Cell-based therapies for cardiac repair NON-CLINICAL ASPECTS - PowerPoint PPT Presentation

Cell-based therapies for cardiac repair NON-CLINICAL ASPECTS Presented by: Beuneu Claire CAT-DGTI-GSCN Workshop, 11 September 2014, Dresden An agency of the European Union

Drug development Pre-marketing development Post-marketing Basic research Marketing Autorisation Non-clinical studies Application Clinical trials - proof of concept - safety Clinical trial applications 1 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

EMA guidance – cell based products 2 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Cell based products: main risks  infections  loss of function  immunogenicity  tumourigenicity  ectopic engraftment 3 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Non-clinical questions 1- Proof of concept and dose-finding studies 2- Biodistribution/migration and persistence of the cells in the body 3- Safety studies : general organ toxicity, tumourigenicity… Duration of the studies Appropriate model small versus large Appropriate level of testing species 4 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Non-clinical issues Intended mode Product of action Route of 3R administration ? Proof of concept Safety Dose Biodistribution/Persistence 5 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Non-clinical questions 6 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Large animal models : pros and cons Pro -Proof of concept Route of administration -Safety, feasibility Allogeneic versus autologous Use of specific medical devices … -Training Con -Healthy young animals -Laborious and expensive 7 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Method of cell delivery Porcine model of ischaemic cardiomyopathy van der Spoel, et al, JCMM 2012; 91(4): 649-658. 8 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Non-clinical models: meta-analysis 9 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Non-clinical models: meta-analysis 304 publications (pig,dog,sheep) Review process:small species, reviews, comments, functionnal endpoints, quality of reporting, etc 52 studies included 34 RCT 18 cohorts 10 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Results -Results RCT = comparable to clinical meta-analysis -No increased mortality - Effect fading away after 8 weeks - Type of cell - Timing of treatment 11 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Cell type - 82 controlled preclinical trials (1415 animals) - unmanipulated stem cells - large animal models Circ Res. 2014 Sep 3. [Epub ahead of print] Similar Effect of Autologous and Allogeneic Cell Therapy for Ischemic Heart Disease: Systematic Review and Meta-Analysis of Large Animal Studies. Jansen Of Lorkeers SJ 1 , Eding JE 1 , Vesterinen HM 2 , van der Spoel TI 1 , Sena ES 2 , Duckers HJ 1 , Doevendans PA 1 , Macleod MR 2 , Chamuleau SA 3 . 12 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014

Conclusions - Large species are relevant for translational research - Interests and limitations of metanalysis: • Publication bias • Incomplete data set • Variety of protocols  CAMARADES www.camarades.info 3R  www.preclinicaltrials.eu 13 CAT-DGTI-GSCN Workshop, Dresden, 11 September 2014