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

2 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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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%)

Biomarker Europe Summit 2013, GTC BIO, Berlin

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


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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?


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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}


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Alain van Gool


Alain van Gool



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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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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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Ho

meo

sta

sis

A

llo

sta

sis

D

isease

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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Alain van Gool


Alain van Gool


Oncology

CVD, neuro, immune

Diabetes

Personal profiles differ per disease phenotype


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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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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 w t=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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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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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


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”

https://www.mediq-apotheek.nl/default.aspx

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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

http://www.google.nl/url?sa=i&rct=j&q=nederland&source=images&cd=&cad=rja&docid=-6d3iBRpg_wauM&tbnid=65v3tY_Y9vxkCM:&ved=0CAUQjRw&url=http://www.plaatsen-gids.nl/&ei=qTQzUpGFOIbHtQajx4DYCA&bvm=bv.52164340,d.Yms&psig=AFQjCNH74pQY8hG8zqhKN6_f3c1ACWjPHQ&ust=1379173831031748


Alain van Gool


Oncology

CVD, neuro, immune

Diabetes

Personal profiles differ per disease phenotype


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Alain van Gool

High attrition in most chronic diseases

{Source: Kola, 2008, Nature 83, 2: 227}

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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


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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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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

Ho

meo

sta

sis

Allo

sta

sis

Dis

ease

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

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• 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

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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: [email protected]


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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 Gerretsen [email protected]

[email protected]

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10 October 2013

Alain van Gool

2013-10-10 gtc bio biomarker europe summit 2013, berlin

Health & Medicine