Dementia research opportunities in the UK The Translational Research Collaboration in dementia, the UK Dementia Platform, and experimental medicine research at Oxford The problem The problem • • • • • • 44 million affected people 800,000 in UK The only disease with increasing deaths since 2000 Current spend > $600b 135 million cases by 2050 Projected spend > $1 trillion by 2050 The banker Andrea Ponti JP Morgan The clinician researcher Ed Richard Amsterdam The regulator Maria Issac EMA The pharma CEO Paul Stoffels Johnson & Johnson The funder Francis Collins NIH What has changed ? No longer a Cinderella subject Dementia funding opportunities to April 2016 ……….. • • • • • • • • Alzheimer’s Society Alzheimer’s Society Alzheimer’s Society ARUK MRC MRC MRC EU Doctoral Training centre Drug Development programme ADDF Drug repurposing programme Alzheimer’s Drug Development Centre Dementia capital UK Dementia Platform Deep and Frequent Phenotyping IMI-EPOC …………… approximately £ 100,000,000 £600k £800k £2m £10m £15m £12m £6m €60m Alzheimer’s disease – What do we know? Alzheimer’s pathology The amyloid cascade hypothesis – 2014 Environment e.g. diabetes Genes for familial AD and FTD and late onset AD Clusterin Wnt signalling GSK3 Innate and adaptive immunity Cholesterol metabolism Protein aggregation Cell survival pathways No shortage of therapeutic possibilities Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol 2010;9(7):702-16. But the trials are failing ! Not confined to dementia http://bic.cs.cmu.edu/jvu/ But worse for dementia • • • • Pathways less defined Brain less accessible Outcomes more uncertain Clinical trials more difficult • Prodromal disease – challenge and opportunity The solution/opportunity • • • • Diversify target development Develop therapeutics with PoC in models and man Rapid trials with early read-outs Trials in prodromal or preclinical disease NIHR Translational Research Collaboration in Dementia • • • • • • Newcastle / NTT Cambridge / Addenbrookes Imperial / IHC UCL / UCLH Substantial core funding KCL/ Maudsley Oxford / OUH / OH outstanding experimental medicine facilities TRC-D; aims and ambitions • A collaboration between BRCs and BRU-Ds • Working with industry – Single point of contact and contract negotiation • Harmonisation and avoiding duplication – Subgroups in MRI, PET and iPSCs – Use of EMRs in mental health and dementia • New projects – – – – Shared informatics – imaging (Oxford; Mackay) PD dementia biomarkers (Oxford; Lovestone) UK Dementia Platform and experimental medicine (Cardiff; Gallacher) Deep and frequent phenotyping in Alzheimer’s disease (Oxford; Lovestone) Enabling research on EMRs CRIS Users CRIS APP Servers (10.16.0.7 / 8) a Lo IS gD din AD Server gn esi Email Server e FA eLin ST Pip (^) s ery ES Qu tage P S ST FA ex d In CR l IS fixm line Up ipe da g P (* ) rs: te FAST Server: Data anin ges lde t / t Sc le fo a n C t (10.16.0.12) e s rip nt tx p a r d re n me g t a ch chil d Att parsin ane child r le o c t/ tra Fil t en ect ns e p a r e rs nn xtrac ve E Co fold r se ge ) LN ource sta r te S r ple ml line a to n m g o ipe e x a c r ily nts cle gg g (p m A c in e o s fa L d ar um XM e 1: r xt p doc g a to g nt te Sta reg ily bld me gg a ch fam LA Att XM ge 2: Sta CR FAST Server: Index (10.16.0.13) PJS30 (PJS01-21, PJSCroydon) XA Data Dictionary (form field ‘gold standard’) Case Records Interactive Search (CRIS) cris_db (SQL Server) EMR re-use for research (Cholinesterase inhibitors and Alzheimer’s disease) 24 • Phase IV of ACHeI > 2500 patient years of therapy > 8 fold dataset compared to Cochrane 18 precompetitive collaboration with pharma Text mining derivation of service utilisation and costs +4.2 (+3.5, +4.9) 20 • Costs and effectiveness MMSE score 22 Slope change • Predictors of response -0.2 (-0.7, +0.2) 16 Biomarkers and clinical Slope change -1 0 1 time(years) 2 3 D-CRIS and then UK-CRIS • D-CRIS – Cambridge & Peterborough, Oxford Health, West London, Camden and Islington – NIHR funding; completion 04/2014 – 1 million plus patients – SWAT team 2014-15 • UK-CRIS – 10 site extension – Proposal in UKDP Capital bid eMPOWERMENT Connected Health Model My HealthLocker Secure Network Data Interchange with GP systems (EMIS) Trust Electronic Patient Record ePJS Pseudonymisation Research Information System CRIS PROMs My Care Plan Personal Health Record (HealthVault) Rate My Day Resources HealthVault Connection Centre UK Dementia Platform • Epidemiologic platform: 21 cohorts (n=2M) – Familial, ‘case-rich’ and prodromal populations • Informatics platform – Single portal for access to all cohorts • Experimental platform – UK Biobank imaging cohort (n=100,000): • 3T Brain (1.5T chest) MRI, Dxa, 3D carotid Ultra-sound • Concurrent imaging, cognitive testing, bio-sampling – 10,000 repeat assessment after two years – Lead in data for early susceptibility markers – Consent for consent for a range of studies Moving from risk through biomarkers to experimental medicine Dementia Dementia Discovery focussed ESM Cohorts Cohort change (n=2M) (n=100k) (n=10k) UKDP Moving from risk through biomarkers to experimental medicine Dementia Dementia Discovery focussed ESM Cohorts Cohort change (n=2M) (n=100k) (n=10k) Readiness cohort D&FPhen UKDP Trials are conducted too late Adapted from Sperling et al (2011) Alzheimer’s and dementia 7 280-92 Biomarkers for secondary prevention Stratification markers Progression markers Adapted from Sperling et al (2011) Alzheimer’s and dementia 7 280-92 Deep and Frequent Phenotyping Deep phenotyping • • • • • • • PET CSF MRI Electrophysiology Peripheral markers Cognitive markers novel markers Ab and tau tracers repeated measures serial imaging with noise reduction strateg EEG and MEG noise reduction, change measurement computerised batteries, web testing integration retinal imaging, quantitative gait measures Frequent phenotyping • Test the limits of acceptability monthly, bi-monthly ? Aims and objectives 1) determine participant acceptability • very extensive (deep) and repeated (frequent) phenotyping 2) establish the operational practicability • Including standardization of acquisition, quality control (QC) and analysis 3) prepare for a full trial • • • • utilising the NIHR TRC-D infrastructure establishing protocols set-up processes including ethics and approvals data management and trials governance. Moving from risk through biomarkers to experimental medicine Dementia Dementia Discovery focussed ESM Cohorts Cohort change (n=2M) (n=100k) (n=10k) UKDP Readiness cohort Early Phase Trials D&FPhen IMI-EPOC European Proof of Concept for prevention IMI-EPOC Prevention of Alzheimer’s – What will it take? June 10-13 2013 http://www.nyas.org/publications/EBriefings European Proof of Concept for prevention IMI-EPOC • • • • 11th call of Innovative Medicines Initiative €60m Public Private Partnership EFPIA members led by J&J Academic consortium being established – Leads Ritchie(Imperial) and Lovestone (Oxford) – UK partners based around TRC-D and UKDP – European partners from France, Spain, Sweden, Finland, Germany, Holland….. – Non-EFPIA industry partners – Advisors include Esserman and Berry I-SPY 2 schema. Berry D A et al. Clin Cancer Res 2012;18:638-644 ©2012 by American Association for Cancer Research cohort 1 cohort 2 cohort 3 Data integration Cohort enhancement cohort… …..n Readiness cohort IMI-EPOC general schema Adaptation on intermediate outcomes Adaptation on efficacy outcomes Stratification and selection placebo Rx 1 Rx 2 Rx …n Trial cohort Others DZNE UKDP Cohort enhancement (consent, PET) EMIF-platform integration EMIF-AD Readiness cohort IMI-EPOC suggested first phase Adaptation by change in amyloid burden Adaptation on cognition outcomes Cognitive decline PET Ab and tau placebo BACE i Ab MAb Ab Mab BACEi Trial cohort The opportunity for Oxford Oxford D3I Dementia Drug Development Institute Dementia Dementia Discovery focussed ESM Cohorts Cohort change (n=2M) (n=10k) (n=10k) Readiness cohort Early Phase Trials D&FPhen IMI-EPOC UKDP Target development & PoC/PoM EMRs, PHRs and Big Data Biomarkers and Imaging Its about preventing dementia Experimental medicine for cognitive health