Epidemiologi, biomarkører og nye drug targets ved bruk av norske
Lifandis Unlocking the Secrets of Disease Epidemiologi, biomarkører og nye drug targets ved bruk av norske register, kohorter og biobanker - Sett i konteksten av persontilpasset medisin og legemiddelutvikling Big data og biomedisinsk næringsutvikling – fra genomikk til real world data Oslo, 7.mai 2015 Christian Jonasson, CSO Lifandis AS [email protected], +4790936941 Lifandis Unlocking the Secrets of Disease Agenda • Lifandis – hvem er vi og hva gjør vi? • Hva menes med persontilpasset medisin og biomarkører? • Biobanker, kohorter og register. Hva er det som gjør Norge unikt? • Anvendelse av biobanker i legemiddelutvikling • Case studies Lifandis • • • • • Profesjonell industri interface for forskning på norske biobanker, kohorter og register Offentlig eiet kommersielt drevet AS (NTNU, HMN, NTFK) Overskudd pløyes tilbake til eierne Våre kunder er legemiddel- og diagnostiske firmaer Tre forretningsområder; biomarkører, epidemiology (RWD) og drug discovery Lifandis Unlocking the Secrets of Disease Epidemiology Clinical Epidemiology • • • • • Understand standard of care Disease natural course Disease Risk factors Burden of illness Cost of illness RWD Pharmacoepidemiology • • • • Drug utilization studies Outcome in real-life Comparative Effectiveness Safety (PASS) RWD Genetic Epidemiology Molecular Epidemiology • • • Disease mechanism Pathophysiology/disease understanding Molecular level data based on omictechnologies Biomarkers • Finding new drug targets based on genomics (genotyping and sequencing) Drug Targeting Lifandis Unlocking the Secrets of Disease HUNT Biobank HUNT Databank Clinical medicine Epidemiology Lifandis collaborator network Bioinformatics Core Genomics Facility Core Proteomics Facility Nordic RWD EMR extraction Genomics Biostatistics Bioinformatics Biostatistics Lifandis Unlocking the Secrets of Disease Persontilpasset medisin og biomarkører Lifandis Unlocking the Secrets of Disease ”23andMe Teams With Big Pharma to Find Treatments Hidden in Our DNA” Jan 12, 2015 – Wired Magazine ”Obama calls for major new precision medicine initiative” Jan 20, 2015 – Reuters News In the news on precision medicine…… The Genomics Network for Enterprises (GENE) Consortium ”Drug companies unite to mine genetic data” Mar 26, 2015 – FT ” In Iceland’s DNA, New Clues to Disease-Causing Genes” Mar 25, 2015 – NY times Lifandis Unlocking the Secrets of Disease Kjært barn har mange navn…. Lifandis Unlocking the Secrets of Disease Effekt Toksisitet Diagnostisk test Biomarkør Effekt Ingen toksisitet Ingen effekt Ingen toksisitet Pasienter med samme diagnose Ingen effekt Toksisitet Hva er persontilpasset medisin? Riktig behandling, riktig dosering, til riktig pasient, til riktig tidspunkt ”An approach to treating illnesses that takes into account a patient's individual genetic make-up as well as molecular subtypes of diseases to improve the chances of successful treatment." Lifandis Unlocking the Secrets of Disease Definition of a biomarker: A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological response to a therapeutic intervention Hva er en biomarkør? • • • • • • Blodtrykk PET/CT LDL kolesterol HbA1c PSA Kreftmutasjoner (BRCA1&2, EGFR, ALK, KRAS) • CYP mutasjoner (PK/PD) CYP2C9, CYP2C19, CYP2D6 • • • • ctDNA miRNA proteom metabolom Lifandis Unlocking the Secrets of Disease Hvordan skal vi bruke biomarkører? Prognostiske biomarkører for stratifisering og design av RCT – “trial enrichment” Lifandis Unlocking the Secrets of Disease Need of new blood-based biomarkers for prodromal Alzheimer’s disease Cognitive function Normal aging Pre-clinical AD MCI Dementia Years • Many failures in large phase III trials in the last decade • Neuropathophysiological process of AD begins years before clinical onset • Are we targeting AD at the wrong stage? • Need of non-invasive biomarkers (metabolome, exosomes, proteome, miRNA) Lifandis Unlocking the Secrets of Disease Longitudinal 20-years cohort with dementia validated diagnoses and predementia biobanked samples Lifandis Unlocking the Secrets of Disease Avansert og offentlig helsevesen Mange og gode helseregistre (landsdekkende) Digitalisert helsevesen, inkl EPJ Lover og etisk regelverk som tillater og støtter helseforskning Personnummer Tradisjon for store helseundersøkelser og biobanker Ekspertsentre for omics og biostatistikk Sterke akademiske miljøer Lifandis Unlocking the Secrets of Disease Phenotype matters! • Phenotype data associated with omics data is of critical importance • Longitudinal data vital for chronic diseases • Higher resolution phenotype than codes (ICD10) often required • Self-reported data must be used with caution Lifandis Unlocking the Secrets of Disease 1973 1975 1984 1995 1999 2002 2011 2015 2017 Norwegian population based cohorts - A unique foundation for tailored services > 1 million Norwegians have so far been recruited into consent based research biobanks based on population based studies only +25-30 million samples in clinical biobanks, including archival tumor tissue Lifandis Unlocking the Secrets of Disease The HUNT Studies (adults more than 20 years old) 1984 86 95 97 06 08 2017 HUNT1 HUNT2 HUNT3 HUNT4 n=77,212 n=65,237 n=50,807 Planning ongoing Questionnaires Questionnaires Questionnaires Clinical Exam Clinical Exam Clinical Exam Open to Blood Samples Blood Samples industry collaboration 10 year follow-up 47,316 10 year follow-up 37,071 20 year follow-up, HUNT 1-3: 27,992 Krokstad S et al, Int. J Epidemiol, 2013 Lifandis Unlocking the Secrets of Disease Selected Endpoints 4,000 8,000 800 1,500 8,000 COPD Asthma RA Atrial Fibrillation Fractures 6,000 3,000 1,600 14,000 Myocardial Infarction Type 2 diabetes with dementia with obesity (class I-III) 13,100 2,400 1,800 1,600 2,400 Cancer Prostate cancer Breast cancer Lung Cancer Colorectal cancer Lifandis Unlocking the Secrets of Disease European Research Biobank of the Year 2013 Biological Samples Stored in HUNT Biobank Material Individuals Storage temp. (°C) Isolated DNA (HUNT2 and/or 3) 73,085 -20 Serum (HUNT2 and/or 3) 77,788 -80/-196 Plasma (HUNT3) 49,072 -80/-196 RNA Tempus Tubes (HUNT 3) 14,874 -80 Urine Samples (Fresh Frozen) 11,879 -80 Lifandis Unlocking the Secrets of Disease HUNT biobank for genotyping and NGS studies • 30,000 subjects already genotyped on different platforms • Genotyping of the whole cohort (n >70,000) ongoing (Illumina’s HumanCoreExome BeadChip) with industry access once completed (in 2015) • Consent allows industry-sponsored genotyping and NGS Lifandis Unlocking the Secrets of Disease Genomic case study: Rare causal variants for dyslipidemia • Exome chip genotyping for new genes involved in dyslipidemia traits performed on 10,000 subjects • Identified a new causal variant, TM6SF2 • Overexpression and knock-down associated with elevated and reduced lipid levels in mice model Norske biobanker og legemiddelutvikling Lifandis Unlocking the Secrets of Disease Population-based biobanks Pharmacogenomics Clinical phenotype Tissue banks and diagnostic biobanks for target expression in large patient cohorts – clinical trial design Tissue banks and diagnostic biobanks for target expression in disease and healthy organs Target ID Target Val Research Hit Lead Tissue banks for validation of animal model relevance to human disease Lead Optim Preclinic Phase I Discovery Tissue, serum, plasma, and urine for biomarker validation (companion diagnostics) Tissue, serum, plasma, and urine for biomarker discovery Phase II Phase III Development Biobanker er viktig for industri FoU Muligheter for persontilpasset legemiddelutvikling • Identifisering og validering av nye targets (farmakogenomikk) • Pasientstratifisering basert på biomarkører for å øke sjansen for positivt utfall av kliniske studier • Identifisering av nye biomarkører for diagnostiske tester • Nye IVD bruksområder, f.eks. tidlig deteksjon biomarkører Lifandis Unlocking the Secrets of Disease Biomarkørforskning Høyteknologisk Biologiske prøver Fenotypedata Ekspertise • Genomics • Proteomics • Metabolomics • Biobanker • Prediagnostiske prøver • Vevsprøver • Longitudinelle data • Databanker • Elektroniske pasientjournaler • Helseregistre • • • • • Epidemiologi Biologi/genetikk Statistikk Bioinformatikk Data modellering Lifandis Unlocking the Secrets of Disease Why do drugs fails? High attrition rates: • 95% i fase I • 66% i fase II • 30% i fase III Main reasons: • Lack of efficacy • Safety Lifandis Unlocking the Secrets of Disease Until recently, it was very difficult to establish accurate genetic maps of human disease… now we can! Cost of genome sequencing continues to drop rapidly… …which results in many more human genomes being sequenced… …and a more accurate molecular understanding of human disease. Slide courtesy of R Plenge, Merck Lifandis Unlocking the Secrets of Disease GWAS to RVAS Common genetic variants to rare genetic variants Genome-wide association studies: - Have identified thousands of genetic loci associated with outcome(s) for common and complex traits - These are common variants (≥5% frequency) “Missing heritability” Sequencing technology (NGS, WGS, WES exome arrays) Rare variant association studies: NGS allows the identification of lower frequency rare genetic variants that has a potential for a larger effect contribution Drug R&D PCSK9 – dyslipidemia APP – Alzheimer's Etc. Lifandis Unlocking the Secrets of Disease Human genetics helps to identify potential drug targets to start drug discovery “Drug” ? “Target” But, tens of thousands of potential targets… …and which one causes disease? …and how do you perturb the target? Disease Healthy “Drug” vs Disease The key steps are: 1. Map genetic differences in those with disease vs healthy; 2. Understand how these genetic differences lead to disease; 3. Develop drugs against these targets that reverse disease processes in the population. Healthy Slide courtesy of R Plenge, Merck Lifandis Unlocking the Secrets of Disease Experiments of nature – human knock-outs. There are encouraging examples of this principle working in drug discovery – example of PCSK9 Many genes influence cholesterol levels and risk of heart disease Atherosclerotic Plaque Thanks to new technologies, we can now find these disease genes… Disease Blood Flow Healthy …and design studies to find drugs that fix the underlying molecular defects – for example, blocking PCSK9 lowers LDL (or “bad”) cholesterol in the blood. PCSK9 LDLR LDL-C mAb LDLR Recycling Lysosome Slide courtesy of R Plenge, Merck Lifandis Unlocking the Secrets of Disease Øket satsing på biobanker og helsedata gir win-win Offentlige • Bidra til persontilpasset behandling • Forbedret helsetjeneste • Kunnskap om helsetjenesten og klinisk praksis Bedre helse • Verdensledende ressurs for drug discovery og biomarkør utvikling • Internasjonal helseindustri investerer i Norge • Ny norsk virksomhet etableres Akademia Industri • Unik plattform for epidemiologisk og genetisk forskning • Publikasjoner • Internasjonalt nettverk • Økt finansiering Lifandis Unlocking the Secrets of Disease Hindringer for øket industri utnyttelse av norske biobanker • Etiske problemstillinger, bla knyttet til samtykke • Biobank kvalitet • Synlighet og markedsføring • Ikke kultur for forskningssamarbeid mellom industri og akademia Epidemiology Takk for oppmerksomheten! • Extensive life style and environmental data • Access to external registries e.g. hospital records, prescription and socio economic registries to create a comprehensive picture • Longitudinal data allowing long term follow up of outcomes • [email protected] Thank you: www.lifandis.com Lifandis - Unlocking the Secrets of Disease Population based cohort including e.g. data on family relations
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