2013-04-17 Pharma-Nutrition Singapore

Pharma-Nutrition:
a pharma perspective
Prof. Alain van Gool
Netherlands Organisation for Applied Scientific Research (TNO)
Radboud University Nijmegen Medical Centre
Radboud University Nijmegen
2nd International Pharma-Nutrition Conference
Singapore, 15-17 April 2013

EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
2
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) (80%; Nov 2011)
– Coordinator Biomarkers for Personalized Medicine
Radboud University Nijmegen Medical Centre (20%; Dec 2011)
– Head Radboud Proteomics Center, co-chair Task Force Personalized Medicine
Radboud University Nijmegen (0%; Nov 2009)
– Visiting Professor Molecular Profiling
Biomarkers, Molecular Profiling, Translational Medicine, Personalized Medicine
www.linkedin.com E alain.vangool@tno.nl T +31-6-11783031
2ND intl Pharma-Nutrition Conference
Singapore, 17 April 2013
Alain van Gool

Alain van Gool
3
Outline
• Lessons learned from pharma
• Successes and failures
• Need for translational medicine
• Data-driven decision making
• Pharma 2.0
• Redefining disease
• Changed health care landscape
• Changed view on personalized health care
• Multi-parameter personal profiles
• Biomarker innovation gap
Alain van Gool

Alain van Gool
Successes and failures in therapeutic fields
{Kola & Landis, Nat. Rev. Drug Disc. (2004) 8: 711}
Alain van Gool

Alain van Gool
First human dose
to First patient
dose
First patient dose
to First pivotal
dose
First pivotal dose
to First
submission
First submission
to First
launch
Year of entry into phaseCurrent success rate
Trends in success rates by phase
CMR benchmarking study
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Alain van Gool

Alain van Gool
Wanted: new toolkit
“A new product development toolkit - containing powerful
new scientific and technology methods such as animal or
computer-based predictive models, biomarkers for safety
and effectiveness and new clinical evaluation techniques -
is urgently needed to improve predictability and efficacy
along the critical path from lab concept to commercial
product.”
FDA
(White paper March 2004)
Alain van Gool

Alain van Gool
Limited view from the outside
Source: Gary Larson
Animal models Patient-related outcome
Source: National University Hospital Singapore
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Alain van Gool

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 Disease state
Mechanism ?
Other (latent) diseases ?
Disease
Alain van Gool

Alain van Gool
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Biomarkers
PSA protein – blood, indicator of prostate cancer
Cholesterol – blood, risk indicator for coronary and vascular disease
MRI scan – shows abnormal tissue, like brain tumor
{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’
Molecular biomarkers provide a molecular impression of a biological system
(cell, animal, human)
Biomarkers can be various analytes:
Alain van Gool

Alain van Gool
Need for translational medicine in pharma
Issue: frequent crossing of systems barriers during drug development
Biopsies
Tissues
etc
Monkey
Pig
etc
Rabbit
Mice
Ex vivo
Rodents
DogTissues
Cell lines
Primary
cells
Diseased
human
Healthy
human
RatCellsHTS
(solution)
assays
Cell lines
Target
discovery
Lead
discovery
Lead
optimization
Pre
clinical
Phase
I
Phase
II(1)
Phase
III
Registration Launch Market
Research Development Marketing
High attrition from Research to Development (90%)
High need for translational models and tools (= biomarkers) to determine
drug exposure, efficacy and safety !!
Alain van Gool

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Translational medicine in pharma
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?
Alain van Gool

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 (1 strategy)
{van Gool et al, Drug Disc Today 2010}
{Kumar, van Gool, in press 2013}
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Alain van Gool

Alain van Gool
Biomarker-based translational medicine strategy plans
Questions Biomarkers
& tools
Studies
& links
Comments Answers
Exposure
Mechanism
Pharmacological
efficacy
Disease
efficacy
Safety
Patient
stratification
Other
Alain van Gool

Alain van Gool
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”
Alain van Gool

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Biomarker-based system biology
Saco de Visser
Adam Cohen
Scrip magazine 2003
Alain van Gool

Alain van Gool
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Outline
• Lessons learned from pharma
• Successes and failures
• Need for translational medicine
• Data-driven decision making
• Pharma 2.0
• Redefining disease
• Changed health care landscape
• Changed view on personalized health care
• Multi-parameter personal profiles
• Biomarker innovation gap
Alain van Gool

Change in disease characterisation
• Multifactorial causes of chronic diseases are 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)
• Joined effort in EU to improve disease definitions and define best potential
therapies
• Translate to personalized / stratified medicine
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{Nature Reviews Drug Discovery 2011, 10: 641}
Alain van Gool

Alain van Gool
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Change in healthcare landscapes
• Health care is changing from paternal medical practice to participatory patient
• Patients involvement and ownership is growing (eg patientslikeme)
• Health care reimbursment change from production to quality (+10 years)
• Alternative ways of funding application-driven research emerge
• Crowd sourcing, stocks by end users
• Fast small grants by industry (e.g. Bayer’s grants4targets)
Alain van Gool

Changed view on personalized health care
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HomeostasisAllostasisDisease
Time
Personalized health
Personalized medicine
“Health management”
Focus on resilience
“Disease management”
Focus on symptom(s)
Medical
treatment
or
Disease
Health
Non-health

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Changed view on target biology:
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
21

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

RISK FACTORS
Multiparameter personal profiles
BIOMARKERS
Statistics
Selection
Ranking
INTERVENTIONS
Alain van Gool
DNA
mDNA
RNA ProteinMetabolites
Imaging
Enzymatic activity
Biochemical process
Attitude in life Social network
Stress work / private
NutritionEnvironmentPERSON-BASED
DATA
MOLECULAR LIFESTYLE / ENVIRONMENT
miRNA

TNO’s Systems Biology and Biomarker Tool Box
Translational preclinical models
Pharma and nutrition industry, academia (1:1, consortia)
Combine phenotypic read-outs with analytical platforms
Human studies, microdosing
Network biology + modelling
Lipidome (78 lipids)
Metabolome (198 metabolites)
Proteome (~ 4.000 proteins)
Transcriptome (~ 30.000 transcripts)
Clinical chemistry (~30 parameters)
Person-based metadata
Part in-house, part through a wide external network
Applied biomarker expertise
Discovery, statistics, validation, development, implementation
A wide network with biomarker academia and industry
Knowledge databases
Metabolic Syndrome
• Atherosclerosis
• Diabetes
• Obesity
• Vascular inflammation
• NASH, fibrosis
24
Alain van Gool

N-of-1 health monitoring through system biology
{Chen et al, Cell 2012, 148: 1293}
Concept:
• Continuous monitoring
• Routine biomarkers to alert
• Omics to explain
• Early intervention
Alain van Gool

The innovation gap in biomarker development
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• Disconnected pipeline from biomarker discovery to 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
Alain van Gool

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Emerging
Discovery Clinical validation/
confirmation
Diagnostic
application
Number of
biomarkers
Experimental
Discovery
Assay kit
development
Assay
development
Early Late
Eg prostate cancer
May 2011: 2,231 biomarkers
Nov 2012: 6,562 biomarkers
{Source: Thomson Reuters Biomarkers Module}
– 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
– Open Innovation Network
Many discovered biomarkers already !
Alain van Gool

Way forward: Open Innovation Network
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Shared R&D in biomarkers:
1. Assay development of (diagnostic) biomarkers
Share resources and time to develop a robust quantitative assay
2. Clinical biomarker quantification/validation/confirmation
Share resources and time by joined multi-center biomarker studies
(Model TNO’s Holst Center)
Alain van Gool

Biomarker stakeholders in open innovation network
29
Alain van Gool

European Biomarker Consortium
• Open Innovation Network
• Joined effort key partners
2013:
- Form consortium (+ EFPIA/IMI)
- Plan development of disease-
related mechanistic biomarkers
- Run projects for showcases
- Expand with projects on shared
biomarker interests
2014:
- Additional funding
- Expand with projects
- Expand to USA, Canada, (Asia?)
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Alain van Gool

Personal profiles
Oncology CVD, neuro, immune Diabetes
31
Risk factor pattern is different per disease phenotype
Alain van Gool

Personalized medicine in Oncology
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• Companion Diagnostics (CDx): right drug, right patient, right dose, right time
• Of 40.000 currently ongoing clinical trials, 18.000 are in oncology of which
9.000 are targeted
• Strongly driven by molecular biomarkers
• Currently 113 drug labels contain biomarker data (Cyp450, targeted) of which
32 in oncology
• CDx testing required for 16 drugs in 2012, up from 4 in 2010
Alain van Gool
Pharmacogenomic
biomarkers in
drug labels
Source FDA
Kumar and van Gool, 2013

Mutation-driven rational drug discovery 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 patient stratification opportunity
33
Alain van Gool

34
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}
34
Alain van Gool

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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
35
Alain van Gool

Alain van Gool
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• BRAFV600D/E is considered the
driving mutation
• However, varying levels of
BRAFV600D/E mutation found in
regions of a primary melanoma
• Escape mechanisms of tumors:
• Molecular heterogeneity in
diseased tissue
• Biomarker levels will vary as
well
• Similar situation within body
fluids (e.g. gradients)
• Challenge for companion
diagnostics
{Source: Yancovitz, PLoS One 2012}
Tumor tissue heterogeneity
Alain van Gool

Personal profiles
37
Alain van Gool

Alain van Gool
• 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
Inhibition/stimulation of a selected step shifts equilibrium to a potential bottle neck elsewhere
A system biology approach is needed
For discovery research, diagnosis and treatment
Most effective therapy is ‘eat better, move more’ (lifestyle change)
Nutriceuticals / Lifestyle
Food
Pharma
38
Alain van Gool

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}

Many drugs interfere with these processes in “health care”
Visceral
adiposity
LDL elevated
Glucose toxicity
Fatty liver
gut
inflammation
endothelial
inflammation
systemic
Insulin resistance
systemic
inflammation
Vioxx
Salicylate
Atorvastatin
Fenofibrate
Metformin
Glibenclamide
LXR agonist
Rosiglitazone
Pioglitazone
Sitagliptin
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
Hepatic
inflammation
Stroke
IBD
fibrosis
Retinopathy
Metabolically
healthy
Physical inactivityCaloric excess
reversibleirreversible

Many dietary ingredients optimize these processes
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
Hepatic
inflammation
Stroke
IBD
fibrosis
Retinopathy
Metabolically
healthy
Carnitine, Choline, …
Caloric restriction
Soy …
Low glycemic index
Physical activity
Stannols, fibre
reversibleirreversible
Omega 3/6 FA
Quercetin, Se, Zn, …
procyanidins
epicathechins
caretonoids
anthocyanins
polyphenols

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.

Important processes in
T2D
Diagnosis Potential interventions
Dietary/LS Pharma
1.Pancreatic β-cell function
(impaired insulin secretion)
*OGTT: I/∆G 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

Alain van Gool
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
44
Alain van Gool

45
Effects on total adipose tissue weight
Most effective therapy is ‘eat better, move more’ (lifestyle change)
But people respond differently to interventions (depending on their personal profile)
Alain van Gool

Alain van Gool
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
46
Alain van Gool

Alain van Gool
P4 field lab
Query customer
Personalized advice
Coaching
Monitoring
Feedback
Analysis
Challenge tests
Personal Omics
Lab-on-chip
Measure preferences
Sense making
Smart querying
Smart algorithms
Knowledge integration
Interactive apps
eHealth
Avatar
Serious gaming
Wearable devices
Activity reporting
Emotion reporting
Intelligent communication
Personal Health Dossier
Data integration
Virtual populations
Dynamic consent
Assess health status
NL Topsector Life Sciences & Health+ links to NL, EU and USA consortia
(nutrition, pharma, P4 medicine,
biomarkers, ICT, systems biology)
Human
interaction
Technological
support

Personal profiles
48
Alain van Gool

Alain van Gool
Redefining disease
{Nature Reviews Drug Discovery 2011, 10: 641}
49
Alain van Gool

Alain van Gool
Human Diseasomes
From Barabási 2007 NEJM 357:4
Redefining disease
50
Alain van Gool

Alain van Gool
Redefining disease
Proposed procedure
for network-based
drug discovery for
personalized therapy
Source: Schadt et al, 2009, Nature, 8:268}
51
Alain van Gool

Alain van Gool
Redefining disease: Medicine 3.0
Concept:
• Identify and quantify common
mechanisms of chronic diseases
• Identify new targets for intervention
• Target causes of disease rather than
symptoms
NL: Proposal submitted (10 yrs, 30MEur)
EU: Align with IMI and Horizon2020
52
Alain van Gool

Bridging Western
and Eastern
medicine
Oltvai et al Science 298 (2002) 763
Chinese Medicine
research
10 januari 2011
53
Western Medicine
research

Alain van Gool
van Wietmarschen H et al. JCR. 2009;15(7):330-337.
RA Cold RA Heat Control
Treatment 1 Treatment 2
64
differentially
expressed
genes
Subtyping of Rheumatoid Arthritis based on Heat & Cold patterns
Hierarchical
clustering
Alain van Gool

Alain van Gool
DXXK consists of the total saponin extract of the rhizomes of Dioscorea nipponica Makino,
mainly composed of steroidal saponins
Patent protected China and EU by DIAO
> 100 scientific studies (16.000 patients)
Used by >100 Million people
Production process DIAO is approved for EU cGMP in 2009
Approved for NL market 14 March 2012
Bridging Tradional Chinese Medicine to the West
Registration as tHMP in NL by
TNO/SU BioMedicine in collaboration with DIAO
NATURE NEWS BLOG, April 19, 2012
Chinese herbal medicine breaks into EU
Market
Alain van Gool

Pharma-Nutrition
56
Alain van Gool
Exchange of best practice
(strategies, knowledge)
Join forces, co-development

Personalized Health = Food + Lifestyle + Pharma

Alain van Gool
Thank you
58
Jan van der Greef
Ben van Ommen
Peter van Dijken
Robert Kleemann
Hans Princen
Tom Rullmann
and many others at
Bas Kremer
Marijana Radonjic
Suzan Wopereis
Lars Verschuren
Rob Stierum
Nard Clabbers
Wim van Hartingsveldt
Robert Ostendorf
Simon Folkertsma
Steven Erpelinck
Gerrit Beumer
alain.vangool@tno.nl
Alain van Gool

2013-04-17 Pharma-Nutrition Singapore

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2013-04-17 Pharma-Nutrition Singapore