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
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
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
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)
?
?
? ?
?
• 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
?
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)
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
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
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
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 +++
Education, Vascular Risk and leisure activities vs APoE4
from Ferrari et al, 2012
Is dementia incidence declining? Trends in dementia since 1990 in the Rotterdam study
Schrijvers et al, 2012