Advances in Alzheimer’s Disease Drug Discovery

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?

Table Of Contents

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