizan ((R) - flurbiprofen)
    • Clinical trial data
      • Phase I
      • Phase II
      • Phase III
    • Patient population
    • Marketing factors
    • Satisfaction of unmet needs
      • Efficacy
      • Disease modification
      • Safety
      • Treatment response
    • Forecasts to 2014
  • Other drugs
    • AAB-001
    • Cereact/ONO-2506
    • LY-450139
    • Gero-46 (clioquinol)
  • Late-stage development compounds recently discontinued
    • PBT-1 (clioquinol)
    • PPI-1019/Apan
  • Comparison of key compounds in the beta-amyloidmodulator class
    • Disease modification
    • Better efficacy than marketed drugs
    • Side-effect profile
    • Treatment unresponsive patients
    • Marketing strength
    • Commercial comparison
    • Comparative forecasts
• CHAPTER 8 ACETYLCHOLINE MODULATORS - LATE-STAGE PIPELINEANALYSIS AND FORECASTS
  • Overview for acetylcholine modulators
    • Pipeline summary
    • Definition of current comparator therapy
  • Phenserine
    • Clinical trial data
      • Phase I
      • Phase II
      • Phase IIb
      • Phase III
    • Patient profile
    • Marketing factors
      • Satisfaction of unmet needs
      • Efficacy
      • Treatment response
      • Forecast to 2014
  • Other drugs
    • ZT-1
    • CI-1017
    • T-588
    • TV-3326
    • Dimebon
  • Late-stage development compounds recently discontinued
    • NS-2330
    • MKC-231
    • SIB-1553A
• CHAPTER 9 NMDA MODULATORS - LATE-STAGE PIPELINE ANALYSISAND FORECASTS
  • Overview for NMDA modulators
    • Pipeline summary
    • Definition of current comparator therapy
  • Neramexane
    • Clinical trial data
      • Phase III
      • Phase II/ III
    • Patient profile
    • Marketing factors
    • Satisfaction of unmet needs
      • Efficacy
      • Safety
      • Treatment response
    • Forecasts to 2014
  • Other drugs
• CHAPTER 10 NEUROPROTECTANTS - LATE-STAGE PIPELINEANALYSIS AND FORECASTS
  • Overview for neuroprotectant drugs
    • Pipeline summary
    • Definition of current comparator therapy
  • Xaliproden (Xaprila)
    • Profile
    • Preclinical data
    • Clinical trial data
      • Datamonitor comments
      • Phase III
    • Patient profile
    • Marketing factors
      • Efficacy
      • Disease modification
      • Safety
      • Treatment response
    • Forecasts to 2014
  • EGb-761 (Tanakan)
    • Profile
    • Clinical trial data
      • Phase III - The GEM Study
      • Phase III - The Guidance Study
  • Other drugs
    • PYM50028 (Cogane)
      • Clinical trial data
      • Marketing factors
    • SR-57667
    • Ampalex/CX516
    • CX717
    • Epadel/MND-21
    • SRA-333 (lecozotan)
    • LY-451395
    • SL65.0155
• CHAPTER 11 OTHER DRUGS - LATE-STAGE PIPELINE ANALYSISAND FORECASTS
  • Overview for other drugs
    • Pipeline summary
    • The role of statins in AD is not yet clear
      • Zocor
      • Lipitor
    • Colostrinin
      • Clinical trial data
    • AC-3933/AVE-3933
    • Avandia (rosiglitazone)
    • Evista (raloxifene)
    • TVP-1012 (rasagiline)
    • SGS-742
    • C-1073/Corlux
    • C-9136
    • Memryte (leuprolide implant)
• CHAPTER 12 INNOVATIVE EARLY-STAGE PROJECTS
  • Immunotherapy and vaccines
    • AN-1792 showed promise but fell on safety issues
    • Evidence of Aβ clearance, but effects on cognitionnot clear
    • New immunotherapeutic approaches reignite hope for anAlzheimers vaccine
      • AAB-001
      • ACC-001
      • CAD-106
      • AutoVac for Alzheimers PX-106
      • PeviPro
      • Mindsets β-amyloid antibodies
      • M266
    • Considerations for immunotherapeutic approaches
• CHAPTER 13 FORECAST ANALYSIS
  • Assumptions and events
    • 2005
      • EU approval of liquid Aricept will increase its use insevere AD
      • EU decision on the use of Namenda in mild to moderate AD
    • 2006
      • NICE to publish its final guidance on AD drugs
      • Aricept set to become the first US full-spectrum AD drug
      • The first transdermal AChEI to be filed
    • 2007
      • Assessment of xaliproden (Xaprila)
      • Novartis aims to differentiate with ExelonTDS
    • 2008
      • AChEI generics enter the US market
    • 2009
      • A new generation of AD products - Alzhemed launched inthe US
      • Flurizans US uptake not expected to be as strong asthat of Alzhemed
      • Memantine finally becomes available in Japan
      • Generic memantine becomes available in Germany and Spain
      • Razadyne makes its entry in Japan
    • 2010
      • Alzhemed available for use in Europe
      • Flurizan launched in the EU
      • Generic donepezil becomes available in the US
    • 2011
      • Generic memantine becomes available in the US
      • The impact of memantine generics may be reduced byneramexanes entry in the US
      • The last of the AChEIs, Exelon, goes off patent in theUS
      • Generic rivastigmine launches in Germany
    • 2012
      • Forest launches neramexane across the EU
      • European AChEIs get hit by generics
      • Generic rivastigmine launches in France and the UK
      • The Japanese market washed out as Aricepts patentexpires
    • 2013
      • Generic rivastigmine launches in Italy and Spain
    • 2014
      • Generic rivastigmine finally becomes available in the US
      • Generic memantine becomes available in the remainingmajor EU markets
• CHAPTER 14 COMMERCIAL IMPACT AND LIFECYCLE MANAGEMENT:CASE STUDIES
  • Case studies
    • Managing the product lifecycle for maximum revenues
      • Formulations not yet tested in the AD market
      • Demonstrating the benefits of combinations can be asource of gains
    • Phase II drugs may limit the success of Alzhemed andFlurizan
• APPENDIX A
  • AD market data
  • Preclinical drug pipeline
  • Bibliography
• APPENDIX B
  • AD drug revenue forecasts by country
  • Report methodology
    • Standard Units
    • Japanese Market Data
    • Derivation of Sales Forecasts and Pricing Trends
    • Regional Launch Dates for New Products
    • Generic Erosion and Pricing Assumptions
    • ABOUT DATAMONITOR
  • Disclaimer
• List of Tables
  • Table 1: Key parameters of AD
  • Table 2: Forecast key pipeline products in AD from2010-14
  • Table 3: Common clinical features in Alzheimersdisease by stage
  • Table 4: Prevalence for moderate and severe AD only
  • Table 5: Population estimates for moderate and severeAD (millions), 1995-2050
  • Table 6: AD comorbidity trials of existing drugs
  • Table 7: DSM-IV criteria for Alzheimers type dementia
  • Table 8: Diagnosis rates across the seven majormarkets, 2005
  • Table 9: Drug-treated AD populations across the sevenmajor markets, 2005
  • Table 10: Prevalence of Alzheimers disease by genderand age
  • Table 11: Prevalence of Alzheimers disease across theseven major markets, 2005
  • Table 12: AD population across the seven major markets(millions), 1995-2050
  • Table 13: Global AD drug revenues, 2004
  • Table 14: US AD drug market, 2004
  • Table 15: AD drug market in Japan, 2004
  • Table 16: AD drug market in France, 2004
  • Table 17: AD drug market in Germany, 2004
  • Table 18: AD drug market in Italy, 2004
  • Table 19: AD drug market in Spain, 2004
  • Table 20: UK AD drug market, 2004
  • Table 21: Measures used for clinical efficacyendpoints in AD
  • Table 22: AD drugs in Phase III clinical development,2005
  • Table 23: AD drugs in Phase II clinical development,2005
  • Table 24: AD drugs in Phase I clinical development,2005
  • Table 25: Eli Lillys AD pipeline, 2005
  • Table 26: Sanofi-Aventiss AD pipeline, 2005
  • Table 27: Axonyxs AD pipeline, 2005
  • Table 28: Mindsets pipeline, 2005
  • Table 29: Aβ modulators in late-stage development2005
  • Table 30: Global revenue forecasts for Alzhemed,2005-14
  • Table 31: Impacting factors on the revenues ofAlzhemed, 2005-14
  • Table 32: Global revenue forecasts for Flurizan,2005-14
  • Table 33: Impacting factors on the revenues ofFlurizan, 2005-14
  • Table 34: Discontinued R&D projects in the Beta-Amyloidmodulator class, 2004-05
  • Table 35: Global sales forecasts for Aβ modulatordrugs, 2006-14
  • Table 36: ACh modulators in late-stage development,2005
  • Table 37: Discontinued R&D projects in the AChmodulator class, 2004-05
  • Table 38: NMDA modulators in late-stage development2005
  • Table 39: Global sales forecasts for neramexane,2005-14
  • Table 40: Impacting factors on the revenues ofneramexane, 2005-14
  • Table 41: Neuroprotectant drugs in late-stagedevelopment, 2005
  • Table 42: Other drugs in late stage development, 2005
  • Table 43: Aricept key facts
  • Table 44: Key Aricept events, 2004-2005
  • Table 45: Razadyne/ Razadyne ER key facts
  • Table 46: Key Razadyne/ Razadyne ER events, 2004-2005
  • Table 47: Exelon key facts
  • Table 48: Namenda key facts
  • Table 49: Key Namenda events, 2004-2005
  • Table 50: AD drugs in preclinical development, 2005
  • Table 51: AD drug comparator score sheet
  • Table 52: US AD drug revenue forecast
  • Table 53: Japan AD drug revenue forecast
  • Table 54: France AD drug revenue forecast
  • Table 55: Germany AD drug revenue forecast
  • Table 56: Italy AD drug revenue forecast
  • Table 57: Spain AD drug revenue forecast
  • Table 58: UK AD drug revenue forecast
  • Table 59: EU5 AD drug revenue forecast
  • Table 60: Global AD drug revenue forecast
• List of Figures
  • Figure 1: AD population across the seven majormarkets, 1995-2050
  • Figure 2: Total global quarterly AD drug sales,1999-2005
  • Figure 3: Global quarterly AD drug sales, 1999-2005
  • Figure 4: AD drug share by revenue across the sevenmajor markets, 1999-2005
  • Figure 5: Key players in the AD market
  • Figure 6: Importance of unmet needs in AD
  • Figure 7: AD relative treatment ratios
  • Figure 8: AD drug market, quarterly revenues,1999-2005
  • Figure 9: US AD market share, by revenue, 1999-2005
  • Figure 10: AD drug market in Japan, quarterlyrevenues, 1999-2005
  • Figure 11: AD drug market in France, quarterlyrevenues, 1999-2005
  • Figure 12: AD market share in France, by revenue,1999-2005
  • Figure 13: AD drug market in Germany, quarterlyrevenues, 1999-2005
  • Figure 14: AD market share in Germany, by revenue,1999-2005
  • Figure 15: AD drug market in Italy, quarterlyrevenues, 1999-2005
  • Figure 16: AD market share in Italy, by revenue,1999-2005
  • Figure 17: AD drug market in Spain, quarterlyrevenues, 1999-2005
  • Figure 18: AD market share in Spain, by revenue,1999-2005
  • Figure 19: AD drug market in the UK quarterlyrevenues, 1999-2005
  • Figure 20: AD market share in the UK, by revenue,1999-2005
  • Figure 21: AD pipeline drugs in each development stageby class
  • Figure 22: Alzhemeds satisfaction of unmet needs
  • Figure 23: Flurizans satisfaction of unmet needs
  • Figure 24: Commercial comparison of beta-amyloidmodulators Alzhemed and Flurizan against gold standard Aricept
  • Figure 25: Commercial comparison of NMDA modulatorneramexane against gold standard Namenda
  • Figure 26: Potential impact of Phase II drugs on USforecasts
  • Figure 27: US forecast for pipeline drugs withoutPhase II drug impact