Evening seminar with great discussion with Utrecht colleagues.

1. Bridging research & healthcare:
Translating biomarkers into patient treatment
Prof. Alain van Gool
Netherlands Organisation for Applied Scientific Research (TNO)
Radboud University Nijmegen Medical Centre
Radboud University Nijmegen
Laboratorium voor Klinische Chemie en Haematologie
UMC Utrecht
29st October 2013

2. Outline
2
Backgrounds
Alain
TNO
Radboudumc
Biomarkers
In pharmaceutical drug development
In personalized healthcare
Biomarker innovation gap
Personal profiles (in oncology, diabetes, others)
Progress through Open Innovation Networks
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

3. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
3
Background
Molecular and cellular biology, biochemistry (BSc Eindhoven, MSc Leiden)
1991-1998 Academia - Transcription-coupled DNA repair (PhD, NL)
- DNA recombination (post-doc, UK)
1999-2011 Pharma - Organon (1999-2007) (NL)
- Schering-Plough (2007-2009) (NL, SG)
- Merck/MSD (2009-2011) (SG)
2011 – present:
Netherlands Organisation for Applied Scientific Research (TNO) (Nov 2011)
– Coordinator Biomarkers for Personalized Medicine
Radboud University Nijmegen Medical Centre (Dec 2011)
– Head Radboud Proteomics Center, co-chair Task Force Personalized Medicine
Radboud University Nijmegen (Nov 2009)
– Visiting Professor Molecular Profiling
Biomarkers, Molecular Profiling, Translational Medicine, Personalized Medicine
www.linkedin.com E alain.vangool@tno.nl, alain.vangool@radboudumc.nl T +31-6-11783031

4. 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
4
Biomarker Europe Summit 2013, GTC BIO, Berlin
10 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

5. TNO
Facts &Figures:
Founded in 1932
Member of EARTO
Non-for-profit research institute
~3500 employees
19 sites in Netherlands
+ 18 sites/countries globally
Funding:
• Government (NL)
• Contract research (world)
• Public-private partnerships (world)
7 main themes
www.tno.nl
5
Biomarker Europe Summit 2013, GTC BIO, Berlin
10 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

6. 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%)
Biomarker Europe Summit 2013, GTC BIO, Berlin
10 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
6

7. Year 1
Applying lessons learned across fields
Biomarker Europe Summit 2013, GTC BIO, Berlin
10 October 2013
Alain van Gool
e.g. System Biology @TNO
Year 2
Year 3
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
7

8. Radboudumc
• Mission: “To have a significant impact on healthcare”
• Strategic focus on Personalized Healthcare
• Core activities:
• Patient care
• Research
• Education
• 11.000 colleagues
• 50 departments
• 3.000 students
• 1.000 beds (ambition to close 500 by improving
healthcare)
• First academic centre outside US to fully implement EPIC
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
8

9. Radboudumc Technology Infrastructure
Preclinical Imaging Centre (PRIME) DTL
Microscopic Imaging Centre (MIC) DTL
Centre for Molecular and Biomolecular Informatics (CMBI) DTL
Genetics DTL
Centre for Proteomics, Glycomics and Metabolomics DTL
Centraal Dierenlaboratorium (CDL)
Clinical Research Centre Nijmegen (CRCN)
Radboud Biobank
Translationeel Malaria Onderzoek
Translational research and cellular therapy
Flow cytometry
Translational Neuroscience Unit (TNU)
Medical Innovation and Technology expert Centre (MITeC)
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
9

10. Centre for Proteomics, Glycomics & Metabolomics
Radboud
Proteomics
Center
Radboud
Metabolomics
Group
Radboud
Glycomics
Facility
Research Biomarkers Diagnostics
Mass spectrometry – NMR based, 16 dedicated fte, part of diagnostic laboratory (Department
Laboratory Medicine), close interaction with Radboudumc scientists and external partners
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
10

11. Outline
11
Backgrounds
Alain
TNO
Radboudumc
Biomarkers
In pharmaceutical drug development
In personalized healthcare
Biomarker innovation gap
Personal profiles (in oncology, diabetes, others)
Progress through Open Innovation Networks
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

12. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Successes and failures in drug development
{Kola & Landis, Nat. Rev. Drug Disc. (2004) 8: 711}
2ND intl Pharma-Nutrition Conference
Singapore, 17 April 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
12

13. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Limited view from the outside
Source: Gary Larson
Animal models Patient-related outcome
Source: National University Hospital Singapore
13
2ND intl Pharma-Nutrition Conference
Singapore, 17 April 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

14. Key is to have a good view inside
High need for molecular tools that allow a look into the black box
and improve disease management: biomarkers
Drug exposure ?
Diagnosis ?
Cross-species differences ?
Patient classification ?
Prognosis ?
Target engagement ?
Modulation of mechanism ?
Off-target drug effects ?
Treatment Phenotype
Mechanism ?
Other (latent) diseases ?
Person
2ND intl Pharma-Nutrition Conference
Singapore, 17 April 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
14

15. Biomarkers
{Biomarkers definition working group, 2001 }
Definition: ‘a characteristic that is objectively measured and evaluated as an
indicator of normal biological processes, pathogenic processes, or
pharmacologic responses to a therapeutic intervention’
Or ‘Whatever works in adding value’
Molecular biomarkers provide a molecular impression of a biological system
(cell, animal, human)
Biomarkers can be various sorts of data, or combinations thereof
15
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

16. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
• 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
16
Biomarker need in pharmaceutical drug development
{Source: Van Gool et al, Drug Disc Today 2010}
Pharma lead way
Nutrition and cosmetics copy
best practices
PharmaNutrition next big thing?
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

17. Biomarker-based translational medicine
Does the compound get to the site of action?
Does the compound cause its intended pharmacological/
functional effects?
Does the compound have beneficial effects on disease or
clinical pathophysiology?
What is the therapeutic window (how safe is the drug)?
How do sources of variability in drug response in target
population affect efficacy and safety?
Lead
Optimization
Exploratory
Development PoC
Lead
Discovery
Target
Discovery
 Exposure ?
 Mechanism ?
 Efficacy ?
 Safety ?
 Responders ?
Start in Lead Discovery, complete in clinical Proof of Concept (one strategy)
{van Gool et al, Drug Disc Today 2010}
{Kumar, van Gool, in press 2013}
17
2ND intl Pharma-Nutrition Conference
Singapore, 17 April 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

18. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Biomarker strategy: (data-driven) Decisions
To be made 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”
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
18

19. Biomarker stakeholders in healthcare
19 EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

20. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
Personalized healthcare
20
HomeostasisAllostasisDisease
Time
Personalized health
Personalized medicine
“Health management”
Focus on resilience
“Disease management”
Focus on symptom(s)
Medical
treatment
or
Disease
Health
Non-health

21. The innovation gap in biomarker research & development
21
• 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
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

22. Some numbers
22
Data obtained from Thomson Reuters Integrity
Biomarker Module, April 2013
Alzheimer’s Disease
Chronic Obstructive
Pulmonary Disease
Type II Diabetes Mellitis
Eg Biomarkers in time: Prostate cancer
May 2011: 2,231 biomarkers
Nov 2012: 6,562 biomarkers
Oct 2013: 8,358 biomarkers
EU: CE marking
USA: LDT, 510(k), PMA
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

23. The innovation gap in biomarker research & development
23
Discovery Clinical validation/
confirmation
Diagnostic
test
Number of
biomarkers
Gap 1
Gap 2
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
– Many new biomarkers are panels (RNA, protein, biochemical, imaging)
– Not wise to discover yet an other biomarker
– Focus on selecting the best biomarker (panels) among those already
found (scientific and patent literature, databases, etc)
– Develop those biomarkers tot clinically applicable tests
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

24. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Reasons for biomarker innovation gap
24
• Not one integrated pipeline of biomarker R&D
• Publication pressure towards high impact papers
• Lack of interest and funding for confirmatory biomarker studies
• Hard to organize multi-lab studies
• Biology is complex on organism level
• Data cannot be reproduced
• Bias towards extreme results
• Biomarker variability
• …
{Source: John Ioannidis, JAMA 2011} {Source: Khusru Asadullah, Nat Rev Drug Disc 2011}
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

25. Uptake of new biomarkers in healthcare
Research/technology push:
Biomarkers can and should provide the molecular part of this healthcare model in
monitoring 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
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)
25
World CDx Frankfurt
21 March 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

26. Personal profiles
Source: Barabási 2007 NEJM 357; 4}
• People are different
• Different networks influences
• Different risk factors
26
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

27. 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
27
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

28. Example personal profile-based patient 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}
28
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

29. Example personal profile-based patient assessment (2)
{Chen et al, Cell 2012, 148: 1293}
Concept:
• Continuous monitoring (n=1)
• Routine biomarkers to alert
• Omics to explain
• Early intervention
29
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

30. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Oncology
CVD, neuro, immune
Diabetes
Personal profiles differ per disease phenotype
30
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

31. Companion Diagnostics
Right drug
in right patient
at right dose
at right time
In other words:
Apply a well characterized therapy in a biological system you know well
to treat a disease you understand well, in a way that you know works.
Use (molecular) biomarkers as diagnostic companions of a drug.
New: diagnostic companions to a person !
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
31
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

32. Companion Diagnostics – some numbers
At present in pharmaceutical development:
40.000 clinical trials ongoing
16.000 trials in oncology
8.000 trials in oncology have a companion diagnostic
At present on market:
113 Biomarker in drug label (2012; up from 69 in 2010 = +64%)
16 CDx testing needed (2012; up from 4 in 2010 = +400%)
Costs of development:
>1.000 MUSD per drug
~10 MUSD per diagnostic
Source: www.fda.gov
32
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

33. Companion Diagnostics
Metabolism
Efficacy or
safety
Source: www.fda.gov
{Kumar and van Gool, 2013}
33
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

34. Example Companion Diagnostics in Oncology
V600D/E
Kinase domain
{Roberts and Der, 2007}
B-RAFV600D/E mutation: constitutively active kinase, oncogenic addiction
Overactivate ERK pathway drives cell proliferation
RAF inhibitors block growth of tumor xenografts with B-RAFV600D/E mutation
Prevalence of B-RAFV600D/E
Melanoma (60%), colon (15%), ovarian (30%), thyroid (30%) cancer
Develop B-RAF inhibitors with B-RAFV600D/E as companion diagnostic
34
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

35. 35
Clinical efficacy of Vemurafenib (PLX-4032, Zelboraf)
Key biomarkers:
Stratification: BRAFV600E mutation
Mechanism: P-ERK
Cyclin-D1
Efficacy: Ki-67
18FDG-PET, CT
Clinical endpoint: progression-free survival (%)
{Source: Flaherty et al, NEJM 2010}{Source: Chapman et al, NEJM 2011}
35
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

36. 36
Clinical effects of Vemurafenib
{Wagle et al, 2011, J Clin Oncol 29:3085}
Before Rx Vemurafenib, 15 weeks Vemurafenib, 23 weeks
• Strong initial effects vemurafenib
• Drug resistancy
• Reccurence of tumors
36
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

37. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
37
• BRAFV600D/E is considered the
driving mutation
• However, varying levels of
BRAFV600D/E mutation found in
regions of a primary melanoma
• Molecular heterogeneity in
diseased tissue
• Biomarker levels in tissue and
body fluids will vary
• New biomarkers are needed
• Challenge for companion
diagnostics
{Source: Yancovitz, PLoS One 2012}
Tumor tissue heterogeneity
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

38. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Oncology
CVD, neuro, immune
Diabetes
Personal profiles differ per disease phenotype
38
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

39. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
• Obesity
• Diabetes type 2
HEALTH DISEASE COMPLICATIONS
• Atherosclerosis
• Nephropathy fibrosis
• Osteoarthritis
• Stroke
• etc
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 really pays off
Most effective therapy is ‘eat better, move more’ (lifestyle change)
Nutriceuticals / Lifestyle
Food
Pharma
39
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

40. Overall scheme of metabolic disorder related processes
Myocardial
infactions
Heart
failure
Cardiac
dysfunction
dyslipidemia
Metabolically
healthy
High cholesterol High glucose Hypertension
Brain
disorders
NephropathyAtherosclerosis StrokeRetinopathy
Risk factors of the ‘metabolic syndrome’
Pathologies resulting from the ‘metabolic syndrome’
Visceral
adiposity
LDL elevated
Glucose toxicity
Fatty liver
gut
inflammation
endothelial
inflammation
systemic
Insulin resistance
systemic
inflammation
Hepatic IR
Adipose IR
Muscle metabolic
inflexibility
adipose
inflammation
Microvascular
damage
Myocardial
infactions
Heart
failure
Cardiac
dysfunction
Brain
disorders
Nephropathy
Atherosclerosis
β-cell failure
Reversible process
β-cell Pathology
High cholesterol
High glucose
gluc Risk factor
Hypertension
dyslipidemia
ectopic
lipid overload
Ìrreversible process
Hepatic
inflammation
Stroke
IBD
fibrosis
Retinopathy
Metabolically
healthy
{Nakatsuji, Metabolism 2009}{Source: Ben van Ommen, TNO}

41. Visceral
adiposity
LDL elevated
Glucose toxicity
Fatty liver
Gut
inflammation
endothelial
inflammation
systemic
Insulin resistance
Systemic
inflammation
Hepatic IR
Adipose IR
Muscle metabolic
inflexibility
adipose
inflammation
Microvascular
damage
Myocardial
infactions
Heart
failure
Cardiac
dysfunction
Brain
disorders
Nephropathy
Atherosclerosis
β-cell failure
High cholesterol
High glucose
Hypertension
dyslipidemia
ectopic
lipid overload
Hepatic
inflammation
Stroke
IBD
fibrosis
Retinopathy
Physical inactivity
Caloric excess
Chronic Stress
Disruption
circadian rhythm
Parasympathetic
tone
Sympathetic
arousal
Worrying
Hurrying
Endorphins
Gut
activity
Sweet & fat
foods
Sleep disturbance
Inflammatory
response
Adrenalin
Fear
Challenge
stress
β-cell Pathology
gluc Risk factor
Heart rate
Heart rate
variability
High cortisol
α-amylase
Systems view on (metabolic) health and disease
Lipids, alcohol, fructose
Carnitine, choline
Stannols, fibre
Low glycemic index
Epicathechins
Anthocyanins
Soy
Quercetin, Se, Zn, …
Metformin
Vioxx
Salicylate
LXR agonist
Fenofibrate Rosiglitazone
Pioglitazone
Sitagliptin
Glibenclamide
Atorvastatin
Omega3-fatty acids
Pharma
Nutrition
Lifestyle
{Source: Ben van Ommen, TNO}

42. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Comparing nutritional 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
42
2ND intl Pharma-Nutrition Conference
Singapore, 17 April 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

43. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
clinicalchemistry
SystemnetworksMetabolomeTranscriptome
fluxes
Analysis: high throughput,
multi organ, multi level
High-end data mining and
warehousing
Extensive molecular phenotyping by ‘Omics’ analysis
43
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

44. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Effects on total adipose tissue weight
Full reversal of obese phenotype by ‘Lifestyle’ change, not by all drug treatments
T0901317 also reverses obese phenotype
44
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

45. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Effects on atherosclerosis
Still increased atherosclerosis in ‘Lifestyle’ group
T0901317 strongly induces atherosclerosis
45
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

46. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
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.
46
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

47. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
47
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 fingerprint assay panel
4. Make actionable personalized decision on health /
disease management
5. Test added value in real life through field labs

48. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
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
48
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

49. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Field labs: test health care concepts in real life
• 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
• Alliance “Expedition Sustainable Care, starting with diabetes”
49
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

50. Field labs: implementation in 1st line health care
• Implementation-plan ‘personalized diagnosis
of (pre)diabetic and their lifestyle treatment in
Dutch Health care’.
• Use of OGTT as a stratification biomarker for
subgroups of (pre)diabetic patients
• Use diagnosis for a tailored lifestyle
(and medical) treatment
for these subgroups
Being implemented in
1st line care
regio Hillegom
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
50

51. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Oncology
CVD, neuro, immune
Diabetes
Personal profiles differ per disease phenotype
51
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

52. High attrition in most chronic diseases
{Source: Kola, 2008, Nature 83, 2: 227}
• 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 (systems medicine)
• Need improved disease definitions and understanding
52
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

53. EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Redefining disease
{Nature Reviews Drug Discovery 2011, 10: 641}
53
Underlying concept: a chronic disease = a collection of rare diseases
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
8th IMI call:
Joined effort in EU to improve disease definitions
and define best potential therapies
1. RA, SLE
2. AD, PD
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

54. 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 defect 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
{Dirk Lefeber et al,
NEJM 2013}
54
Incomplete glycosylation Complete glycosylation
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

55. Outline
55
Backgrounds
Alain
TNO
Radboudumc
Biomarkers
In pharmaceutical drug development
In personalized healthcare
Biomarker innovation gap
Personal profiles (in oncology, diabetes, others)
Progress through Open Innovation Networks
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

56. The innovation gap in biomarker development
56
• 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
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

57. Needed: A Biomarker Development Pipeline
57
• 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
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

58. Topsector LS&H - Roadmap Molecular Diagnostics
{www.rijksoverheid.nl}
{http://www.zonmw.nl/nl/roadmaps-lsh/}
Roadmap Molecular Diagnostics:
• Build an efficient biomarker development pipeline in Netherlands
• Bring all stakeholders together in a functional open innovation network
based on public-private-partnerships
• Have end-users (patients) direct biomarker discovery in beginning
• Improve progress of biomarkers from discovery to clinical implementation
9 TopSectors Multiple Roadmap teams per TopSector
58
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

59. Open Innovation Networks
(Next Generation Life Science)
59
(Source: Model TNO’s Holst Center)
Old New
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

60. Features of an Open Innovation Network
60
Pharma cies
Biobanks
Analytical
laboratories
Diagnostic cies
D
C
BA
Others
Access to a network of relevant scientists, reagents and technologies
Access to relevant markets and secondary networks
Flexible use of expertise and capabilities in network under standardised agreements
Funding for joined and bilateral projects
Accelerated translation of knowledge to innovation
C1
C2
C3
C..
Technology 1
Technology 2
Technology 3
Technology ..
Eg for biomarker R&D:
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

61. Biomarker Development Center
Concept
A functional public-private partnership network of multiple partners with strong
complementary biomarker expertise to develop innovative clinical biomarkers
to application, with a strong initial focus on pharmaceutical drug development
Pipeline
Biomarker Development
Center
Projects
A matrix network:
Pipeline: focus on improvement of available biomarker technologies
Projects: process well-defined biomarker development projects
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
61

62. Focus
Emerging
Discovery Clinical validation
and confirmation
Diagnostic
application
Number of
biomarkers
Experimental
Discovery
Assay kit
development
Assay
development
Early Late
Academia
(discovery)
Industry
(development)
Shared R&D in biomarkers:
1. Assay development of (diagnostic) biomarkers
2. Clinical biomarker validation (quantification/confirmation, multicenter)
Leading to standardised clinical applications
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
62

63. Biomarker Development Center (Netherlands)
STW perspectief application
Biomarker Development Center
Public-private partnership 4 years
Project budget 4.3M Eur
Close interactions with:
- Clinicians (biomarker application)
- Industry (+ 0.94MEur cash + 1.24MEur kind)
- Patient stakeholder associations
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
63

64. Biomarker Development Center (Netherlands)
64
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool
64

65. Biomarker Development Center (Europe)
• Open Innovation Network
• Joined effort by key partners
2013:
- Form consortium
- Plan development of disease-related
mechanistic biomarkers
- Secure initial funding (NL, private)
2014:
- Secure funding (IMI2, Horizon2020, COST)
- Run projects for showcases
- Expand with projects on shared biomarker
interests
- Expand to USA, Canada
65
+ >30 partners
65
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

66. Outline
66
Backgrounds
Alain
TNO
Radboudumc
Biomarkers
In pharmaceutical drug development
In personalized healthcare
Biomarker innovation gap
Personal profiles (in oncology, diabetes, others)
Progress through Open Innovation Networks
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

67. Personalized Healthcare by Food + Lifestyle + Pharma
67
Dutch CC meeting ‘Personalized Health Care”
Ede, 2 October 2013
Alain van Gool
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool

68. Acknowledgements
Jan van der Greef
Ben van Ommen
Peter van Dijken
Robert Kleemann
Lars Verschuren
Bas Kremer
Ton Rullmann
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 Gerretsen
68
alain.vangool@tno.nl
alain.vangool@radboudumc.nl
Lecture LKCH, UMC Utrecht
29 October 2013
Alain van Gool