Cord Blood for Cellular Therapy: A Snapshot of this Evolving Market Landscape

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1 GENReports: Market & Tech Analysis Cord Blood for Cellular Therapy: A Snapshot of this Evolving Market Landscape > Enal Razvi, Ph.D. Biotechnology Analyst, Managing Director SELECTBIO US enal@selectbio.us

2 Topic Introduction and Scope The focus of this GEN Market & Tech Analysis Report is to characterize the cord blood marketplace as it relates to cellular therapy based on the following classes of data which we have been collecting as part of our industry analysis of this field: Growth of Cord Blood Units in the Public Banks Quantitative Utilization Trends of Cord Blood Evolution of this Space Current Status of Cord Blood Banking Takentogether,thesedataframethecurrentquantitativemetrics and provide a snapshot of the cord blood space

3 Growth of Stored Cord Blood Units in the Public Banks Worldwide 700, ,000 Stored Units as of September ,000 Number of Stored Cord Blood Units 500, , , , ,000 Source: Bone Marrow Donors Worldwide.

4 The Changing Profile of Hematopoietic Stem Cell Transplantation 1998 PBSCs Bone Marrow 2012 Cord Blood Source: Dr. Brian Freed, Professor of Medicine and Immunology University of Colorado Executive Director, ClinImmune Labs

5 Different Types/Number of Hematological Progenitors Needed for Different Types of Hematological Malignancies For Pediatric Populations with Sickle Cell Anemia Using Cord Blood Pre cryopreservation total nucleated cell dose of per kg body weight (range: x 10 7 cells per kg body weight) 1 10% of the cells infused are progenitors Post thaw infused CD34 + cell dose of per kg body weight (range: ) 10% of the cells are progenitors For Adult Patients with Chronic Myeloid Leukemia (CML) Using Cord Blood The median number of nucleated cells infused is 1.7 x 10 7 per kg body weight (range: 1.2 to 4.9 x 10 7 cells per kg body weight) 1 10% of cells are progenitors Different Cell Numbers and Routes of Delivery Being Utilized Across the Landscape For Cellular Therapy using Cord Blood as the Therapeutic Agent

6 Banked Cord Blood TNC Evolution What Does the Transplant Physician Want? An average TNC of 1.8 x 10 9 What Does the Typical Transplant Physician Find Today? Source: Dr. Brian Freed, Professor of Medicine GENReports: and Immunology Market & Tech Analysis, Produced by Enal Razvi, Ph.D University of Colorado Executive Director, ClinImmune Labs HLA-A, B and DRB1 Match

7 Annual Utilization Rate of Cord Blood in the US vs. Worldwide 1.2% of Inventory Utilized in the US Currently % increase in cord blood inventory 12% increase in cord blood transplants Growth Opportunity in Cord Blood Turnover Source: NMDP Worldwide % of Inventory Utilized Source: Dr. Brian Freed, Professor of Medicine and Immunology University of Colorado Executive Director, ClinImmune Labs

8 Beyond Cell Dose: Selection of the Optimal Cord Blood Unit for Transplant Cell dose [the TNC count] is an important factor for ensuring engraftment success The nucleated cell dose > 3.7 x 10 7 per Kg of body weight is the most important factor for neutrophil engraftment The average TNC of a banked unit of 1.2 x 10 9 is not sufficient for an adult transplant Size of US adults is 10 Kg higher than that of the Europeans, and 15 Kg higher than that of the Asians therefore higher TNCs required in the US There is a higher incidence of GVHD and Prolonged Platelet Recovery with HLA class I and II mismatches HLA match is most important when cell dose is low Survival is best with 6/6 matched cord blood unit in pediatric recipients Generally: 1 mismatch with x 10 7 nucleated cells/kg body weight = 2 mismatches with > 5.0 x 10 7 nucleated cells/kg body weight Low CD34 cell viability Predictor for Poor Engraftment Infused [post thaw] CFUs correlate best with neutrophil and platelet engraftment Pediatric Cell Dose: > 3 x 10 7 NCs/kg body weight, >5 x 10 7 NCs/kg for non malignant disease Adult Cell Dose: 2 cords mixed together > 3 x 10 7 NCs/kg body weight IntraBone Cord Blood Transplant Cell Dose > 1.5 x 10 7 NCs/kg body weight [need 5/6 HLA match rather than a 4/6 HLA match]

9 Cord blood is licensed as a biological drug, not a blood product Cord blood banking requires a significant investment in cgmp facilities, protocols and validations Cord blood banking is labor intensive Each unit is considered a batch Cord blood banking requires significant informatics support Cord blood banking requires highly trained regulatory oversight 90% of the banked cord blood is never used Cord blood resides in a freezer in a cord blood bank, therefore, it can be shipped out to a recipient immediately Very distinct from bone marrow or PBSC registries wherein the Donor needs to be located and convinced to donate, which takes time and is inherently unpredictable and fraught with risks and uncertainties Even though, we report the hundreds of thousands of units of cord blood that are banked in public and private banks, only ~ 10% of this banked cord blood is usable due to the fact that the TNC count of much of this cord blood is low and unsuitable for transplantation The cord blood inventory in a cord blood bank has an approximately 10 year usable lifespan FDA Requirement of TNCs per unit of cord blood = 0.5 x 10 9 Generally, a transplant physician needs 1.8 x 10 9 TNCs per transplantation As of October 2011, cord blood banks in the US need to be FDA licensed Cord blood in the US is available under an IND through the NMDP ~5,000 cord blood transplants performed per year in the US These insights are based on personal communications GENReports: Market with & Tech industry Analysis, Produced participants by Enal especially Razvi, Ph.D. Dr Brian Freed from UC Denver US FDA-Licensed Cord Blood Characteristics

10 Comparison of the Main Features of Cord Blood Transplants vis-à-vis Bone Marrow Transplants Characteristic Cord Blood Transplantation Bone Marrow/Peripheral Blood Transplantation Number of Available Donors Worldwide (as of September 2013) in Public Registries 587,000 Units Stored and Available 21.7 Million Donors in the Registries Major Limiting Factor Fixed Unit Cell Count HLA Match and Donor Attrition Minimum Total Number of Nucleated Cells (TNCs) Needed for Transplantation ~2.5 x 10 7 per Kg of body weight [Generally 1.8 x 10 9 total TNCs needed] ~2.0 x 10 8 per Kg of body weight Second Graft Impossible Possible Median Speed of Donor Availability ~1 day ~3-4 months Donor Morbidity None Fatigue/Pain EBV/CMV Transmission to Recipient Risk of Transmission of Congenital Disease Negligible Possible Possible None Standard HLA Match Requirements MinimumGENReports: 4 out of 6Market & Tech Analysis, Mostly Produced 8 of by 8Enal Razvi, Ph.D. 2013

11 Key Takeaways: Quantitative Utilization Trends of Cord Blood and the Associated Challenge in this Space Cost per Unit from Public Banks for Transplantation: $35,000 per unit [US/EU] Generally need 1 2 units per transplant [2 cords for transplant into adult patients] Annual Turnover (Utilization) of cord blood units from public banks: 1 3% of units inventoried These are some of the challenge in this space Large numbers of stored cord blood units have sub optimal total nucleated cell (TNC) count and therefore are unsuitable for transplantation/cellular therapy The turnover of stored cord blood is exceedingly low and this is a driver for the high costs of the stored cord blood units New therapeutic applications will drive forward the utilization of cord blood