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
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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
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•
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Understand standard of
care
Disease natural course
Disease Risk factors
Burden of illness
Cost of illness
RWD
Pharmacoepidemiology
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Drug utilization studies
Outcome in real-life
Comparative Effectiveness
Safety (PASS)
RWD
Genetic
Epidemiology
Molecular
Epidemiology
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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?
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•
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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
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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!
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Extensive life style and environmental data
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Access to external registries e.g. hospital records, prescription and socio economic registries to create a
comprehensive picture
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Longitudinal data allowing long term follow up of outcomes
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[email protected]
Thank you: www.lifandis.com
Lifandis - Unlocking the Secrets of Disease
Population based cohort including e.g. data on family relations