PROOF of the Pudding in Canada PROOF of the Pudding in Canada 2010 ITMAT International Symposium Wednesday, October 27, 2010 Bruce McManus
PROOF Centre Background PROOF Centre Background Who are we? � Not ‐ for ‐ profit Society established with competitive federal funding from the NCE secretariat in 2008 secretariat in 2008 � Created as an NCE CECR devoted to developing useful biomarker products that provide useful biomarker products that provide socioeconomic benefits for Canada � Based at St. Paul’s Hospital (Institute for Heart Based at St. Paul s Hospital (Institute for Heart + Lung Health) in Vancouver, Canada � Hosted by the University of British Columbia y y www.proofcentre.ca 3
Biomarkers Biomarkers A measurable characteristic that is an indicator of normal Distinct biological indicators (cellular, biochemical or biologic processes, pathogenic processes, and/or response molecular) of a process, event or condition that can be to therapeutic or other interventions measured reliably in tissues, cells or fluids y , Health Canada Monitor Progression Assess Refine Predict / Diagnose Sensitive and specific Predict Events Risk Assessment Inform Therapeutics Inform Therapeutics Typical Earliest Baseline Initiating Earliest Reproducible and cost Current Clinical Risk Events Molecular effective assay + platform Intervention Detection Detection rden ity Disease Bur Irreversibili Temporal relationship with Cost clinical status Add value to current clinical tools Time 4
PROOF Centre Focus on “ ‐ Omics” PROOF Centre Focus on ‐ Omics Integration of whole blood genomics and plasma proteomics adds value as they reflect different biomarker compartments adds value as they reflect different biomarker compartments DNA RNA Protein Metabolite Ubiquitin Epigenetics Genetics / Genomics / Proteomics Metabolomics Genotype yp Transcriptomics p
PROOF Centre Mission PROOF Centre Mission Can we do better? Prevent Discover Discover Improved Improved Predict Heart failure Healthcare Develop BIOMARKER Diagnose Lung failure Commercialize SOLUTIONS Economic Manage Kidney failure Development Development Implement Implement Treat Biomarkers in Transplantation is the lead project of the Centre Programs are also underway in heart, lung, and kidney failure 6
Biomarker Journey Biomarker Journey Our end ‐ to ‐ end approach to biomarkers Clinical Biomarker Biomarker Clinical Question Development Implementation Discovery Biomarker Refinement / Work with Validation / Qualification physicians, Where can a Computational Diagnostic Assay healthcare new blood test new blood test strategies discover strategies discover Development organizations, improve patient sets of genes and governments and care and create proteins to Health Economics private partners socio ‐ economic diagnose a type of to implement value? value? patient patient R Regulatory Filing l t Fili biomarker tests in clinical settings Reimbursement 7
Our Community of Partners Our Community of Partners Patient Cohorts Technology Platforms USC/CHLA Microarray Core Microarray Core Computation Financial Resources Biomarker Science Health Economics Health Systems Commercialization 8
Biomarker Programs Biomarker Programs Clinical C ca Biomarker Biomarker Biomarker Biomarker Clinical Clinical Question Discovery Development Implementation Biomarkers in Transplantation Biomarkers in Transplantation Chronic Kidney Disease Chronic Kidney Disease Diagnostic / predictive blood tests for acute Blood tests that predict rate of and chronic rejection progression of kidney disease Chronic Obstructive “Cured” Organ g Pulmonary Disease Failure Blood tests for lung function Blood tests to endpoints to develop therapies determine when a therapy is working Chronic Heart Failure Blood tests that diagnose diastolic New Biomarker versus systolic heart failure Technology Multiplex peptide Acute Heart Failure Acute Heart Failure and gene blood tests Blood tests that guide ventricular assist device removal 9
The Life Cycle of Organ Failure The Life Cycle of Organ Failure “Recovered” Organ Function Baseline Risk Disease Presence Disease Progression Improved Earlier Organ Organ Intervention ction (%) Function rgan Func End ‐ stage Recurrent Organ Organ Failure Failure O Time (years) Transplantation/Assist Devices 10
Acute Organ Rejection Acute Organ Rejection Current diagnostic approaches Tissue biopsies remain the gold standard for diagnosis of acute rejection HIGHLY INVASIVE NOT TIMELY EXPENSIVE DIAGNOSTIC ONLY, UNCOMFORTABLE PRONE TO SAMPLING NOT PROGNOSTIC AND FEAR ‐ EVOKING ERROR SUBJECT TO INTERPRETATIVE VARIABILITY VARIABILITY 11
Chronic Organ Rejection Chronic Organ Rejection Current diagnostic approaches Normal Artery � A major hurdle for the long ‐ term A j h dl f th l t survival of cardiac allograft transplant recipients is development of cardiac recipients is development of cardiac allograft vasculopathy (CAV) as an expression of chronic rejection p j CAV � The current (gold) standard for The current (gold) standard for diagnosis of CAV is invasive – Coronary Angiography – Intravascular Ultrasound
Timeline Timeline….Transplant Patient s Life Transplant Patient’s Life Chronic Rejection / Recurrence T End ‐ r Organ a Failure Acute Rejection j n s p Heart: Protocol biopsies Heart: Angiography, IVUS, l HLA, HLA, Echocardiography h di h a Kidney: Creatinine, GFR, For ‐ cause PRA, n biopsies Kidney: Creatinine, GFR, For ‐ viruses t cause biopsies Predictive genes and Diagnostic genes and proteins Diagnostic genes and proteins proteins 6 months 12 months 13
Reflection on improvement of Reflection on improvement of care for heart transplant patients Maxine’s presentation and first year post ‐ transplant ~12 ‐ 14 Heart Biopsies During 1 st Year Post ‐ Heart Acute Viral Sudden Ventricular transplant; “Standard” Immunosuppressive t l t “St d d” I i Myocarditis Death Assist Device Transplant Therapy First steps for implementing test Blood Test to Heart +/ ‐ “Standard” Immunosuppressive Guide Need for Therapy Transplant Biopsy Biopsy Future implementation + / ‐ Pre ‐ dose Blood Test to Blood Test to Heart Altered Immunosuppressive Predict if Rejection Immunosuppressive Replace the Need Therapy py Transplant Transplant Will O Will Occur Th Therapy for Biopsy f Bi 14
Biomarkers in Transplantation Biomarkers in Transplantation 2004 2009 Discovery and internal validation Discovery and internal validation FDA of blood based biomarkers: Voluntary • Genomic eXploratory • Proteomic Data Patient Cohorts: Patient Cohorts: Submission b i i • Acute heart rejection (VXDS) • Chronic heart rejection Acute kidney rejection • • Chronic kidney rejection Eight Potential Tests: i h i l • Diagnostic • Predictive Funded by Genome Canada, IBM, Novartis, Vancouver Hospital Foundation, St. Paul’s Hospital Foundation, UBC, Genome BC, The James Hogg iCAPTURE Centre, BC Transplant Research Institute, Affymetrix, and Eksigent 15
Biomarkers in Transplantation Biomarkers in Transplantation Discovery strategy ~36,000 Probe Sets are normalized and pre ‐ filtered DATA PATIENT COHORT Apply protein group code algorithm to ~ 2,000 Peptides ~10,000 Probe Sets and ~ 200 Protein Groups assessed by BIOLOGICAL CLINICAL multiple robust and classical t ‐ tests for differences among SAMPLES DATA patient groups ~250 Genes Proteins & Clinical Variables combined into a 250 Genes , Proteins, & Clinical Variables combined into a P DRIVEN Patient Review / discriminative score by support vector machine classification Sample Selection BIOMARKER PANEL TRANSCRIPTOMICS Biologically validated with ELISA and qPCR • Whole blood RNA (PAXgene) Statistically validated with leave ‐ one ‐ out cross validation to Statistically validated with leave one out cross validation to SO • Affymetrix Microarray estimate sensitivity, specificity and AUC PROTEOMICS INTERNALLY VALIDATED BIOMARKER PANEL • Depleted Plasma • iTRAQ Mass Spectrometry IO Informatics Knowledge Explorer IO I f ti K l d E l (www.io ‐ informatics.com) METABOLOMICS • Plasma, Serum, Urine • NMR, Mass Spectrometry Include known biomarkers or essential clinical variables 16
Predictive Markers Predictive Markers – Acute Heart Rejection Acute Heart Rejection Whole blood genomics Biological Processes Regulation of actin cytoskeleton organization .2 Regulation of actin filament-based process Regulation of actin filament based process 0 MDS 2 Protein amino acid dephosphorylation 0.0 Dephosphorylation Regulation of cytoskeleton organization -0.2 2 Regulation of organelle organization Regulation of protein kinase cascade -0.4 -0.2 0.0 0.2 0.4 Negative regulation of catalytic activity Regulation of hydrolase activity future AR future AR future non ‐ AR future non ‐ AR Regulation of biological quality Sensitivity 83% Specificity 88%
Diagnostic Markers – Acute Heart Rejection Diagnostic Markers – Acute Heart Rejection What value does the endomyocardial biopsy add? Wh l Whole Blood Bl d E d Endomyocardial Biopsy di l Bi Sensitivity 83% S iti it 83% Specificity 88% Samples Tissues Affymetrix U133 Microarray Affymetrix U133 Microarray 54,675 PROBE SETS 54,675 PROBE SETS 2,186 PROBE SETS 17,610 PROBE SETS Elastic Nets WHOLE BLOOD + BIOPSY PROBE SETS Leave-one-out Cross-Validation Leave one out Cross Validation Sensitivity 100% BIOMARKER PANEL Specificity 100%
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