Terapie Cellulari Immunomodulazione e Medicina Rigenerativa per la

Terapie Cellulari, Immunomodulazione e Medicina Rigenerativa per la Cura del Diabete Camillo Ricordi, MD, FNAI Director, Diabetes Research Institute and Cell Transplant Center University of Miami Chairperson, NIH CIT SC Fellow, National Academy of Inventors ricordi@miami. edu

DRI FEDERATION UMEA EDMONTON UCSF OXFORD HACKENSACK STANFORD MANAGUA GENEVE VALENCIA STOCKHOLM MILAN, BOLOGNA, TIBLISI ROME, PALERMO SHANGHAIFOUZO SEOUL MIAMI TEL AVIV SAN PAULO BUENOS AIRES KYOTO

1988 – 2018 30 Years of the Ricordi Chamber (Diabetes, 1988)

1991

TRANSPLANTATION OF INSULIN PRODUCING CELLS FOR TREATMENT OF DIABETES

• • • Preclinical data Manufacturing information Detailed Clinical protocols Investigator information Informed consents Assurances: IRB, IND 9336 Biologic License Application Diabetes Care 2016 Jul; 39(7): 1230 -1240

Manufacture of a Complex Cellular Product • Eight manufacturing centers jointly developed and implemented a harmonized process for the manufacture of an allogeneic purified human pancreatic islet product. • Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, islet product specifications, certificate of analysis, and test methods. • The process was compliant with c. GMP and c. GTP. • No adverse events attributable to the product and no cases of primary nonfunction were observed in 48 patients participating in the CIT-07 Phase 3 trial. Diabetes 2016 Nov; 65(11): 3418 -3428

Primary Endpoint • Proportion of subjects with Hb. A 1 c < 7. 0% at day 365 AND free of severe hypoglycemic events from Day 28 to Day 365 inclusive following the first islet transplant • Multiple secondary endpoints for safety and efficacy Diabetes Care 2016; 39: 1230 -1240

Primary Endpoint Diabetes Care 2016; 39: 1230 -1240

Hb. A 1 c [%] Diabetes Care 2016; 39: 1230 -1240

% of Patients with SHE Diabetes Care 2016; 39: 1230 -1240

Islet Allograft Survival L ONS A I NT ATI E ERV D I NF OBS CO HED LIS B U P UN

Proposed treatment algorithm for patients with T 1 D and problematic hypoglycemia. MDI: Multiple Daily Injections SMBG: Self Monitoring Blood Glucose CSII: Continuous SC Insulin Infusion SAP: Sensor SAugmented Pump LGS: Low Glucose Suspend

Outcomes for Adults with Type 1 Diabetes Referred with Severe Hypoglycaemia and/or Referred for Islet Transplantation to a Specialist Hypoglycaemia Service M. L. Byrne, D. Hopkins, W. Littlejohn, R. Beckford, P. Srinivasan, N. Heaton, S. A. Amiel, P. Choudhary King’s College London 47. 2% of patients presenting with problematic hypoglycaemia resolved with optimal medical therapy, with a further 25% achieving clinically relevant improvement, however 27. 8% required transplantation despite access to all therapies. Horm Metab Res 2015; 47 (01): 9 -15

www. thelancet. com/diabetes-endocrinology Published online May 15, 2018 http: //dx. doi. org/10. 1016/S 2213 -8587(18)30078 -0 QOL

Hb. A 1 c C-Peptide % PTS with Hb. A 1 c <7 Insulin Requirements

• Data on 16, 061 patients updated between 2013 and 2014. • Overall average Hb. A 1 c was 8. 4 ± 1. 6%, in patients 30 to 65 yrs of age it was between 7. 5 -7. 8%. • ADA Hb. A 1 c goals of <7. 0% were met by 14% of 18 -25 year-olds and by 30% in older adults. • About 60% of patients used insulin pumps; 7% used CGM.

MSCs in the DRI Bio. HUB Strategy BIOLOGIC CURE OPTIMIZATION OF THE TRANSPLANT SITE TOLERANCE INDUCTION REVERSAL OF AUTOIMMUNITY IMMUNOISOLATION SOURCE OF INSULIN PRODUCING CELLS

Bioengineering of an Intraabdominal Endocrine Pancreas

Version 2. 0 In vivo studies in Non. Human Primates, models of diabetes, are ongoing Thrombin Plasma + MSC Islets Thrombin Plasma + MSC Omental surface