The document discusses how French clinical networks can accelerate the discovery of new treatments for cardiovascular and metabolic diseases. It describes the network of Clinical Investigation Centers in France and their resources like biobanks, databases, and cohorts. It provides examples of successes like discoveries of new medications and biomarkers. It discusses opportunities for industry-academic collaboration on multicenter clinical trials through an proposed European Drug Development Hub.

2. Biotargets, drug discovery and therapeutic innovation. How French clinical networks can accelerate the discovery of new treatments in the field of cardiovascular and metabolic diseases? Faiez Zannad, MD, PhD, Nancy

3. 54 modules de CIC dans 23 des 29 CHU Bichat Henri Mondor (94 Créteil) Pitié- Salpêtrière Necker Enfants Malades HEGP Robert Debré Saint-Louis Saint- Antoine HEGP Les 15-20 Cochin Pasteur IGR/Curie (Villejuif/Paris) Ile de la Réunion Lille Rennes Nantes Tours Nancy Strasbourg Lyon Montpellier Marseille Bordeaux Toulouse Grenoble Rouen Saint-Etienne Dijon Brest Clermont-Ferrand Besançon Garches Poitiers Limoges Cayenne Pointe-à-Pitre Fort-de-France The network of Clinical Investigation Centers CARDIOVASCULAR CIC-P (27) CIC-EC (9) CIC-IT (8) CIC-BT (10)

4. The network of Clinical Investigation Centers DIABETES and METABOLIC DISORDERS Lille Rennes Tours Nancy Strasbourg Montpellier Marseille Bordeaux Toulouse Rouen Bichat Saint- Antoine Robert Debré Saint-Pierre Ile de la Réunion Lille Rennes Tours Nancy Strasbourg Montpellier Marseille Bordeaux Toulouse Rouen Bichat Saint- Antoine Robert Debré Saint-Pierre Ile de la Réunion U545 U476 U608 U561 U695 U620 U522 U690 U626 U498 U499 U308 U317 U383 U530 U680 EMI9906 EMI9920 EMI586 U921 UMR5232 UMR6061 IRD EA4188 ESPRI25 UR545

5. Academic resources within a basic research and sophisticated technological environment and with immediate access to patients in University Hospitals Biobanks Databases COHORTS Clinical trials Patient organisations Disease Management programs

6. International funding bodies and consortia, with specific schemes of partnering with Industry

8. Academic Research Organization Network of private practice Physicians - research practicioners GPs Cardiologists National network of technicians and Technical research nurses  Experienced  Working in hospitals , Physician’s office , patient’s home • INSERM label • standardized procedures • professional clinical researchers Coordination of 16 cardiovascular CICs Network of private practice Physicians - research practicioners GPs Cardiologists Network of private practice Physicians - research practicioners GPs Cardiologists Psychiatrists National network of technicians and Technical research nurses  Experienced  Working in hospitals , Physician’s office , patient’s home National network of technicians and Technical research nurses National network of technicians and Technical research nurses  Experienced  Working in hospitals , Physician’s office , patient’s home • INSERM label • standardized procedures • professional clinical researchers Coordination of 16 cardiovascular CICs • INSERM label • standardized procedures • professional clinical researchers Coordination of 16 cardiovascular CICs EDDH

9. An Industry- Academic collaboration with the aim to Assist Investigators to enroll more patients in clinical trials

11. Biomarker Substudy Confirms mechanism of action Circulation 2000 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0 6 12 18 24 30 36 Placebo Spironolactone % Survival 30% reduction in risk P < 0.001 N Engl J Med. 1999;341:709-717 . RALES: Trial based Evidence Circulation.1991;83:1849-1865. Fibrosis No fibrosis Aldosterone blockade prevents myocardial fibrosis

12. 70 75 80 85 90 95 100 1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181 Days Cumulative survival rate (%) Quartile 1 (lowest) Quartile 2 Quartile 3 Quartile 4 (highest) Log-rank p=0.005 Circulation 2006 ACS French Registry; Aldosterone levels at admission are associated with poor outcome. N Engl J Med. 2003 New Trial in Post MI, New drug (Eplerenone) acquired by Pfizer EPHESUS

14. New drugs : Aldosterone inhibitors +++++ 0 ++++ +++ 0 Fourth Non renal ++ + ++ +++ ++++ Third Non steroidal ++ + + ++ +++ Second Eplerenone ++ + + ++ + First Spiro Anti-inflammatory Priamry Aldo Vasculra/renal effect potency Selectivity (sex side effects) Genration

17. Pharmacological postconditioning ( Inhibition of mitochondrial permeability transition) INSERM Unité 886, Lyon Am J Physiol Heart Circ Physiol. 2007

18. From Bench to Bedside Pharmacological postconditioning Cyclosporine A Hôpital Arnaud de Villeneuve, Montpellier, Hospices Civils de Lyon, Service de Cardiologie, Mulhouse NEJM, 2008 PHRC CYCLADE, Post Surgical conditioning

19. Pro-M22: a new biomarker in acute heart failure A Mebazaa, JL Samuel, A Cohen Solal et al U 942 Inserm Validation plasma of dyspneic patients BNP (ELISA) Pro-M22 (MS) Sensitivity 0 1 0 1 1 – Specificity AUC BNP: 0.86; AUC Pro-M22: 0.88 GREAT Network (15 countries) Discovery: Proteomics, human failing heart P1 P2 S2 S1 Pronota, Inserm, AP-HP, Paris 7

20. Innovative biomarkers of post MI remodelling Exp MI U644 (Rouen) « OMICS » U744 (Lille) CIC Network

21. Derivation to Validation: CV CIC Network

22. The Stanislas Cohort Feasibility Visit 1 Visit 2 Visit 3 1993 1995 2000 2004 1006 families, 4295 subjects enrolled in the program 600 demographics and laboratory dataset values Preventive Medicine Center and Clinical Investigation Center, Nancy 117 original publications « Open access » to international scientific community Visit 4 2010

23. One common ancestor born in the XVIth century Aortic stenosis genetics Probst et al, Circulation 2006 Genetic Epidemiology and Biobanks

24. SYNERGISM