Camillo Ricordi , MD, FNAI Director, Diabetes Research Institute and Cell Transplant Center

1. TerapieCellulari, Immunomodulazione e MedicinaRigenerativa 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

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

4. 1988 – 2018 30 Years of the Ricordi Chamber (Diabetes, 1988)

6. 1991 

7. TRANSPLANTATION OF INSULIN PRODUCING CELLS FOR TREATMENT OF DIABETES

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

9. 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 cGMP and cGTP. • 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

10. Primary Endpoint • Proportion of subjects with HbA1c < 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

11. Primary Endpoint Diabetes Care 2016; 39:1230-1240

12. HbA1c [%] Diabetes Care 2016; 39:1230-1240

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

14. Islet Allograft Survival CONFIDENTIAL UNPUBLISHED OBSERVATIONS

15. Proposed treatment algorithm for patients with T1D and problematic hypoglycemia. MDI: Multiple Daily Injections SMBG: Self Monitoring Blood Glucose CSII: Continuous SC Insulin Infusion SAP: Sensor S\Augmented Pump LGS: Low Glucose Suspend

16. 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 HormMetab Res 2015; 47 (01): 9-15 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.

17. www.thelancet.com/diabetes-endocrinology Published online May 15, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30078-0 QOL

18. HbA1c % PTS with HbA1c <7 C-Peptide Insulin Requirements

19. Data on 16,061 patients updated between 2013 and 2014. • Overall average HbA1c was 8.4 ± 1.6%,in patients 30 to 65 yrs of age it was between 7.5-7.8%. • ADA HbA1c 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.

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

24. Bioengineering of an Intraabdominal Endocrine Pancreas

25. Version 2.0 In vivo studies in NonHuman Primates, models of diabetes, are ongoing Plasma + MSC Islets Thrombin Thrombin Omental surface Plasma + MSC