global dementia legacy event: professor lefkos middleton
DESCRIPTION
Session Two: Barriers to investment in research to find a disease modifying therapy or cure for dementia. Professor Lefkos Middleton, Professor of Neurology, Neuroepidemiology and Ageing Research at School of Public Health, Imperial College LondonTRANSCRIPT
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Barriers and Opportunities for Investment in Research to find a Cure for Dementia by 2025:
Funding the Scientific Challenge Ahead
Lefkos T Middleton MD, FRCPNeuroepidemiology and Ageing Research Unit
School of Public HealthImperial College London
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Life cyclemanagement
File andlaunch
Phase IIIPoC to
Phase IIIFTIH-
ph II toPoC
Pre-clinical
Lead toCandidate
Target toLead
Genefunctionto target
Diseaseselection
Target selection
Success rate <8% 25% <30%
~1,000,000,000 USD
> 12 years
The R&D Pipeline: A Saga of High Attrition and High Financial Risk
For dementia, 3 NMEs (only symptomatic drugs) out of 106 since 1998 = Market Failure
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P-tau NFTs
GSK3b
Dementia
A oligomers
A aggregates
AP
P
2
COOH
-g secretaseBACE1
NH
+ APP
Insulin Degrading Enzyme (IDE)
pro-inflammatorycytokine & ROS release
pro-inflammatorycytokine & ROS release
Cell Death
Still more unknowns than knowns in the Amyloid – Tau CascadeDespite their dominance in R&D over 2 decades (also in funding)
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• Common, chronic and slowly progressive.
• Heterogeneity and Nosological Boundaries still not fully understood (AD vs VaD vs LBD). But 75% of dementia patients >75 years of age have mixed pathologies.
• NIA-AA 2011 Criteria for AD
• Etiology and physiopathology neither linear nor additive but, like a ballet choreographed interactively over time, involving genomic and a multitude of evolving environmental factors.
Envrn’tGenes
A Key Barrier resides in our poor understanding of disease and it’s boundaries
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In order to fully explore the Causes of Dementias, we need to create a new “Innovation Eco-system”
Aggregation of Misfolded A and phosphorylated Tau
Metabolic Syndrome Insulin Resistance
Mitotoxicity-Mitochondrial dysfunction
Ca2+ homeostasis
ExcitotoxicityMetabolic stress
Oxydative stress
Inflammation
Ageing Processes
Telomere Length
Age-related
Neurotrophic Factor Withdrawal Neurotransmitters(GABA, etc)
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Complex Human Diseases are
heterogeneous
Epidemiology
Clinical Manifestations
DNA variation -
RNA-omics
Imaging
Systems BiologyTargetedDisease
Phenotypes
Understanding Disease
New TargetsNew drugs
New indications
Biomarkers for Risk/
Prediction Progression Response
Unravelling Disease through Studies of Prospective Cohorts is a key R&D step in the Precision Medicine era
(2015 and beyond)
L Middleton, GSK R&D Conference, 2005
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Life cycleman’ment
File andlaunch
Phase IIIPoC to
commit toPhase III
FTIH-ph II to
PoC
Pre-clinical
Lead toCandidate
Target toLead
Genefunctionto target
Diseaseselection
Target selection
Understanding Disease New Targets & New Indications
BiomarkersOmics & Imaging
Prospective cohorts Clinical & Genetic, Biomarkers & Systems Biology
Big Data Studies
Susceptibility Alleles & Rare Variants
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Life cycleman’ment
File andlaunch
Phase IIIPoC to
commit toPhase III
FTIH-ph II to
PoC
Pre-clinical
Lead toCandidate
Target toLead
Genefunctionto target
Diseaseselection
Target selection
Understanding Disease New Targets & New Indications
BiomarkersOmics & Imaging
Prospective cohorts Clinical & Genetic, Biomarkers & Systems Biology
Big Data Studies
Susceptibility lleles & Rare Variants
The Dementia Innovation Eco-system
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Next Steps
• Recognise our failures (and their causes) over last 20 years.• Change Gear to accelerate, action is needed now:
Create a new Global Dementia Innovation Fund to Invest in and leverage the Innovation Eco-system
to develop new cures for dementia faster
Stimulate “Out of the box” thinking & new ideas. Identify and implement evidence based new & disruptive solutions. New people, diversity of skills, expertise & disciplines. Transparency +++
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Education, Vascular Risk and leisure activities vs APoE4
from Ferrari et al, 2012
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Is dementia incidence declining? Trends in dementia since 1990 in the Rotterdam study
Schrijvers et al, 2012