Alzheimer’s disease Platforms for translational research

The Problem More than 36m people with dementia Consumes 1% global GDP Serial trials failure

January 2014

Diversify target development Trials in prodromal or preclinical disease Rapid trials with early read-outs The Solution

Alzheimer’s Research UK Oxford Drug Development Institute Wellcome Neuroinflammation consortium Wellcome Target Enabling Packages Alzheimer’s Research UK Oxford Drug Development 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 European Prevention of Alzheimer’s disease Readiness register, cohort 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 Pre-competitive data driven PoC/PhII Dementias Platform UK Dementia Discovery cohorts (n=2m) Dementia UK BioBank cohort (n=10k) Deep and Frequent Phenotyping cohort 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 intermediate phenotype Rx 1 Rx 2 Adaptation on cognition outcomes Adaptation on cognition outcomes Selection criteria Trial cohort Readiness cohort EPAD Registry

Alzheimer’s Research UK Oxford Drug Development Institute Wellcome Neuroinflammation consortium Wellcome Target Enabling Packages Alzheimer’s Research UK Oxford Drug Development 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 European Prevention of Alzheimer’s disease Readiness register, cohort 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 Pre-competitive data driven PoC/PhII Dementias Platform UK Dementia Discovery cohorts (n=2m) Dementia UK BioBank cohort (n=10k) Deep and Frequent Phenotyping cohort 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)

Dementias Platform UK

Adapted from Sperling et al (2011) Alzheimer’s and dementia Biomarkers for secondary prevention Stratification markers Progression markers

UK Biobank for Dementia Research 500,000 participants; baseline assessments 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+

Alzheimer’s Research UK Oxford Drug Development Institute Wellcome Neuroinflammation consortium Wellcome Target Enabling Packages Alzheimer’s Research UK Oxford Drug Development 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 European Prevention of Alzheimer’s disease Readiness register, cohort 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 Pre-competitive data driven PoC/PhII Dementias Platform UK Dementia Discovery cohorts (n=2m) Dementia UK BioBank cohort (n=10k) Deep and Frequent Phenotyping cohort 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)

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 dataAdministrative data Regional record-linkage systems Registries and cohorts (broad and disease specific) Biobanks >40,000 subjects in AD cohorts >90,000 subjects 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 ControlsSCIMCI All Plasma DNA RNA CSF Urine MRI FDG-PET Amyloid PET EEG Either access to results from analysis or access to samples/scans

Alzheimer’s Research UK Oxford Drug Development Institute Wellcome Neuroinflammation consortium Wellcome Target Enabling Packages Alzheimer’s Research UK Oxford Drug Development 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 European Prevention of Alzheimer’s disease Readiness register, cohort 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 Pre-competitive data driven PoC/PhII Dementias Platform UK Dementia Discovery cohorts (n=2m) Dementia UK BioBank cohort (n=10k) Deep and Frequent Phenotyping cohort 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)

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 team Collaborating 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