Advances in Alzheimer’s Disease Drug Discovery

Date: May 22, 2011
Pages: 273
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US$ 3,835.00
Publisher: Business Insights
Report type: Strategic Report
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ID: A05110F2AA4EN
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Advances in Alzheimer’s Disease Drug Discovery
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Introduction

This report details existing and emerging hypotheses to explain the cause of late-onset AD. The progress of multiple potential under investigation is reviewed. In addition the potential application of neurogenic stimulation using intrinsic (or extrinsic) stem cells and related neurotrophic factors has been considered.

Features and benefits
  • Gain an overview of disease-modifying approaches in discovery and early clinical development for the treatment of Alzheimer's disease.
  • Identify the major hypotheses proposed to explain the cause of AD and evaluate potential clinical development candidates testing each hypothesis.
  • Assess the competitor landscape and progress of specific compounds for disease modification in AD.
  • Analyze the potential of active and passive immunization strategies with particular reference to previous trials that failed on safety grounds.
  • Gain insight into newer therapeutic strategies, including neurogenic stimulation and the use of stem cells.
Highlights

In 2010 an estimated 35.6 million people worldwide had dementia. This number will double every 20 years, reaching 65.7 million in 2030 and 115.4 million in 2050. Over 50% of these individuals will be in developing countries. The total estimated worldwide costs of dementia, including direct and indirect costs of care, were $604bn in 2010.

Inhibition of BACE1( β-secretase) is a preclinically validated disease-modifying target in AD. Inhibitors of BACE1 have been reported by several groups, but clinical progress has been slow owing to difficulties in identifying compounds that are selective, non-peptide mimics, orally active, and CNS penetrant.

Passive and active immunization strategies against Aβ are being pursued by many companies and are in late Phase ll and Phase lll trials. To avoid a Th1 response most vaccines and monoclonal antibodies now in development are targeted towards the N-terminal amino acids.

Your key questions answered
  • What therapeutic targets are being explored as disease-modifying agents in Alzheimer's disease and which are likely to demonstrate efficacy?
  • Are there alternative approaches to the “amyloid cascade hypothesis” and what progress has been made?
  • Do the novel cognitive enhancers under investigation have properties that may make them especially useful in disease modification?
  • Do the novel cognitive enhancers under investigation have properties that may make them especially useful in disease modification?
  • Which drugs currently in the clinic are best placed to achieve the badly needed breakthrough in the treatment of Alzheimer's disease?
Executive Summary
  Introduction
  Prevalence and economic burden of AD
  Risk factors for AD
  Amyloid and AD
  α-Secretase upregulation
  N-Truncation and creation of toxic species
  β-Secretase in AD
  γ-Secretase: inhibitors versus modulators
  Enhanced amyloid clearance
  Active and passive immunization
  Tau and the GSK3 hypothesis of Alzheimer’s disease
  Phosphodiesterase inhibition
  Regulation of epigenetic phenomena by HDAC and sirtuin
  Inhibition of amyloid and tau aggregation
  Mitochondria
  Inflammation – cause or effect?
  Neurogenesis and neurotrophic factors
  Histamine: an alternative cognition enhancer
  Role of 5HT receptors in AD
  Nicotinic receptor agonists as cognition enhancers and disease modifiers
About the author
  Disclaimer
Introduction
  Summary
  Introduction
  Diagnosis of Alzheimer’s disease and mild cognitive impairment
Prevalence and economic burden of AD
  Summary
  Introduction
  Prevalence
  Economic burden
  Potential impact of achieving delayed onset or slowed progression of AD
Risk factors for AD
  Summary
  Introduction
  Risk factors for familial Alzheimer’s disease
  Risk factors for sporadic or late-onset AD
  Genetic risk factors
    Apolipoprotein E
    Cystatin C
  Non-genetic risk factors
    Homocysteine
    Race/ethnicity
    Others
Amyloid and AD
  Summary
  Introduction
  The amyloid cascade hypothesis
    Amyloid generation and clearance
    What is the toxic species of Aβ?
α-Secretase upregulation
  Summary
  Introduction
  Upregulation of α-secretase may have beneficial effects in AD
    Potential beneficial effect of statins in AD
    Other compounds acting on α-secretase activity
    Decreased APP synthesis
    Posiphen and bisnorcymserine
N-Truncation and creation of toxic species
  Summary
  Introduction
  Does N-truncation and cyclization of Aβ have a role in AD?
    N-truncation of Aβ
    Pyroglutamate Aβ generation
β-Secretase in AD
  Summary
  Introduction
  BACE1, a β-secretase
  Targeting BACE1 in the treatment of Alzheimer’s disease
  BACE1 and BACE2: selectivity or dual inhibitor?
  Downsides of BACE1 inhibition
  BACE1 inhibitors in development
    ACI-91
    ARC050
    CTS-21166
    E2609
    GRL-8234
    GSK188909
    HPP854
    LY2811376
    TAK-070
    SCH-785532 and SCH-1359113
  Anti-BACE1 antibody
  Additional approaches based on BACE1
    Regulation of BACE1 transcription/translation
    Role of miRNA
  Is BACE1 the real β-secretase?
  CatB: contradictory role in the production and degradation of amyloid
γ-Secretase: inhibitors versus modulators
  Summary
  Introduction
  γ-Secretase: need for Notch-sparing compounds?
  γ-Secretase inhibitors in development
    BMS-708163
    CHF5074
    Begacestat (GSI 953)
    ELND-007/ELND-006
    EVP-0015962
    E2212/E2012
    Flurbiprofen
    Semagacestat (LY450139)
    MK-0752
    NIC5-15
    PF-3084014
    RO4929097 (RG4733)
    Gleevec
Enhanced amyloid clearance
  Summary
  Introduction
  Could enhanced clearance of Aβ be a therapeutic option?
    Role of transporters
    Enhanced proteolysis to reduce Aβ
Active and passive immunization
  Summary
  Introduction
  Is vaccination the answer? Progress in active immunization
  Active immunization strategies – progress to date
    CAD-106
    AD02
    ACI-24
    ACC-001 (vanutide cridificar)
    UB311
    Ablynx
    V950
    RV01/RV02
  Passive immunization: multiple antibody strategies
    Bapineuzumab (AAB-001)
    AAB-003
    Solanezumab (LY2062430)
    Ponezumab (PF-04360365)
    Gantenerumab (R1450; RO4909832)
    Intravenous immunoglobulin (IVIg)
    BAN2401
    MABT5102A
    ACU-5A5
    IN-N01
    DNA vaccines
    Tau antibody
Tau and the GSK3 hypothesis of Alzheimer’s disease
  Summary
  Introduction
  Tau-GSK3 hypothesis
    Tideglusib (NP-12, NP031112; Nypta)
    Lithium
    Valproic acid
Phosphodiesterase inhibition
  Summary
  Introduction
  PDE inhibitors have both symptomatic and disease-modifying effects
    HT-0712
    PF-04447943
    BAY73-6691
Regulation of epigenetic phenomena by HDAC and sirtuin
  Summary
  Introduction
  Role of histone acetylase and deacetylase in AD
  Sirtuins
    Resveratrol /SRT501
    SRT2104
    SRT2379
    EX-527/SEN196
Inhibition of amyloid and tau aggregation
  Summary
  Introduction
  Anti-aggregatory compounds in clinical trials
    Aβ aggregation
    Tau aggregation
Mitochondria
  Summary
  Introduction
  Mitochondrial cascade hypothesis and oxidative stress
    Latrepirdine (Dimebon)
    Oxidative stress
  Aberrant cell cycle re-entry
Inflammation – cause or effect?
  Summary
  Introduction
  TNF-α
  Thalidomide
  IL-1
  NF-κB and vinpocetine
  Masitinib
  Glitazones
Neurogenesis and neurotrophic factors
  Summary
  Introduction
  Neurogenesis – can lost neurons be replaced?
    Is there a role for neurogenesis in AD?
    Cerebrolysin
    Ginkgo
    Valproic acid
    Neurotrophic factors
    Small-molecule TrkA and TrkB agonists
Histamine: an alternative cognition enhancer
  Summary
  Introduction
  H3 receptor antagonists
    GSK239512
    PF-03654746
    SAR110894
    ABT-288
    MK-0249
    MK-3134
    Others
Role of 5HT receptors in AD
  Summary
  Introduction
  5HT6 receptor antagonists
    GSK742457 (SB-742457)
    PF-05212365 (SAM-531)
    Lu AE58054 (SGS-518)
    SYN-120
    SUVN-502
    AVN-322
  5HT4 receptor agonists
    TD-5108 (velusetrag)
    VRX-03011/ PRX-03140
    PF-04995274
    Prucalopride (R093877; R108512)
    Naronapride (ATI-7505)
  5HT1A receptor antagonists
    Lecozotan
    AV965
Nicotinic receptor agonists as cognition enhancers and disease modifiers
  Summary
  Introduction
  α7 Nicotinic agonists in development for AD
    EVP-6124
    TC-5619-238
    RO5313534 (RG3487, MEM3454) and R4996 (MEM63980)
  Discontinued α7 agonists
    PNU-282987
    SSR180711
    GTS21
  α4β2 Agonists
    AZD1446
    AZD3480
    ABT-560, ABT-894
    Pozanicline (ABT-089)
    Varenicline (Chantix)
Conclusion
  Conclusions
Appendix
  Methodology
    Primary research
    Secondary research
  Scope
  Bibliography
  Abbreviations
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