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)

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?

? ?

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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)

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