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
Global Dementia Legacy Event: Professor Lefkos Middleton
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. 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. 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 â Tau Cascade
Despite their dominance in R&D over 2 decades (also in funding)
?
?
? ?
?
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.
Envrnât
Genes
A Key Barrier resides in our poor
understanding of disease and itâs boundaries
?
5. In order to fully explore the Causes of Dementias, we need to
create a new âInnovation Eco-systemâ
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. 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. Life cycle
manâment
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. Life cycle
manâment
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. Next Steps
⢠Recognise our failures (and their causes) over last 20 years.
⢠Change Gear to accelerate, action is needed now:
ď Create a new Global Dementia Innovation Fund to
ď Invest in and leverage the Innovation Eco-system
to develop new cures for dementia faster
ď§ Stimulate âOut of the boxâ thinking & new ideas.
ď§ Identify and implement evidence based new & disruptive solutions.
ď§ New people, diversity of skills, expertise & disciplines.
ď§ Transparency +++