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2013-10-29 Seminar LKCH, Utrecht
This document discusses bridging research and healthcare by translating biomarkers into patient treatment. It provides background on Prof. Alain van Gool and his roles at TNO, Radboud University Nijmegen Medical Centre, and Radboud University Nijmegen. It outlines the need for biomarkers in pharmaceutical drug development and personalized healthcare to address the biomarker innovation gap and develop personal profiles for conditions like oncology and diabetes. Progress may be made through open innovation networks.
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2013-10-29 Seminar LKCH, Utrecht
- 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 drugdevelopment 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 forResearch 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 Organisationfor 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 in1932 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 Europeanpublic-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 lessonslearned 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: “Tohave 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 PreclinicalImaging 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 drugdevelopment 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 forResearch 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 forResearch 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 tohave 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 workinggroup, 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 forResearch 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 Doesthe 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 forResearch 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 inhealthcare 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 forResearch 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 gapin 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 obtainedfrom 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 gapin 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 forResearch 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 newbiomarkers 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: Barabási2007 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 MOLECULARLIFESTYLE / 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-basedpatient 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-basedpatient 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 forResearch 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 inright 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 Diagnosticsin 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 ofVemurafenib (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 ofVemurafenib {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 forResearch 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 forResearch 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 forResearch 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 ofmetabolic 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 Fattyliver 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 forResearch 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 forResearch 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 forResearch 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 forResearch 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 forResearch 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 forResearch 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 forResearch 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 forResearch 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: implementationin 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 forResearch 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 inmost 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 forResearch 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 Omicsto 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 drugdevelopment 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 gapin 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 BiomarkerDevelopment 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 (NextGeneration Life Science) 59 (Source: Model TNO’s Holst Center) Old New Lecture LKCH, UMC Utrecht 29 October 2013 Alain van Gool
- 60. Features of anOpen 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 Afunctional 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 andconfirmation 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 drugdevelopment 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 byFood + 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 derGreef 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