2nd Central European Congress on Obesity October 1-3, 2009 Budapest, Hungary

1. O B E K O N Consortium Identification of molecular targets and biomarkers in the mechanism and the treatment of obesity. Introduction of the activity of the „OBEKON”Tamás Pázmány, PhD 2nd Central European Congress on Obesity October 1-3, 2009 Budapest, Hungary CECON II Budapest

2. O B E K O N Consortium Treatment of obesity • Soranus - 2nd century – Alexandria and Rome • elixirs of laxatives and purgatives, • heat, massage, and exercise. • Current strategies to treat obesity • Lifestyle changes in diet • Physical activity • Gastrointestinal surgery • Pharmacological intervention • Suppression of the appetite • Increase of the body's metabolism • Interference with the body's ability to absorb specific nutrients in food. CECON II Budapest

3. O B E K O N Consortium FDA approved prescription medication – for long-term weight loss • Sibutramine • Appetite suppressant. Serotonin-norepinephrine reuptake inhibitor • Meridia(US) – Reductil (EU) – prescription • Orlistat • Reduces intestinal fat absorbtion by inhibiting pancreatic lipase • Xenical - prescription • Alli - OTC …and for short term (up to 12 weeks): • Phentermine • Appetite suppressant by inducing norepinephrine release in the hypothalamus CECON II Budapest

4. O B E K O N Consortium Pipeline of anti-obesity compounds (2006-) Phase III Merck’s MK 0557 Neuropeptid Y receptor (NPY5R) antagonist. Stopped after phase III – 2006.Oct. Merk’s Taranabant (MK 0364) is an selective inverse agonist to the human cannabinoid type 1 receptor. Stopped after phase III – 2008.10.02. Pfizer’s selective antagonist of the cannabinoid type 1 receptor Stopped after phase III – 2008.11.06. Arena Pharmaceutical’s Lorcaserin is an selective serotonin 2C receptor agonists. Phase III trials hase been completed: + results 7190 patients – 2009.09.18. Orexigene Therapeutics’ Contrave is a combination of Wellbutrin ( antidepressant) and Naltrexone (addiction) Phase III trials hase been completed: + results 4500 patients – 2009.07.20. CECON II Budapest

5. O B E K O N Consortium OBEKON consortium – the start – 2006 • Collaboration / alliance - consortium • 7 members of academic institutions + university and industry – OBEKON • 40 researcher - > 20 PhD and 4 members of the HAS • Submitted grant: „Identification of molecular targets and biomarkers in the mechanism and the treatment of obesity” • Start – 2006, summer with the significant financial support from the NKTH • Duration: 2.5 yrs – ends December, 2009 • 2006, spring - call for a grant application by the National Office for Research and Technology CECON II Budapest

6. O B E K O N Consortium Members of the OBEKON • Richter Gedeon Plc. www.richter.hu • Semmelweis Universitywww.sote.hu • Institute of Genetics, Cell- and Immunobiology • Pázmány Péter Catholic Universitywww.ppke.hu • Faculty of Information Technology • HAS, Chemical Research Centerwww.chemres.hu • Structural Chemistry Institute • BioSystems International Ltd. www.biosys-intl.com • TargetEx Research and Development Ltd. www.targetex.com • QSX Quality Software Expert Ltd. www.qsx.hu CECON II Budapest

7. O B E K O N Consortium Our goals are: • Using „systems biology” approach we intend to identify new molecular targets and biomarkers by mapping of the molecular network of obesity. • To collect large number of blood sample from obese and non-obese donors, prepare plasma, DNA and RNA. • Generate quality genomics and proteomics data. • Analyse the data to identify new molecular targets and biomarkers by mapping of the molecular network of obesity using bioinformatic tools. …and the possible results - future • Initiate R & D project for the development of new obesity drug. • Initiate the development of new diagnostic / prediction of the evolvement of obesity. CECON II Budapest

8. O B E K O N Consortium Work flow • Sample collection (human blood) • Data generation • Clinical • Genomics • Proteomics • Data analysis - Bioinformatics • Sample and Data management – „Biobanking” CECON II Budapest

9. O B E K O N Consortium Collection of human samples • Inclusion criteria • Age >18 yrs • BMI > 30 kg/m2 - obese • BMI <25 kg/m2 - control • Exclusion criteria • Cancer • Psychiatric disease • Medication cause weight gain • Endocrine disease • Chronic kidney disease • Severe lung disease (e.g.asthma bronchiale, COPD III.st.) • Severe heart disease • Liver diseases (cirrhosis hepatis, hepatitis) • GI surgery • Sport at competition level 8 clinical sites >1500 blood sample CECON II Budapest

10. O B E K O N Consortium Data generation - clinical data • Electronic questionnaire • Anamnesis & family anamnesis • Physical condition • Current medication • Life-style • Clinical laboratory data • Socio-demographic data • Numeric output: education, family status, economic situation • Dietary data (3 days diary) • Numeric output: energy, protein, fat, carbohydrates, fatty acids, amino acids, etc…. CECON II Budapest

11. O B E K O N Consortium Data generation - genomics gene polymorphism: SNP SNPstream® Genotyping System Biomek FX Dual Arm System Bioinformatics gene expression profile: mRNA, miRNA, CGH micro-array CECON II Budapest

12. O B E K O N Consortium Data generation - proteomics • Chromatography: ion-exchange, affinity,reverse phase,… • Protein identification: HPLC-MS/MS • Protein glycosylation pattern analysis: HPLC-MS • Monoclonal antibodies production: hybridoma technology • Epitop mapping: phage display • Protein separation: one and two D gel-electrophoresis • Cloning and expression CECON II Budapest

13. O B E K O N Consortium Data Generation summary CECON II Budapest

14. O B E K O N Consortium Data Analysis - Bioinformatics: Preparation Phase • Huge amount of data • Too many variables in some of the data sources • Reduction and modification using • Data evaluation • Statistical analysis • Discretization • Normalization • Stratification CECON II Budapest

15. O B E K O N Consortium Summary of Data Generation /Human CECON II Budapest

16. O B E K O N Consortium Sample and data management: „OBEKON Biobank” • Store samples • DNA, RNA, and plasma and data • clinical, genomics, proteomics • Continuous maintenance • Clinical sample • Data • Organized / regulated operation : SOP - in progress • Regulated accessibility • Member of the National Biobank Network - www.biobank.hu CECON II Budapest

17. O B E K O N Consortium Summary • Large biobank: sample and data • Wide methodological arsenal – genomics, proteomics, and bioinformatics • Strong bases for further collaborative studies / analysis CECON II Budapest

18. O B E K O N Consortium Thank you foryour attention CECON II Budapest

19. O B E K O N Consortium Further presentations: lectures 1.Csaba Szalai: Investigation of the genomic background of obesity using single nucleotide polymorphism analysis in candidate genes 2.István Kurucz: Application of proteomics methods in the identification of biomarkers, suitable for studying obesity and obesity related diseases. 3.Katalin Éder: Obesity related mRNA and miRNA profiling 4.Viola Tamasi: Obesity: genetic update by CGH analysis and its potential clinical implications CECON II Budapest

20. O B E K O N Consortium Further presentations: posters 1., Glycosylation pattern analysis with mass spectrometry Lívia Budai, Ferenc Pollreisz, Olivér Ozohanics, Krisztina Ludányi, László Drahos, Károly Vékey 2., Epitope mapping of mABs recognizing protein markers of obesity: a phage display Flachner Beáta, Dobi Krisztina, Varga János, Lõrincz Zsolt, Cseh Sándor 3.,Pharmacologic therapy of obesity. Study of ligand-binding mode to lysophosphatidic acid receptors by molecular modelling methods Andras Szilagyi, B Balogh, B Jojart, P Matyus CECON II Budapest