My Translational View 6 th International Symposium on Stem Cell Therapy & Cardiovascular Innovations Madrid, April 23-24, 2009

Cardiac Cell Therapy : The Translational Leap Bench To Bedside Models Translation Trial design Concept Regulation Bench

The Gatekeepers

Cell Therapy : The Translational Leap Key Steps of the Process  CMC package  Preclinical testing  Delivery system evaluation

Cell Therapy : The Translational Leap The CMC Package : Chemistry  Traceability of starting and raw materials, including cells if allogeneic  Preferential use of xeno-free products  Clinical upgrade of antibodies used for yielding a cell population enriched for a specific surface antigen

Cell Therapy : The Translational Leap The CMC Package : Manufacturing  Cell processing and scale-up in GMP- approved facilities  Detailed description of storage/shipping/labeling conditions  Implementation of quality-approved processes for ensuring product consistency until release

Cell Therapy : The Translational Leap The CMC Package : Controls  Sterility  Oncogenicity (whenever relevant)  Safety/quality of the selection system  Detailed description of release criteria : Phenotypic characterization Stability Purity Potency Viability

Cell Therapy : The Translational Leap Key Steps of the Process  CMC package  Preclinical testing  Delivery system evaluation

Cell Therapy : The Translational Leap Preclinical Testing  In vitro data (i.e., immunophenotype, functional assays)  Small animal models (comparative screening of cell types, cell survival and differentiation, potential safety issues)  Large animal models

Nature Methods 2009;6: *P = 0.016

Cell Therapy : The Translational Leap Why Large Animal Models Are Mandatory  They yield functional data which are more reliable than those generated in rodents  They allow a closer simulation of clinical settings  They provide the only possiblity of testing clinically relevant cell delivery route and systems

Klocke et al. Cardiovasc Res 2007;74: Limitations of Small Animal Models Comparative duration of action potentials and resting EKGs between rodent and human

The G-CSF Saga Harada et al. Nature Medicine 2005;11: G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model Norol et al. Blood 2003;102: Abdel-Latif et al. Am Heart J 2008;156: Meta-analysis of RCTs

Cell Therapy : The Translational Leap Why Large Animal Models Are Mandatory  They yield functional data which are more reliable than those generated in rodents  They allow a closer simulation of clinical settings  They provide the only possiblity of testing clinically relevant cell delivery routes and systems

Markkanen et al. Cardiovasc Res 2005;65: Cell Therapy : The Translational Leap Dosing Scalability Distribution

Cell Therapy : The Translational Leap Why Large Animal Models Are Mandatory  They yield functional data which are more reliable than those generated in rodents  They allow a closer simulation of clinical settings  They provide the only possiblity of testing clinically relevant cell delivery routes and systems

Eur J Cardio-thorac Surg 2003;24:393-8.

Effect of Delivery Technique on MSC Engraftment Freyman et al. Eur Heart J 2006;27: Pig model of MI; Tx of iridium-loaded male MSCs (50 million) ; Ex vivo measurement of the iridium nanoparticle concentration in the infarct

Hofmann et al. Circulation 2005;111: Myocardial Homing of Unselected Bone Marrow Cells Following Intravenous/Intracoronary Transfer

Cell Therapy : The Translational Leap Key Steps of the Process  CMC package  Preclinical testing  Delivery system evaluation

Cell Therapy : The Translational Leap Delivery System Evaluation  In vitro testing of mechanical performance (i.e., burst pressure, flow rate, tensile/bending and torsional strength)  Delivery system/patient biocompatibility  Delivery system/product biocompatibility (i.e., cell viability, activity, adhesion to the device)

Bekarta et al. Acad Emerg Med 2003;10: Animal studies that do not utilize randomization and blinding are 5 times more likely to be outcome-positive than studies that use either or both of these methods Impact of Randomization and Blinding on the Outcome of Animal Studies

Wylan et al. Nature Biotechnology 2005;23: Cardiac Cell Therapy ; The « Reverse » Translational Leap

Cell Therapy : The Translational Leap Keys to a Successful Bench to Bedside Process ■ Upfront interactions with the regulatory authorities and regular update of the guidance documents to incorporate new knowledge ■ Tight cooperation between the clinical and basic scientist project managers to try achieving a reasonable trade-off between preclinical data, regulatory constraints and practicality of clinical implementation ■ Acceptance that « zero risk does not exist »

Cell Therapy : The Translational Leap Keys to a Successful Bench to Bedside Process ■ Upfront interactions with the regulatory authorities and regular update of the guidance documents to incorporate new knowledge ■ Tight cooperation between the clinical and basic scientist project managers to try achieving a reasonable trade-off between preclinical data, regulatory constraints and practicality of clinical implementation ■ Acceptance that « zero risk does not exist »

Cell Therapy : The Translational Leap Keys to a Successful Bench to Bedside Process ■ Upfront interactions with the regulatory authorities and regular update of the guidance documents to incorporate new knowledge ■ Tight cooperation between the clinical and basic scientist project managers to try achieving a reasonable trade-off between preclinical data, regulatory constraints and practicality of clinical implementation ■ Acceptance that « zero risk does not exist »