Alzheimer’s disease Platforms for translational research

Alzheimer’s disease

Platforms for translational research

The Problem

• More than 36m people with dementia

• Consumes 1% global GDP

• Serial trials failure

January 2014

Imprecision medicine !

• Diversify target development

• Trials in prodromal or preclinical disease

• Rapid trials with early read-outs

The Solution

Alzheimer’s Research UK Oxford

DrugDevelopment

Institute

Wellcome Neuroinflammation

consortium

Wellcome Target Enabling Packages

IMI-EPAD

European Prevention of Alzheimer’s

disease

Readiness register, cohort

and Early Phase

Trials

IMI-EPAD


disease


and Early Phase

Trials

Pre-competitive data driven

drug development

Pre-competitive cohort repurposing for experimental medicine

Pre-competitive reutilisation of research

and real-world data


PoC/PhII

Dementias Platform UK

Dementia Discovery cohorts (n=2m)

Dementia UK BioBank cohort (n=10k)

Deep and Frequent Phenotyping cohort

Collaboration for translational research in dementia

NIHR Translational Research Collaboration

in dementia (TRC-D)

placebo

Rx

cognition outcomes

Trial cohort

Cohort A

Cohort B

Cohort C

integration

placebo

Rx … n

Adaptation by change in interm

ediate phenotype

Rx 1

Rx 2

Adaptation on cognition outcom

es

Selection criteria

Trial cohort

Readiness cohort

EPAD Registry


DrugDevelopment

Institute


consortium


IMI-EPAD


disease


and Early Phase

Trials

IMI-EPAD


disease


and Early Phase

Trials


drug development



and real-world data


PoC/PhII







in dementia (TRC-D)

http://www.dementiasplatform.uk/


Adapted from Sperling et al (2011) Alzheimer’s and dementia 7 280-92

Biomarkers for secondary prevention

Stratification markers

Progression markers

UK Biobank for Dementia Research

• 500,000 participants; baseline assessments 2005-8

• Web-based questionnaires for additional exposures and outcomes (cognition, mental health, occupation..)

• Multimodal imaging in 100,000 - brain, cardiac and body fat MRI; bone & joint DEXA; 3D carotid ultrasound

• Repeat Neuroimaging, cognition and sampling in 20,000

• Genotyping of all participants (820,000 SNPs)

• Connectivity to EMRs for mental health

A biomarker funnel

55+


DrugDevelopment

Institute


consortium


IMI-EPAD


disease


and Early Phase

Trials

IMI-EPAD


disease


and Early Phase

Trials


drug development



and real-world data


PoC/PhII







in dementia (TRC-D)

European Medical Information Framework

Data available through consortium Large variety in “types” of data

Data is available from more than 53 million subjects from seven EU countries, including

Primary care data sets

Hospital data Administrative data

Regional record-linkage

systems

Registries and cohorts (broad

and disease specific)

Biobanks

>40,000subjects in AD cohorts

>90,000subjects in metabolic cohorts

EMIF Catalogue

Research cohorts on AD or aging

• Type of cohorts:– Population-based cohorts– Clinical cohorts– National multicenter studies – European multicenter studies– Clinical trial cohorts

Data available through cohorts in catalogue

Number of subjects

Controls SCI MCI

All 31219 3173 11976

Plasma 3537 1764 3961

DNA 8763 3163 5731

RNA 1637 484 2128

CSF 846 1336 3757

Urine 2307 1116 2349

MRI 3449 1035 5586

FDG-PET 551 308 1942

Amyloid PET 335 143 492

EEG 301 773 1173Either access to results from analysis or access to samples/scans


DrugDevelopment

Institute


consortium


IMI-EPAD


disease


and Early Phase

Trials

IMI-EPAD


disease


and Early Phase

Trials


drug development



and real-world data


PoC/PhII







in dementia (TRC-D)

Target Enabling and Development

• Oxford basic sciences and neurodegeneration research

• Building on SGC success - TEPs• O3DI collaborative group and beyond

• Target selection by Data and by Biomarkers• Open Innovation• Bringing to dementia research tools and pathways

from– Inflammation– Oncology– Metabolic disease

The Drug Discovery Alliance

• Host Institution is a centre of

excellence in neurodegenerative

disease

• The Institute is integrated into the

host environment

• The DDI scientists are experts in

translating basic science into

therapies

• Provide clear mission

• Stable funding

• £30M over 5 years

• ~30 staff per institute

Partners in the Oxford DDI

Lead Academic Scientist

Prof. Simon Lovestone

Prof. Chas Bountra

Co-applicant PIs

DPAG

NDCN

Dept Psychiatry

LICR

Kennedy Inst. Rheumatology

SGC

TDI / UK NPSC

StemBANCC

CSO John Davis

HoC to be appointed

HoB to be appointed

Chemistry team

Biology teamCollaborating

companies

CROs

Pharma

Research Expertise Drug Discovery Expertise

Portfolio

Project Teams

Robust Lead Series

with proof of principle

New drug discovery programmes

Collaborators

Eg.

Cardiff

KCL

Southampton

Dundee

Other DDIs

Under-exploited

Novel

Targets

Global problems require global solutions

With thanks to….> 50 executive members> 150 principal investigators> 500 scientists>1500 collaborators> 50,000 volunteers> 50,000,000 individuals contributing data> 200,000,000 euros from funders

Documents

Alzheimer’s disease Platforms for translational research