Safety Review. 2 Sources of Safety Information BLA 125397 (Applicant’s data) –1993-2007: Voluntary questionnaires –2008-present: SCTOD FDA Dockets Literature.

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Safety Review

2 Sources of Safety Information BLA (Applicant’s data) – : Voluntary questionnaires –2008-present: SCTOD FDA Dockets Literature Search The COBLT Study –Prospective clinical study of safety and efficacy of unrelated donor cord blood transplantation –Sponsored by the NHLBI

3 Review Strategy Characterize the safety profile of the applicant’s product –Units manufactured using the method intended for licensure –TNC dose >2.5 x 10 7 /kg Summarize the safety information from the additional public sources Emphasis on product-related outcomes –Infusion reactions, delayed neutrophil recovery, graft failure, early mortality

4 Agenda Describe the datasets used Summarize safety outcomes Summarize infusion reactions

5 Datasets Used In FDA Analyses BLA (Applicant) –Datafile for 3619 patients transplanted with 3946 cord blood units –Limited to 409 patients transplanted 2007 to 2011 with 432 cord blood units manufactured using the method intended for licensure Pooled Dataset (Public Information) –NYBC: 550 patients transplanted –COBLT: 356 patients transplanted –NMDP: 577 patients transplanted

6 Patient Demographics Applicant’s DatasetPooled Dataset Number Median Age (Range)19 yrs (2 mos – 73 yrs)7 yrs (0-66 yrs) Age >17 yrs216/409 (52.8%)275/1483 (18.5%) Male226/409 (55.3%)537/933 (57.6%) Caucasian89/198 (44.9%)571/851 (67.1%) Diagnoses: Hematologic malignancies Hurler Syndromes Krabbe Disease X-linked Adrenoleukodystrophy Primary immunodeficiency diseases Bone marrow failure Beta thalassemia Other or Unknown 324 (79.2%) 4 (1.0%) 0 (0.0%) 5 (1.2%) 17 (4.2%) 31 (7.6%) 4 (1.0%) 24 (5.8%) 1103 (74.4%) 55 (3.7%) 4 (0.3%) 18 (1.2%) 97 (6.5%) 110 (7.4%) 8 (0.5%) 88 (5.9%)

7 Transplant Characteristics Applicant’s DatasetPooled Dataset Number Year of Transplantation (0.0%) 409 (100%) 624 (42.1%) 859 (57.9%) 0 (0.0%) Lowest HLA Match Level < Unknown 0 (0.0%) 194 (41.3%) 186 (49.5%) 29 (9.3%) 0 (0.0%) 53 (3.6%) 679 (45.8%) 575 (38.8%) 165 (11.1%) 11 (0.7%) Median TNC Dose (x 10 7 /kg) Adult (Range) Children 3.0 ( ) 6.8 ( ) 2.3 ( ) 6.2 ( ) TNC Dose >2.5 x 10 7 /kg317 (77.5%)1212 (81.7%)

8 Agenda Describe the datasets used Summarize safety outcomes Summarize infusion reactions

9 Hematopoietic Recovery TNC Dose >2.5 x 10 7 /kg Applicant’s Dataset Pooled Dataset Literature ( Any TNC Dose) Primary graft failure (%, 95% CI)*14% (9-21%)17% (15-19%)10-20% Cumulative Incidence of ANC>500 by Day 42 (%, 95% CI) 83% (76-88%)76% (74-79%) Median time to ANC>50020 days26 days22-27 days * Includes death, 2nd transplantation or autologous recovery for patients surviving at least 14 days without neutrophil recovery For all patients in the pooled dataset: Primary graft failure was associated with TNC dose, degree of HLA mismatch and diagnosis Time to ANC>500 was associated with TNC dose and degree of HLA mismatch

10 Hematopoietic Recovery by Diagnosis (Pooled Dataset -TNC Dose >2.5 x 10 7 /kg) Diagnosis Median TNC/kg (Range) Median Time to ANC>500 Primary Graft Failure (95% CI) Primary immunodeficiency diseases (n=94) 10.6 ( )19 days13% (7-22%) Krabbe Disease (n=4)12.8 ( )21 days50% (7-93%) Hurler Syndromes (n=44)10.3 ( )22 days11% (4-22%) Hematologic malignancies (n=862) 5.4 ( )26 days16% (14-19%) X-linked (n=13) Adrenoleukodystrophy 5.9 ( )26 days8% (0-39%) Bone marrow failure (n=91)5.5 ( )30 days31% (22-42%) Beta thalassemia (n=8)6.4 ( )31 days29% (4-71%)

11 Day 100 Mortality TNC Dose >2.5 x 10 7 /kg Applicant’s Dataset (n=156) Pooled Dataset (n=1212) Primary Disease2.6%3.4% Total Nonrelapse Deaths22.4%22.6% Graft Failure -3.2%2.7% Infection -5.8%8.0% GVHD -1.9%3.1% Other or Unknown -11.5%8.8% For all patients in the pooled dataset: Day-100 Mortality was associated with TNC dose, degree of HLA mismatch, diagnosis and gender.

12 Additional Outcomes of Interest Applicant’s Dataset Pooled DatasetLiterature Rare Product-Related Events Donor Cell Leukemia0/3619-9/10,000 Transmission of Infection0/3619-1/10,000 Transmission of Genetic Disorder1/ Other Outcomes Mediated By The Product Grades 2-4 GVHD*59/137 (43.1%)459/1100 (41.4%)14-52% Grades 3-4 GVHD*17/137 (12.4%)215/1110 (19.4%)- Engraftment Syndrome-15% % ∙ GVHD in patients who received a TNC dose >2.5 x 107/kg. For all other outcomes, patients receiving any TNC dose are considered. +From The COBLT Study dataset only.

13 Safety Outcomes Overview Applicant’s Data (TNC Dose >2.5 x 10 7 /kg) –Primary graft failure in 14% –Median time to neutrophil recovery is 20 days –Day-100 mortality is 25% –Mortality due to graft failure is 3.9% –Transmission of a genetic disorder is rare Additional Information –Donor cell leukemia and transmission of infections are additional rare events. –Engraftment syndrome is an additional common event.

14 Agenda Describe the datasets used Summarize safety outcomes Summarize infusion reactions

15 Infusion Reaction Characterization Applicant’s Data (n=244 infusions) –Data questionnaire: Requested information on any SAE or any event that required intervention –SCTOD: Requested information on 17 specific adverse events and SAEs –No grading The COBLT Study (n=523 infusions) –Prospectively requested information on 13 specific adverse events with grading by NCI CTC criteria –Any SAE also graded and reported.

16 Infusion Reactions Applicant’s Dataset TNC Dose >2.5 x 10 7 /kg (n=153) Any TNC dose Not graded (n=244) Any reaction18.3%16.8% Nausea4.6%4.1% Vomiting3.9%3.7% Hemoglobinuria0.0%0.4% Allergy0.0% Fever0.0% Chills0.0%

17 Infusion Reactions Applicant’s DatasetThe COBLT Study TNC Dose >2.5 x 10 7 /kg (n=153) Any TNC dose Not graded (n=244) Any TNC dose All Grades (n=523) Any TNC dose Grades 3-4 (n=523) Any reaction18.3%16.8%65.4%26.6% Nausea4.6%4.1%15.0%6.1% Vomiting3.9%3.7%15.7%0.2% Hemoglobinuria0.0%0.4%1.9% Allergy0.0% 3.1%0.2% Fever0.0% 5.5%0.2% Chills0.0% 1.3%0.0%

18 Infusion Reactions - Cardiopulmonary Applicant’s DatasetThe COBLT Study TNC Dose >2.5 x 10 7 /kg (n=153) Any TNC dose Not graded (n=244) Any TNC dose All Grades (n=523) Any TNC dose Grades 3-4 (n=523) Hypertension14.4%13.1%46.5%19.9% Hypoxemia2.6%1.6%3.1%2.8% Dyspnea1.3%0.8%1.9%1.1% Tachycardia1.3%0.8%5.2%0.8% Bradycardia0.0%0.4%10.3%0.0% Hypotension0.0% 2.9%0.6%

19 Cardiopulmonary SAEs Spectrum of signs and symptoms includes hypertension, cardiomyopathy, pulmonary edema, acute respiratory distress and acute renal failure. Applicant reports 4 infusion-related SAEs (0.1%) –None of the reports involved units manufactured with the method intended for licensure Four (0.8%) such SAEs were also reported in The COBLT Study dataset. Five additional published cases

20 Composition of Prepared Unit PreparationVolumeDMSODextran 40 Thawed25 mL2.5 mL1% Diluted*170 mL2.5 mL4.4% Washed*>100 mL> 0.8 mL~4.7% ∙ Prepared according to applicant’s instructions. The instructions do not include an infusion rate. Dextran 40 Side effects include pulmonary edema, congestive heart failure, acute renal failure, bleeding disorders and anaphylactoid reactions Recommended dose is 5-10 mL/kg over hours (available as a 10% solution)

21 Infusion Reactions Overview Applicant’s Data (TNC Dose >2.5 x 10 7 /kg) –Reported infusion reaction rate is 18% –Serious cardiopulmonary events in 0.1% –The most common infusion reactions are hypertension (14%), nausea (5%), vomiting (4%), and hypoxemia (3%) Additional Information –Reported infusion reaction rate is 65% –Serious cardiopulmonary events in 0.8% –Severe allergic reactions occurred in 0.2%.