2013-10-10 GTC Bio Biomarker Europe Summit 2013, Berlin

Using system biomarkers to combat
preventable diseases
Prof. Alain van Gool
Netherlands Organisation for Applied Scientific Research (TNO)
Radboud University Nijmegen Medical Centre
Radboud University Nijmegen
Biomarker Europe Summit 2013
GTC Bio, Berlin
9-10th October 2013

TNO =
Netherlands Organisation for Applied Scientific Research
Mission = to drive ideas to reach their full market value.
We partner with:
Governmental & regulatory organisations
Universities
Pharma, chemical and food companies
International consortia
Knowledge
development
Knowledge
application
Knowledge
exploitation
Develop
fundamental
knowledge
With
universities
With
partners
With
customers
Embedded in the
market
TNO TNO Triskelion
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Biomarker Europe Summit 2013, GTC BIO, Berlin
10 October 2013
Alain van Gool

A van Gool, CHI World Biomarker Congress 2012
TNO
= Netherlands Organisation for
Applied Scientific Research
Member of EARTO.
Founded in 1932.
Structure:
Non-for-profit research institute
7 main themes
~4000 employees
19 sites in Netherlands
+ 18 sites/countries globally
www.tno.nl
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10 October 2013
Alain van Gool

TNO in European public-private partnerships
Healthy Living
Defence, Safety & Security
Transport & Mobility
Information Society
Industrial Innovation
Energy
Built Environment
Participation in EU projects:
(Jan 2013)
260 projects (3100 partners)
Roles of TNO:
Technical expertise
Focus on applications
PPP management skills
(in 10% role as coordinator)
32% success rate
(average FP7 is 21%)
10 October 2013
Alain van Gool
www.tno.nl

2011 2012 2013
New knowledge
developed in 1 project
(example from TNO system biology)
Applied in 4 more projects Applied in 11 more projects
Applying lessons learned across fields
10 October 2013
Alain van Gool

• Translational medicine
 Exposure
 Mechanism
 Efficacy
 Safety
• Personalized medicine
 Diagnosis
 Prognosis
 Response
Tools for data-driven decision making
 Biologically relevant
 Clinically accepted
 Quantitative !
 Different analytes/types
 Fit-for-purpose application
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Biomarkers in pharmaceutical drug development
{van Gool et al, Drug Disc Today 2010}
Pharma leads way,
Nutrition and cosmetics copy
best practices,
Pharma-Nutrition: next big thing?
10 October 2013
Alain van Gool

EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Biomarker-based decision making
During testing of drug in preclinical and clinical disease models:
Target engagement? Effect on disease?
yes yes !
no no
• No need to test current
drug in large clinical trial
• Need to identify a more
potent drug
• Concept may still be
correct
• Concept was not
correct
• Abandon approach
• Proof-of-Concept
• Proceed to full
clinical development
“Stop early, stop cheap”
More shots on goal”
{Kumar and van Gool, intro chapter, Comprehensive Biomarker Discovery and Validation for Clinical Application, 2013}
10 October 2013
Alain van Gool

Alain van Gool
10 October 2013
Alain van Gool
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Working in complex human biological systems
requires a systems biology approach
Way forward:
1. Focus on key processes
2. Measure key node biomarkers
3. Convert to a functional biomarker fingerprint panel
4. Make actionable personalized decision on health and
disease management
5. TNO: test added value in real life through field labs

Biomarkers in clinical care
Research/technology push:
Biomarkers can and should provide the molecular part of the personalized healthcare
model in selection of best therapy, monitoring of effect, and follow-up
Daily practice in clinical assessment:
Combination of personal opinion (patient and physician), physical examination, clinical
chemistry to generate personal profiles
New biomarkers are added where deemed useful by physician
Costs important factor in decision on application
Act accordingly in follow-up care (more or less personalized)
Medication (a.o. personalized medicine)
Nutrition (a.o. individualized diets)
Life style (a.o. individualized exercise, counseling)
Slow uptake of new biomarkers
Limited by careful / conservative attitude of clinicians (added value of new biomarker?)
Limited by reimbursement options by insurers (increasingly important)
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Alain van Gool

Personal profiles
Source: Barabási 2007 NEJM 357; 4}
• People are different
• Different networks influences
• Different risk factors
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10 October 2013
Alain van Gool

BIODATA
PERSONALIZED
INTERVENTIONS
RISK FACTOR PATTERN
MOLECULAR LIFESTYLE / ENVIRONMENT
Metabolites RNA Protein
DNA Biochemical process
Enzymatic activity Imaging
mDNA Nutrition
Environment Social
network Attitude in life
Stress work / private
MULTIPARAMETER
PERSONAL PROFILES Statistics
Selection
Ranking
LIFESTYLE
NUTRITION
PHARMA
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Alain van Gool

Personalized management of health and disease
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HomeostasisAllostasisDisease
Time
Personalized health
Personalized medicine
“Health management”
Focus on resilience
“Disease management”
Focus on symptom(s)
Intervention
or
Disease
Health
Non-health

Example personal profile-based assessment (1)
4 components:
1. Number of tender joints
2. Number of swollen joints
3. Acute phase reactants
(ESR or CRP in blood)
4. Patient’s self-assessment
Disease Activity Score (DAS) 28 composite outcome measure
On line calculator:
Formula: 0.56x(TEN28) + 0.28x(SW28) + 0.70ln(ESR) + 0.014(GH)
1.0 - 3.1: low disease activity
3.2 - 5.1: moderate disease activity
> 5.1: high disease activity
{www.das-score.nl}
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Alain van Gool

Example personal profile-based assessment (2)
{Chen et al, Cell 2012, 148: 1293}
Concept:
• Continuous monitoring (n=1)
• Routine biomarkers to alert
• Omics to explain
• Early intervention
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10 October 2013
Alain van Gool

Alain van Gool
Oncology
CVD, neuro, immune
Diabetes
Personal profiles differ per disease phenotype
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10 October 2013
Alain van Gool

Alain van Gool
• Obesity
• Diabetes type 2
HEALTH DISEASE COMPLICATIONS
• Atherosclerosis
• Nephropathy fibrosis
• Osteoarthritis
• Stroke
• etc
Diabetes part of metabolic syndrome
metabolic disturbance local inflammation
Not a single cause but complex multifactorial diseases
Disturbed equilibrium between multiple pathways and key components
A system biology approach is needed
For discovery research, diagnosis and treatment
Continuous monitoring is crucial
Most effective therapy is ‘eat better, move more’ (lifestyle change)
Nutriceuticals / Lifestyle
Food
Pharma
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10 October 2013
Alain van Gool

TNO’s Applied Systems Medicine toolbox
Widely used preclinical translational models
Pharma, nutrition and chemical industry, academia
Focus on etiology of disease and mechanism of action
Human studies
Experimental medicine
Microtracer dosing
Validated analytical platforms
Metabolomics profiling and targeted analysis, with focus on
lipids, ceramids, cannabinoides
Genomics, transcriptomics, proteomics and imaging through
a wide network of selected partners
Clinical chemistry
Data analysis
Data handling
Network biology for mechanistic understanding
Multiparameter statistics and chemometrics
PK/PD translational modelling
Comprehensive system dynamics modelling
Biomarker expertise
Best practise strategies and approaches
A wide network with biomarker academia and industry
Metabolic Syndrome
• Atherosclerosis
• Diabetes
• Obesity
• Vascular inflammation
• NASH, fibrosis

Alain van Gool
Comparing nutrition versus drug intervention
Age-matched “healthy” control group
t=16 w
(sampling)
t=9 wt=0
Induction of Diabetes intervention period
High-fat (HF) diet
High-fat diet “diseased” control group
Nutrition/Life style switch
HF + Drug 1
HF + Drug 2
HF + Drug 3
….HF + Drug 10
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Alain van Gool

Alain van Gool
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Alain van Gool
Effects on total adipose tissue weight
Full reversal of obese phenotype by ‘Lifestyle’ change, not by all drug treatments
T0901317 also reverses obese phenotype

Alain van Gool
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10 October 2013
Alain van Gool
Effects on atherosclerosis
Still increased atherosclerosis in ‘Lifestyle’ group - longer wash-out needed
T0901317 strongly induces atherosclerosis – a system biology evaluation is needed

Alain van Gool
Each organ has its own
characteristics in
maintaining/loosing
flexibility and this
determines the
health to diabetes
transition.
{Nolan, Lancet 2011}
A sure need for system biology
High need to study the
effect of drugs/nutrition
on each of these organs
and their interaction
within the whole system
of each person.
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10 October 2013
Alain van Gool

Systems view on (metabolic) health and disease

Alain van Gool
Important processes in
T2D
Diagnosis Potential interventions
Dietary/LS Pharma
1.Pancreatic β-cell function
(impaired insulin secretion)
*OGTT: I/ΔG and DI(0)
*PYY, Arg, His, Phe, Val, Leu
Lifestyle; β-cell
protective nutrients
(MUFA/isoflavonoids);
β -cell protective
medication (TZDs,
GLP-1 analogs,
DPP4-inhibitors)
2.Muscle insulin resistance
(decreased glucose uptake)
*OGTT: Muscle insulin resistance index,
Insulin secretion/insulin resistance index
*Val, Ile, Leu, Gamma-glutamylderivates,
Tyr, Phe, Met
PUFA/SFA balance;
Physical activity;
Weight loss;
TZDs (e.g.PPARγ)
3.Hepatic insulin resistance
(decreased glucose uptake and
increased hepatic glucose
production-HGP)
*Hepatic insulin resistance index *OGTT:
Hepatic insulin sensitivity index
*ALAT, ASAT, bilirubine, GGT, ALP, ck-18
fragments, lactate, α-hydroxybutyrate,
β-hydroxybutyrate
Decrease SFA and n-
6 PUFA, and increase
n-3 PUFA;
Weight loss;
Metformin;
TZDs;
Exenatide (GLP-1
analog);
DPP4 inhibitors
4. Adipocyte insulin resistance
and lipotoxicity
*basal adipocyte insulin resistance index
*FFA platform, glycerol
α-lipoic acid;
PUFA/SFA balance;
Omega 3 fatty acids;
Chitosan/plantsterols;
TZDs; Acipimox
5. GI tract (incretin
deficiency/resistance)
*ivGTT vs OGTT
*GLP-1, GIP, glucagon, galzuren
MUFA; Dietary fibre
(pasta/rye bread);
Exenatide
6. Pancreatic α-cell
(hyperglucagonemia)
*fasting plasma glucagon ? Glucagon receptor
antagonists;
Exenatide;
DPP4 inhibitors
7A.Chronic low-grade
inflammation in pancreas,
muscle, liver, adipose tissue,
hypothalamus
7B. Vascular inflammation
*CRP, total leucocytes
* V-CAM, I-CAM, Oxylipids, cytokines
Fish oil/n-3 fatty
acids; Vit. C/Vit.
E/Carotenoids;
Salicylates; TNF-α
inhibitors and others
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Alain van Gool

Alain van Gool
Field labs: test health care concepts in real life
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10 October 2013
Alain van Gool
Build field lab with pre-diabetic patients, physicians, dietitians, insurers, etc
Measure individual ‘risk’ parameters for metabolic syndrome +/- challenge
phenotypes, clinical chemistry, specific Omics, etc
Convert data into a personal profile + personalized health advice
life style +/- nutrition +/- pharmaceutical drugs
Test personalized health concept in field lab following P4 medicine principle
Predict, Prevent, Personalize, Participate
Alliance “Expedition Sustainable Care, starting with diabetes”

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Diabetes Field Lab in Hillegom
Aim:
reduce diabetes incidence and complications
Approach:
tackle newly diagnosed diabetes type 2 with lifestyle changes
Method:
personalized diagnosis and advice
use OGTT (oral glucose tolerance test) to stratify
Diabetes type
2
Moderate β
cel function
1. Liver IR
VLCD
2. Muscle IR
Power /
endurance
training
3. Liver &
Muscle IR
Tailored!
Poor β cel
function
Caseïne/
leucine

Alain van Gool
Oncology
CVD, neuro, immune
Diabetes
Personal profiles differ per disease phenotype
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10 October 2013
Alain van Gool

High attrition in most chronic diseases
{Source: Kola, 2008, Nature 83, 2: 227}
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10 October 2013
Alain van Gool
Multifactorial causes of disease, mostly not well understood
Risk factors include both molecular as lifestyle/environmental factors
Treatment is often symptom-based, not mechanism-based
System approach in diagnosis and treatment needed (systems medicine)
Need improved disease definitions and understanding (taxonomy)

Alain van Gool
Redefining disease
{Nature Reviews Drug Discovery 2011, 10: 641}
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Underlying concept: a chronic disease = a collection of rare diseases
8th IMI call:
Joined effort in EU to improve disease definitions
and define best potential therapies
1. RA, SLE
2. AD, PD
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Alain van Gool

From clinical Omics to personalized treatment:
• 12 families with liver disease and dilated cardiomyopathy (5-20 years)
• Initial clinical assessment didn’t yield clear cause of symptoms
• Specific sugar loss of serum transferrin identified via glycoproteomics
• Genetic mutation in glycosylation enzyme identified via exome sequencing
• Outcome 1: Explanation of disease
• Outcome 2: Dietary intervention as succesful personalized therapy
• Outcome 3: Glycoprofile developed as diagnostic test (by mass spectrometry)
Personalized Health Care in rare diseases
Dietary
intervention
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Incomplete glycosylation Complete glycosylation
10 October 2013
Alain van Gool
{Dirk Lefeber et al,
NEJM 2013}

Personalized Health Care using Food + Lifestyle + Pharma
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Alain van Gool

Issues in system biomarkers (1):
How to determine personal profiles?
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Alain van Gool
healthy disease disease +
treatment
healthy disease disease +
treatment
• Biomarkers in populations often have a wide range
• Within this range, individuals can behave quite differently
• Chemometric methods dealing with multiple biomarker data points are needed
to reveal such individual differences and enable personalized healthcare
(Jasper Engel, Udo Engelke, Ron Wevers and Lutgarde Buydens)

Translate personal profiles to personal risk profiles
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10 October 2013
Alain van Gool
Following P4 Health model:
Predictive - predicting disease progression and treatment effect
Personalized - intervention based on personal profile and preference
Participatory - self-monitoring and management, related to own risk profile
Preventive - timely action will prevent disease
HomeostasisAllostasisDisease
Time
Personalized health
Personalized medicine
Disease
Health
Intervention
Big Data
Risk
profiles
Molecular
Non-molecular
Environment
…

Issues in system biomarkers (2)
The innovation gap in biomarker development
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Imbalance between biomarker discovery and application:
• Gap 1: Strong focus on discovery of new biomarkers, few biomarkers progress
beyond initial publication to multi-center clinical validation.
• Gap 2: Insufficient demonstrated added value of new clinical biomarker and
limited development of a commercially viable diagnostic biomarker test.
Discovery Clinical validation/
confirmation
Diagnostic
test
Number of
biomarkers
Gap 1
Gap 2
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Alain van Gool
Which biomarker to choose?

Some numbers
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Data obtained from Thomson Reuters Integrity
Biomarker Module
Alzheimer’s Disease
Chronic Obstructive
Pulmonary Disease
Type II Diabetes Mellitis
Eg Biomarkers in time: Prostate cancer
May 2011: 2,231 biomarker records
Nov 2012: 6,562 biomarker records
9 Oct 2013: 8,106 biomarker records (25,053 uses)
EU: CE marking
USA: LDT, 510(k), PMA
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Alain van Gool

Needed: A Biomarker Development Pipeline
35
• A focus on application of innovation, not on new technologies or biomarker discovery
• The innovation is a clinically validated biomarker that can be applied as diagnostic test
• Bring together available state-of-the art biomarker expertise in an industrial process flow
• Sponsors and end-users define objectives (a.o. pharma, diagnostics, patients)
• Shared biomarker R&D in Open Innovation Network based on Public-Private-Partnership
Shared knowledge,
technologies and objectives

Open Innovation Network in Biomarker R&D
36
Shared R&D in biomarkers (driven by industry needs):
1. Assay development of (diagnostic) biomarkers
2. Clinical biomarker validation (quantification/confirmation, multicenter)
Standardised application in own projects
(Model TNO’s Holst Center)

European Biomarker Consortium
• Open Innovation Network
• Joined effort key partners
2013:
- Form consortium (pharma, nutrition)
- Plan development of disease-related
mechanistic biomarkers
- Secure funding (NL, private)
2014:
- Secure funding (IMI2, Horizon2020)
- Run projects for showcases
- Expand with projects on shared
biomarker interests
- Expand to USA, Canada, (Asia?)
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Contact: alain.vangool@tno.nl
10 October 2013
Alain van Gool

Acknowledgements
Jan van der Greef
Ben van Ommen
Peter van Dijken
Bas Kremer
Ton Rullmann
Robert Kleemann
Lars Verschuren
Marijana Radonjic
Thomas Kelder
Suzan Wopereis
and others
Ron Wevers
Jolein Gloerich
Dirk Lefeber
Monique Scherpenzeel
Leo Kluijtmans
Udo Engelke
and others
Lutgarde Buydens
Jasper Engel
Lionel Blanchet
Jeroen Jansen
and others
Radboud UMC Personalized Healthcare Taskforce:
Andrea Evers, Alain van Gool, Joris Veltman, Jan Kremer, Bas
Bloem, Maroeska Rovers, Jack Schalken, Paul Smits + Gerdi
Egberink, Viola Peulen, Martijn Hoogboom, Martijn Gerretsenalain.vangool@tno.nl
alain.vangool@radboudumc.nl
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10 October 2013
Alain van Gool

2013-10-10 GTC Bio Biomarker Europe Summit 2013, Berlin

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2013-10-10 GTC Bio Biomarker Europe Summit 2013, Berlin