Collaborative research - the EPAD (European Prevention of Alzheimer s Dementia) Project

Transcription

1 Collaborative research - the EPAD (European Prevention of Alzheimer s Dementia) Project Prof Craig Ritchie Director: Centre for Dementia Prevention University of Edinburgh NHS Research Scotland Annual Conference Glasgow: 26 th October 2016

2 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) Project 2 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): : 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

3 Biomarkers and Alzheimer s Disease

4 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

5 PREVENTION PREMISED ON UNDERSTANDING DISEASE BEFORE DEMENTIA

6 PREVENTION PREMISED ON UNDERSTANDING DISEASE BEFORE DEMENTIA PRIMARY PREVENTION SECONDARY PREVENTION

7 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?

8 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)

9 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

10 Ongoing clinical trials in Alzheimer disease (AD) β amyloid Tau More than 200 drug development failures in the last 30 years Aß production Schneider Aß aggregation Mangialasche Kivipelto Aß clearance et al., JIM 2014 Currently approved for AD treatment Cholinergics Others Mangialasche, Kivipelto et al, modified 2013 from Lancet Neurology, 2010

11 The Problem Statement: 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

12 EPAD Consortium Developed 64M+ Funding from IMI Commenced January 2015 Managed and Sponsored by University of Edinburgh

13 European Prevention of Alzheimer s Dementia (EPAD) 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.

14 Stepped Approach Define criteria for identifying AD pathology early in the course of disease in people who have no or minimal symptoms. EPAD Register: JANUARY 2016 Identifying these individuals from existing population and clinical cohorts or registers. EPAD Cohort: MAY 2016 (n=42) Developing a large longitudinal cohort study to ease identification for trial inclusion, provide trial run-in data and generate high quality data for updating AD disease models, including defining risk for developing AD and evaluating efficacy. EPAD Trial: Q 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

15 This is EPAD!! The EPAD Delivery Cluster WP 5-8: Supporting Work Packages 15

16 From Parent Cohort to PoC 16

17 The EPAD PoC Trial (n=1,500) Allows early decisions on progression to longer term clinical outcomes by impact on pre-defined and target-specific intermediary phenotype. 17

18 Scandinavian Collaborations Partner: GEDOC and SNAC-K External partners: FINGER CAIDE DDRC Register Oslo cohort Miia Kivipelto/ Laura Fratiglioni Miia Kivipelto Miia Kivipelto Steen Hasselbalch Nenad Bogdanovic

19 Benelux Collaborations Partner: Amsterdam External partner: Antwerp Philip Scheltens Sebastian Engelborghs

20 French Collaborations Partner: Toulouse External partners: Bordeaux Lille Lyon Montpellier Nantes Paris Sud Rennes Bruno Vellas Dijon Limoges Marseille Nancy Paris -Broca Paris Nord Strasbourg

21 Spanish and Portugese Collaborations Partner ALFA (BBRC)/IDIBAPS External partners CITA Fundacion Reina Sofia Sant Pau Coimbra Lisbon José Luis Molinuevo Pablo Martínez-Lage Miguel Medina Alberto Lleó Catarina Oliveira Alexandre de Mendonça

22 Swiss Collaborations Partner: Geneva External partners: Zurich Lausanne cohort 65+ Bus Sante MentDis_ICF65+ Colaus/PsyCoLaus Panteleimon Giannakopoulos Christoph Hock/ Anton Gietl Brigitte Santos- Eggimann Idris Guessous Alessandra Canuto Martin Preisig

23 Italian Collaborations Partner: ADWIBO Brescia External partners: InChianti ILSA Giovanni B Frisoni/ Cristina Muscio Luigi Ferrucci Emanuele Scafato

24 UK and Irish Collaborations Partners: PREVENT Generation Scotland UK Biobank DCR Craig Ritchie David Porteous Cathie Sudlow Simon Lovestone Numerous DPUK Cohorts Potentially NICOLA and TILDA from NI &Eire

25 Conclusions 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

26 Acknowledgements National Leads Ritchie/Gallacher - UK & Ireland Miia Kivipelto - Scandinavia José Luis Molinuevo Spain/Portugal Philip Scheltens - Benelux Giovanni Frisoni - Switzerland/Italy Bruno Vellas - France 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) Work Package Leads WP1 Simon Lovestone (UOXF) Andrew Satlin (Eisai) Gary Romano (JPNV) WP2 Adrian Mander (MRC) Shobha Dhadda (Eisai) Scott Berry (BERRY) Kristian Windfeld (Lundbeck) WP3 Pieter Jelle Visser (VU-VUmc) Gerald Luscan (Pfizer) WP4 Craig Ritchie (UEDIN) Catherine Debove (BI) Miia Kivipelto (KI) Mila Etropolski (JPNV) WP5 Carlos Díaz (SYNAPSE) Serge Van der Geyten (JPNV) WP6 Jean Georges (AE) Sean Knox (NOV) WP7 José Luis Molinuevo (BBRC) Frank Tennigkeit (UCB) Saira Ramasastry (SYNAPSE) WP8 Edo Richard (RUMC) Luc Truyen (JPNV) Carol Brayne (UCAM) Shirlene Badger (UCAM Sandra Pla (member of PMO) Lennert Steukers (member of PMO) Mila Eltropolski (JPNV member of PMO) Judi Syson (UEDIN member of PMO)

27 Acknowledgment The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n , resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/ ) and EFPIA companies in kind contribution.