Barriers and Opportunities for Investment in
Research to find a Cure for Dementia by 2025:
Funding the Scientific Challeng...
Life cycle
management
File and
launch
Phase III
PoC to
Phase III
FTIH-
ph II to
PoC
Pre-
clinical
Lead to
Candidate
Target...
P-tau NFTs
GSK3b
Dementia
Ab oligomers
Ab aggregates
APP
2
COOH
g-secretase
BACE1
NH
+ APP
Insulin Degrading Enzyme
(IDE)
...
• Common, chronic and slowly progressive.
• Heterogeneity and Nosological Boundaries still not
fully understood (AD vs VaD...
In order to fully explore the Causes of Dementias, we need to
create a new “Innovation Eco-system”
Aggregation of Misfolde...
Complex Human
Diseases are
heterogeneous
Epidemiology
Clinical
Manifestations
DNA variation -
RNA-omics
Imaging
Systems Bi...
Life cycle
man’ment
File and
launch
Phase III
PoC to
commit to
Phase III
FTIH-
ph II to
PoC
Pre-
clinical
Lead to
Candidat...
Life cycle
man’ment
File and
launch
Phase III
PoC to
commit to
Phase III
FTIH-
ph II to
PoC
Pre-
clinical
Lead to
Candidat...
Next Steps
• Recognise our failures (and their causes) over last 20 years.
• Change Gear to accelerate, action is needed n...
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
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Global Dementia Legacy Event: Professor Lefkos Middleton

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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 London

Published in: Health & Medicine, Technology
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Global Dementia Legacy Event: Professor Lefkos Middleton

  1. 1. Barriers and Opportunities for Investment in Research to find a Cure for Dementia by 2025: Funding the Scientific Challenge Ahead Lefkos T Middleton MD, FRCP Neuroepidemiology and Ageing Research Unit School of Public Health Imperial College London
  2. 2. Life cycle management File and launch Phase III PoC to Phase III FTIH- ph II to PoC Pre- clinical Lead to Candidate Target to Lead Gene function to target Disease selection 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
  3. 3. P-tau NFTs GSK3b Dementia Ab oligomers Ab aggregates APP 2 COOH g-secretase BACE1 NH + APP Insulin Degrading Enzyme (IDE) pro-inflammatory cytokine & ROS release pro-inflammatory cytokine & ROS release Cell Death Still more unknowns than knowns in the Amyloid – Tau Cascade Despite their dominance in R&D over 2 decades (also in funding) ? ? ? ? ?
  4. 4. • 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’t Genes A Key Barrier resides in our poor understanding of disease and it’s boundaries ?
  5. 5. In order to fully explore the Causes of Dementias, we need to create a new “Innovation Eco-system” Aggregation of Misfolded Ab and phosphorylated Tau Metabolic Syndrome Insulin Resistance Mitotoxicity- Mitochondrial dysfunction Ca2+ homeostasis Excitotoxicity Metabolic stress Oxydative stress Inflammation Ageing Processes Telomere Length Age-related Neurotrophic Factor Withdrawal Neurotransmitters (GABA, etc)
  6. 6. Complex Human Diseases are heterogeneous Epidemiology Clinical Manifestations DNA variation - RNA-omics Imaging Systems Biology Targeted Disease Phenotypes Understanding Disease New Targets New 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
  7. 7. Life cycle man’ment File and launch Phase III PoC to commit to Phase III FTIH- ph II to PoC Pre- clinical Lead to Candidate Target to Lead Gene function to target Disease selection Target selection Understanding Disease New Targets & New Indications Prospective cohorts Clinical & Genetic, Biomarkers & Systems Biology Big Data Studies Susceptibility Alleles & Rare Variants
  8. 8. Life cycle man’ment File and launch Phase III PoC to commit to Phase III FTIH- ph II to PoC Pre- clinical Lead to Candidate Target to Lead Gene function to target Disease selection Target selection Understanding Disease New Targets & New Indications Prospective cohorts Clinical & Genetic, Biomarkers & Systems Biology Big Data Studies Susceptibility lleles & Rare Variants The Dementia Innovation Eco-system
  9. 9. 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 +++
  10. 10. Education, Vascular Risk and leisure activities vs APoE4 from Ferrari et al, 2012
  11. 11. Is dementia incidence declining? Trends in dementia since 1990 in the Rotterdam study Schrijvers et al, 2012

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