New Organizational Models for Optimal Cell Processing and Application

1. New Organizational Models for Optimal Cell Processing and Application Robert D. Simari Chair, Cardiovascular Research Professor of Medicine Madrid 2009

2. NHLBI Working Group onTranslation of Cardiovascular Cell Based Therapies 2005 …the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites)…

3. What is an NIH Clinical Trial Research Network ? • Provides opportunities for collaborative Phase 1-2 studies. • Success in pulmonary medicine. • Extends single center results (NIH or industry based) • Builds infrastucture to do so.

5. Clinical Center Selection • Expertise in cell therapy • Preclinical studies • Early clinical trials • Ability to recruit subjects in studies of acute and chronic LV dysfunction. • Willingness to prioritize network studies.

6. NHLBI Cardiovascular Cell Therapy Research Network Organization NHLBI Sonia Skarlatos Robert Simari Network Chair PRC Steering Committee DSMB Data Coordinating Center TSPH Lem Moye’ Skills Development Core Skills Development Core Tex HI Willerson U Fla Pepine Cleveland Clinic Ellis Vanderbilt Zhao U Mn Henry Cell processing Cell processing Cell processing Cell processing Cell processing 7 Clinical Satellites

7. CCTRN Network 4, 8 6 1, 10 5, 13 Core Labs 8 - Bio-Repository Minneapolis, Minnesota 9 - Bio-Repository Gainesville, Florida 10 – Echo Core Lab Cleveland, Ohio 11 – MRI Core Lab Gainesville, Florida 12 – MV02 Core Lab Gainesville, Florida 13 - SPECT Core Lab Nashville, Tennessee 2, 7, 14 3, 9, 11, 12 Clinical Centers 1 - Cleveland Clinic Cleveland, Ohio 2 - Texas Heart Institute 3 - University of Florida at Gainesville Gainesville, Florida 4 - Minneapolis Heart Institute Minneapolis, Minnesota 5 - Vanderbilt University Medical Center Nashville, Tennessee Administration 6 – Study Sponsor, NHLBI Bethesda, Maryland 7 - Data Coordinating Center Houston, Texas 14 – Cell Processing Quality Control Lab Houston, Texas

8. January 2007 • Met to select clinical trials to pursue • Criteria • ability to obtain an IND for trial • Likely performed/completed early phase 1 • Without need for more preclinical studies • Demonstrate need for network resources/sites

9. January 2007 • Acute MI • MHI pilot study (Traverse/Henry) • Broad European experience • Chronic LV dysfunction • Based on THI experience (Perin/Willerson)

10. Cardiovascular Cell Therapy Research Network (CCTRN) Regulatory hurdles • CCTRN • Protocol development committee • Steering committee • NHLBI • Protocol Review Committee (Dzau) • DSMB (March) • FDA • IND • Sites • IRB • IBC

11. Cardiovascular Cell Therapy Research Network (CCTRN) • BMCs in Acute anterior MI • TIME • Timing of delivery (d3 vs d7) • Fixed dose, isolation, delivery • Late TIME • Timing 2-3 weeks • BMCs in chronic ischemic LV dysfunction • Biorepository

12. Cardiovascular Cell Therapy Research Network (CCTRN) Challenges • Who holds the IND (regulatory responsibility)? New or amended? • Cell preparation-central vs local? And how? • Very high, high or moderate risk population? • Biorepository and cell evaluation-central vs local? • ? Placebo and if so blinding? • Global, regional or clinical endpoints?

13. Acute MI studies • 2000+ pt studied worldwide • Safety parameters well established • Phase 1 human trial ongoing at MHI (Traverse)-now completed • Basis for IND • Many important unanswered questions

14. TIME and Late TIME Study Rationale • Changing myocardial milieu following AMI may impact on cell delivery retention. • Prior studies had not randomized to different times. • Cell dose varied greatly within and between studies.

15. TIME dependence of delivery Schachinger Circ 2008

16. PILOT TRIAL - Administration of BMCs Following Acute Myocardial Infarction at Minneapolis Heart Institute • IND: September 2005 • 40 patients with acute anterior MI’s who received PTCA / Stenting of LAD ( 30% < EF <50% ). • Randomized ( 3:1 Active Treatment vs Placebo). • 100 million BMMC (intracoronary infusion). • Serial Cardiac MRI at Baseline, 3, 6, 12 months. • Potential for cross-over at 6 months

17. PILOT TRIAL - Administration of BMCs Following Acute Myocardial Infarction at Minneapolis Heart Institute • 40 Patients (31M 9 F), 8 NIDDM, Age= 54yrs • 7 IABP, 2 hypothermia • 37/40 received DES • Transplant Day =5±2 days • Average Ischemic Time = 6:30 hrs • Peak CK = 3308, CKMB = 244 • Baseline LVEF (ECHO 1 day p MI) = 37±12% • Baseline LVEF (cMRI, 4 days p MI) = 49±9% • All Patients had severe MVO on cMRI. • CD34+ count was 2%, Viability > 96% Results at AHA ‘09

18. TIME Study • Large first Ant MI (EF<45%) • Randomized • cells (2) vs placebo (1) • 3 days vs 7 days • 150 million BMMNCs • Stop flow delivery • 120 pts

19. Late TIME Study • Large first Ant MI (EF<45%) • Randomized • cells (2) vs placebo (1) • 14-21 days • 150 million BMMNCs • Stop flow delivery • 86 pts

20. TIME and Late TIME Study Endpoints • Regional and global LV function (cMR) • Core evaluation • Clinical endpoints

21. Sepax System for BMMNC Plasma (yellow) MNC Ficoll (blue) RBCs (red) G Force G Force Manual G Force Sepax

22. Blinding procedure 50ul 100ul 250ul 500ul Autologous blood as blinding agent

23. Nonrandomized, open label 14 tx, 7 control BMNNCs (2M cells x 15 injection sites) via NOGA Safe At 4 months Increased EF Decreased ESV

24. FOCUS-HF • Two center US study (THI, MHI) • Perin, Willerson, Henry • Randomized delivery of 30M BMMNCs using NOGA • To be presented at AHA 2009 • Basis for new IND

25. FOCUS rationale-endpoints • Severe ischemic LV dysfunction • Increased dose (100M cells) in multi-center study. • Placebo controlled • Combined Endpoints = SPECT, Echo (LVV), MVO2 (all core assessed) • 86 pts

26. Cardiovascular Cell Therapy Research Network (CCTRN) • Cells are processed locally using standardized devices. • Release criteria are local. • Blood and BM is shipped to central biorepository • Univ Minnesota (Taylor) • Univ Florida (Cogle)

27. CCTRN Biorepository The specific aim of the Biorepository is to examine the relationship between cell therapy clinical outcomes and cell characteristics such as phenotype and function. As a core laboratory, the Biorepository will: • provide storage of critical biomaterials from patients enrolled in CCTRN trials; (BM, PB cells, serum) • provide long-term integrity (up to 10 years) of these specimens • provide phenotypic and functional analyses of BM and PB cells on freshly available samples. Central, rigorous, robust and available

28. Confidential and Privileged CCTRN Biorepository Investigating the active agent Defining mechanisms of cell based repair “Biorepository” Bone marrow harvested Blood drawn for PC and cytokine measurements CCTRN Biorepository University of Minnesota When a patient enters a clinical trial Web Interface Sends an e-mail to Coordinator and Technician to expect shipped samples Shipments Date Entered into Web Interface Arrival Logged in Web Interface Samples are Prepared FACS Stem cells Inflammation Effect Results Entered into Web Interface Cytokines Real time status and tracking Report generation Blinded data analysis Easy data sharing Regulatory compliance Reduced work load Functional Measurements

29. Functional assays iNO CFU-Endo MSC Migration Viability Cell Count Rheology Endo SDF-1 ECFC PB BM Courtesy of Cogle, UFla

30. CCTRN Biorepository Product phenotype and function Disease PB phenotype and function Product delivery Patient outcome

31. Cardiovascular Cell Therapy Research Network (CCTRN) Ongoing Challenges • Declining severity of acute MI in the U.S. • Focus on the very sick (yet first MI) has generated recruitment challenges. • Rapidly changing scientific landscape of stem cells. We should complete all 3 studies in late 2010/early 2011

32. NHLBI Working Group onTranslation of Cardiovascular Cell Based Therapies 2005 …the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites) with an integrated preclinical investigative component. …the primary recommendation of the Working Group is that the NHLBI establish a cardiovascular cell therapy research network consisting of a clinical research network component (5-7 primary sites)

33. NHLBI Progenitor Cell Biology Consortium NHLBI funded- preclinical network to be funded in 2009

34. CCTRN Key Personnel Clinical Centers Cleveland Clinic Stephen Ellis – PI, Marc Penn – Co-PI Linda Clarke – Study Coordinator Texas Heart InstituteJames Willerson – PI, Emerson Perin – Co-PI Lynette Westbrook, Casey Kappenman, Fred Baimbridge, James Chen – Study Coordinators University of Florida Carl Pepine – PI, Barry Byrne – Co-PI Eileen Handberg, Tempa Curry – Study Coordinators Minneapolis Heart Institute Tim Henry – PI, D Taylor, Jay Traverse – Co-PI Rachel Olson, Beth Jorgenson – Study Coordinators Vanderbilt University David Zhao – PI, Antonis Hatzopoulos – Co-PI Judy Francescon, Sherry Bowman – Study Coordinators Administration Project Office, NHLBI Sonia Skarlatos – Project Officer David Gordon – Deputy Project Officer Wendy Taddei-Peters – Clinical Trials Specialist Data Coordinating Center Lem Moyé – Coordinating Center PI Linda Piller – Safety Officer Shelly Sayre, Rachel Vojvodic, Judy Bettencourt – Project Managers Cell Processing Quality Control Lab Adrian Gee – Director Sara Richman – Senior QA Analyst Core Labs Bio-Repository Doris Taylor – Director Bio-Repository Chris Cogle – Director Echo Core Lab James Thomas – Director MRI Core Lab John Forder – Director MV02 Core Lab Daniel Martin – Director SPECT Core Lab Marvin Kronenberg – Director