Collaborative research - the EPAD

(European Prevention of Alzheimer’s

Dementia) Project

Prof Craig RitchieDirector: Centre for Dementia Prevention

University of Edinburgh

NHS Research Scotland Annual Conference

Glasgow: 26th October 2016

Presentation Summary

• An (overdue) ‘paradigm shift’

– “Alzheimer’s Disease is a condition of midlife

presenting as Alzheimer’s dementia in late life”1

• European Prevention of Alzheimer’s Dementia

(EPAD) Project2

1: Ritchie K, Ritchie CW et al. Does late onset Alzheimer's Disease really begin in mid-life.

Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2015; 1(2):122–130

2: Ritchie CW et al. The European Prevention of Alzheimer's Dementia (EPAD) Consortium: A

platform to enable the secondary prevention of Alzheimer's Dementia through improved Proof of

Concept Trials. Lancet Psychiatry 2016 Feb;3(2):179-86

Biomarkers and Alzheimer’s Disease

Biomarkers and Alzheimer’s Disease

• Amyloid Pathology

• Tau Pathology

• Cerebrovascular Changes

• a-synuclein

• Blood Brain Barrier Integrity

• Glial activation and inflammation

• Oxidative stress

• Mitochondrial dysfunction

• Synaptic dysfunction

• Metal dyshomeostasis

• Apoptosis

• Insulin resistance

• mTOR signalling

• b-HSD function

PREVENTION PREMISED ON

UNDERSTANDING DISEASE BEFORE

DEMENTIA

SECONDARY PREVENTIONPRIMARY

PREVENTION

PREVENTION PREMISED ON UNDERSTANDING DISEASE BEFORE DEMENTIA

Secondary Prevention of Dementia

The three steps to achieve secondary prevention:

•STEP 1: Identifying the ‘at risk’ person– Risk factors (fixed and modifiable)

– Cognitive profile (not ‘symptoms’)

– Biomarker evidence of disease

– Changes in these over time

Can we develop an accurate prediction algorithm/score?

Secondary Prevention of Dementia

The three steps to achieve secondary prevention:

• STEP 2: Tailoring treatment– Reducing modifiable risk factors

– Enhancing resilience

– Disease course modification through specific drug intervention(s)

Secondary Prevention of Dementia

The three steps to achieve secondary prevention:

STEP 3: Measuring success

– Individual’s probability status reduces• Cognition improves

• Biomarkers normalise

• Risk of dementia decreases

Ongoing clinical trials in Alzheimer disease (AD)

β amyloid

† Currently approved for AD treatment

Tau

Cholinergics

Others

Mangialasche , Kivipelto et al, modified 2013 from Lancet Neurology, 2010

Aß production

Aß clearance

Aß aggregation

More than 200 drug

development failures in

the last 30 yearsSchneider Mangialasche

Kivipelto et al., JIM 2014

WRONG METHODOLOGY

– High Screen Failure

WRONG POPULATION

– Target population pre-clinical

WRONG OUTCOMES

– Outcome measures (biological and clinical) need to

track relevant change

WRONG ANALYTICAL APPROACH

– No interim decision points for adaptation

The Problem Statement:

EPAD Consortium Developed

• €64M+ Funding from IMI

• Commenced January 2015

• Managed and Sponsored by University of Edinburgh

“The European Prevention of Alzheimer's Dementia

(EPAD) project aims to develop an infrastructure

that efficiently enables the undertaking of adaptive,

multi-arm Proof of Concept studies for early and

accurate decisions on the ongoing development of

drug candidates or drug combinations for the

secondary prevention of Alzheimer’s dementia”.

European Prevention of

Alzheimer’s Dementia (EPAD)

1

4

Stepped Approach

Define criteria for identifying AD pathology early in the course ofdisease in people who have no or minimal symptoms.

EPAD Register: JANUARY 2016

– Identifying these individuals from existing population and clinical cohorts orregisters.

EPAD Cohort: MAY 2016 (n=42)

– Developing a large longitudinal cohort study to ease identification for trialinclusion, provide trial run-in data and generate high quality data for updatingAD disease models, including defining risk for developing AD and evaluatingefficacy.

EPAD Trial: Q4 2017

– Establishing a protocol and infrastructure for a standing, double-blind, adaptive,proof-of-concept clinical trial for secondary prevention of AD.

IMI Expert Panel Hearing, 7 October 2014

This is EPAD!!

15

WP 5-8: Supporting Work Packages

The E

PAD

Deliv

ery

Clu

ster

From Parent Cohort to PoC

16

The EPAD PoC Trial (n=1,500)

17

Allows early decisions on progression to longer term clinical outcomes by impact onpre-defined and target-specific intermediary phenotype.

Scandinavian Collaborations

Partner:

GEDOC and Miia Kivipelto/ Laura

SNAC-K Fratiglioni

External partners:

FINGER Miia Kivipelto

CAIDE Miia Kivipelto

DDRC Steen Hasselbalch

Register Oslo cohort Nenad Bogdanovic

Benelux Collaborations

Partner:

Amsterdam Philip Scheltens

External partner:

Antwerp Sebastian Engelborghs

French Collaborations

Partner:

Toulouse Bruno Vellas

External partners:

Bordeaux Dijon

Lille Limoges

Lyon Marseille

Montpellier Nancy

Nantes Paris -Broca

Paris Sud Paris Nord

Rennes Strasbourg

Spanish and Portugese Collaborations

Partner

ALFA (BBRC)/IDIBAPS José Luis Molinuevo

External partners

CITA Pablo Martínez-Lage

Fundacion Reina Sofia Miguel Medina

Sant Pau Alberto Lleó

Coimbra Catarina Oliveira

Lisbon Alexandre de Mendonça

Swiss Collaborations

Partner:

Geneva Panteleimon

Giannakopoulos

External partners:

Zurich Christoph Hock/

Anton Gietl

Lausanne cohort 65+ Brigitte Santos-

Eggimann

Bus Sante Idris Guessous

MentDis_ICF65+ Alessandra Canuto

Colaus/PsyCoLaus Martin Preisig

Italian Collaborations

Partner:

ADWIBO Brescia Giovanni B Frisoni/

Cristina Muscio

External partners:

InChianti Luigi Ferrucci

ILSA Emanuele Scafato

UK and Irish Collaborations

Partners:

PREVENT Craig Ritchie

Generation Scotland David Porteous

UK Biobank Cathie Sudlow

DCR Simon Lovestone

Numerous DPUK Cohorts

Potentially NICOLA and TILDA from NI &Eire

EPAD is a massive and ambitious EU collaboration led

from Scotland.

The driving force for EPAD was that multiple design,

scientific and delivery features of AD trials needed a

reboot…

Recruitment methodology is ambitious, costly and

innovative BUT…..

If successful will have major impact on delivering more

therapies more quickly to prevent dementia

Conclusions

National Leads

Ritchie/Gallacher - UK & Ireland

Miia Kivipelto - Scandinavia

José Luis Molinuevo – Spain/Portugal

Philip Scheltens - Benelux

Giovanni Frisoni - Switzerland/Italy

Bruno Vellas - France

Acknowledgements

Work Package Leads

WP1Simon Lovestone (UOXF)

Andrew Satlin (Eisai)

Gary Romano (JPNV)

WP2Adrian Mander (MRC)

Shobha Dhadda (Eisai)

Scott Berry (BERRY)

Kristian Windfeld (Lundbeck)

WP3Pieter Jelle Visser (VU-VUmc)

Gerald Luscan (Pfizer)

WP4Craig Ritchie (UEDIN)

Catherine Debove (BI)

Miia Kivipelto (KI)

Mila Etropolski (JPNV)

WP5Carlos Díaz (SYNAPSE)

Serge Van der Geyten (JPNV)

WP6Jean Georges (AE)

Sean Knox (NOV)

WP7José Luis Molinuevo (BBRC)

Frank Tennigkeit (UCB)

Saira Ramasastry (SYNAPSE)

WP8Edo Richard (RUMC)

Luc Truyen (JPNV)

Carol Brayne (UCAM)

Shirlene Badger (UCAM

Executive Committee & PMO

Serge Van der Geyten (JPNV)

Luc Truyen (JPNV)

Andrew Satlin (Eisai)

Craig Ritchie (UEDIN)

Simon Lovestone (UOXF)

José Luis Molinuevo (BBRC)

Carlos Díaz (Project Manager)

Sandra Pla (member of PMO)

Lennert Steukers (member of PMO)

Mila Eltropolski (JPNV – member of PMO)

Judi Syson (UEDIN – member of PMO)

The research leading to these results has received support

from the Innovative Medicines Initiative Joint Undertaking

under grant agreement n° 115736, resources of which are

composed of financial contribution from the European

Union's Seventh Framework Programme (FP7/2007-2013)

and EFPIA companies’ in kind contribution.

Acknowledgment