2014 02-24 Oxford Global biomarker congress, Manchester
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This document summarizes a presentation given by Alain van Gool on biomarkers in a changing world. It discusses the shift from personalized medicine to personalized healthcare, which takes a more holistic systems view of an individual. It also notes disruptive technologies that can accelerate biomarker development and the need to translate biomarkers into useful tools. Throughout, it provides examples of challenges like tumor heterogeneity and factors beyond genetics that influence disease and response to treatment.
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2014 02-24 Oxford Global biomarker congress, Manchester
- 1. Biomarkers in a changing world Prof Alain van Gool Head Radboud Center for Proteomics, Glycomics and Metabolomics Coordinator Radboud Technology Centers Head Biomarkers in Personalized Healthcare
- 2. Mixed perspectives 8 years academia (NL, UK) (molecular mechanisms of disease) 13 years pharma (EU, USA, Asia) (biomarkers, Omics) 2.5 years applied research institute (NL, EU) (biomarkers, personalized health) 2.5 years med school (NL) (Omics, biomarkers, personalized healthcare) A person / citizen / family man (adventures in EU, USA, Asia) 1991-1996 1996-1998 2009-2012 1999-2007 2007-2009 2009-2011 2011-now 2011-now 2 2 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 3. Biomarkers in a changing world 3 • From Personalized Medicine to Personalized Healthcare • Disruptive technologies for biomarker R&D • Need to accelerate the development of useful biomarkers and tools 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 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 companies 4
- 5. TNO Netherlands Organisation for Applied Scientific Research Founded in 1932 Non-for-profit research institute Member of EARTO ~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
- 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%)
- 7. TNO’s applied biomarker tool box Widely used preclinical translational models Pharma, nutrition and chemical industry, academia Focus on etiology of disease and mechanism of action Human studies Experimental medicine through CRO’s Microdosing 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 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 7
- 8. Year 1 Applying lessons learned across fields e.g. System Biology @TNO Year 2 Year 3
- 9. 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 • First academic centre outside US to fully implement EPIC
- 10. Radboud Personalized Healthcare Stratification by multilevel diagnosis Exchange experiences in care communities + Patient’s preference of treatment People are different 10 Select personalized therapy
- 11. Translational medicine @ Radboudumc
- 12. Radboudumc Technology Centers Genomics Bioinformatics Preclinical therapies Flow cytometry Translational neuroscience Novel concepts in surgery Imaging Microscopy Biobank Data stewardship Proteomics Metabolomics Radboudumc Technology Centers GMP products Clinical trials (February 2014)
- 13. Biomarkers in a changing world 13 • From Personalized Medicine to Personalized Healthcare • Disruptive technologies for biomarker R&D • Need to accelerate the development of useful biomarkers and tools 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 14. Personalized Medicine Right patient with right drug at right dose at right time for right outcome Only part of the biomarker use in pharmaceutical development. Driven by the need to develop better drugs that work optimal in a selection of patients, rather than work mediocre in a larger patient group. Often translated to: Co-develop (molecular) biomarkers as diagnostic companions of a drug. In changing world: biomarkers are diagnostic companions of a person. 15 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 15. 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 (many genetic) 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 16 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 16. Companion Diagnostics Metabolism Efficacy or safety Source: www.fda.gov {Kumar and van Gool, RSC, 2013} 17 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 17. 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} 18 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 18. 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 19 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 19. Tumor tissue heterogeneity 20 • BRAFV600D/E is driving mutation • However, also no BRAFV600D/E mutation found in regions of a primary melanoma • Molecular heterogeneity in diseased tissue • Biomarker levels in tissue will vary • Biomarker levels in body fluids will vary • Major challenge for (companion) diagnostics {Source: Yancovitz, PLoS One 2012} 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 20. ‘Complicating’ factors in oncology therapy Source: 11 Sept 2013 @de Volkskrant • Biological clock • Smoking • Pharma-Nutrition • Drug-drug interaction • Alternative medicine • Genetic factors • … Interview with Prof Ron Matthijssen, ErasmusMC, Rotterdam 21 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 21. Changing world: Personalized Medicine@ USA “The term "personalized medicine" is often described as providing "the right patient with the right drug at the right dose at the right time." More broadly, "personalized medicine" may be thought of as the tailoring of medical treatment to the individual characteristics, needs, and preferences of a patient during all stages of care, including prevention, diagnosis, treatment, and follow-up.” (FDA, 1 nov 2013) 22 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 22. Changing world: Personalized Medicine@ EU (ESF, 30 Nov 2012) (IMI2, 8 July 2013) (EC, draft Nov 2013) 23 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 23. Emerging: Personalized Healthcare in a systems view Source: Barabási 2007 NEJM 357; 4} • People are different • Different networks and influences • Different risk factors 24 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 24. Personalized Healthcare in a systems view 25 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 25. System biology model for Personalized Health(care) (a.k.a. Next Generation Life Sciences) HomeostasisAllostasisDisease Time Disease Health Personalized Intervention of patients-like-me Big Data Risk profiles of persons-like-me Molecular Non-molecular Environment … Personal profile Selfmonitoring Adapted from Jan van der Greef (2013) 26 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 26. Example personal profile-based healthcare {Chen et al, Cell 2012, 148: 1293} Concept: • Continuous monitoring (n=1) • Routine biomarkers to alert • Omics to explain • Early intervention 27
- 27. The big current bottleneck in Next Generation Life Sciences: 28 (Big) data Knowledge Understanding Decision Action Translation ! 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 28. 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}
- 29. EC DG for Research and Innovation Alain van Gool Brussels, 11 Sept 2012 Important processes in T2D Diagnosis Potential interventions Dietary/Lifestyle 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 30 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 30. 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 31 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 31. Pharma-Nutrition Effect Dose Currently consortium building in Horizon2020, call PHC-13 Coordinator Bas Kremer ([email protected])
- 32. However … 33 The world is changing and doesn’t wait for scientific rigor to catch up 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 33. Learn from Next Generation Life Sciences in USA 34 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 34. Singularity University’s FutureMed 2013 speakers Exponential technologies Digital medicine Integrated care Artifical intelligence Robotics Patients included Lifestyle Self quantification Global health WatsonArtifical intelligence Regenerative medicine 23andme Robotics and Jamie Heywood (Patientslikeme) 35 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 35. Singularity University’s FutureMed 2013 conference 36 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 36. Exponential progress “The only constant is change, and the rate of change is increasing” We are at the knee of the exponential curve of progress 37 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 37. 1. Imaging of every part of human body in high resolution 2. Smartphone as the most important pieve of clothing 3. Self-diagnosis as a continous monitoring to quantified self 4. Artifical intelligence and robots 5. Digital medicine, Big Data and wisdom of the crowd 6. Our body as a lego box using 3D printing for spare parts 7. Our brain online using brainsensing headbands to transfer thoughts Exponential trends 38 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 38. Digital medicine 39 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 39. Self-diagnosis 40 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 40. The future is nearly there … 41 Personalized advice Action Selfmonitor Cloud Lifestyle Nutrition Pharma 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 41. Big Data
- 42. Exponential health(care) technologies • IBM Watson • AI system on top of recorded medical data + connected to Big Data clouds • Independent data-driven clinical diagnosis with very high accuracy • Artifical intelligence 43 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 43. 44 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 44. 3 days high speed innovation in one slide • Buzzwords: • Exponential technologies • Disruptive innovation • Progress and beyond • Digital quantified self • Focus on: • Where will we be in 5-20 years? • Technologies, genomics, robotics, Big Data, eHealth, patient empowerment • Less focus on: • What to do next year? • Biomarkers, robustness assays for decision, translating data to knowledge, innovation in clinical drug testing 45 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 45. A problem in biomarker land 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 The innovation gap in biomarker research & development 46 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 46. Some numbers 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 24 Feb 2014: 9,240 biomarkers with 28,538 biomarker uses EU: CE marking USA: LDT, 510(k), PMA 47 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 47. Reasons for biomarker innovation gap • 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} 48 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 48. “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.” Marcia Angell, MD Former Editor-in-Chief NEJM Oct 2010 49 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 49. Shared biomarker research through open innovation We need to set up a open innovation network to share biomarker knowledge and expertise to jointly develop and validate biomarkers : 1. Assay development of (diagnostic) biomarkers 2. Clinical biomarker quantification/validation/confirmation Shared knowledge, technologies and objectives through public-private partnerships (national, European, world-wide) 50 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 50. Biomarker Development Center (Netherlands) STW perspectief grant Biomarker Development Center Public-private partnership 4 years Project grant 4.3M Eur of which 2.2M government, and 2.1M industry (0.9M cash/1.2M kind) Close interactions with: - Clinicians (biomarker application) - Industry - Patient stakeholder associations 51 51 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 51. Personalized healthcare Ways forward: • Participation + collaboration • Selfmonitoring • Personal profiles • System biology • (Big) Data sharing • Personal preferences • Personalized therapies • Lifestyle + Nutrition + Pharma 52 52 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool
- 52. Acknowledgements Jan van der Greef Ben van Ommen Peter van Dijken Ton Rullmann Lars Verschuren Bas Kremer Marijana Radonjic Thomas Kelder Robert Kleemann Suzan Wopereis William van Dongen and others Ron Wevers Jolein Gloerich Hans Wessels Dirk Lefeber Monique Scherpenzeel Leo Kluijtmans Udo Engelke Ulrich Brandt Lucien Engelen and others Lutgarde Buydens Jasper Engel Lionel Blanchet Jeroen Jansen and others Radboud umc Personalized Healthcare Taskforce: Paul Smits, Andrea Evers, Alain van Gool, Maroeska Rovers, Joris Veltman, Jan Kremer, Bas Bloem, Jack Schalken, Gerdi Egberink, Nathalie Bovy, Bob de Jonge, Viola Peulen, Marcel Wortel, Martijn Hoogboom, Martijn Gerretsen [email protected] [email protected] www.linkedIn.com And external collaborators 53 9th Annual Biomarker Congress Oxford Global, Manchester 25th February 2014 Alain van Gool