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

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 – 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.
Envrn’t
Genes
A Key Barrier resides in our poor
understanding of disease and it’s boundaries
?

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. 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
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. 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. 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. Education, Vascular Risk and leisure activities vs APoE4
from Ferrari et al, 2012

11. Is dementia incidence declining? Trends in
dementia since 1990 in the Rotterdam study
Schrijvers et al, 2012