1 Hemacord BLA Hematopoietic Progenitor Cells, Cord (HPC-C) CTGT Advisory Committee Meeting September 22, 2011

2 Hemacord FDA Review Team CMC –Steven Bauer, PhD –Joydeep Ghosh, PhD –Bharat Joshi, PhD –Safa Karandish, BS, MT –Brenton McCright, PhD –Mercy Quagraine, PhD DMPQ –Mohammad Heidaran, PhD –Gang Wang, PhD Pharmacology/Toxicology –Atm Hoque, PhD Clinical –Peter Bross, MD –Bindu George, MD –John Hyde, PhD, MD –Maura O’Leary, MD –Donna Przepiorka, MD, PhD Statistics –Renee Rees, PhD Labeling –Lisa Stockbridge, PhD –Loan Nguyen, PharmD Pharmacovigilance –Damon Green, MD, MS Project Management –Terrolyn Thomas, MS, MBA

3 Hematopoietic Progenitor Cells, Cord (HPC-C, UCB) HPC-C is a minimally manipulated placental/ umbilical cord blood product containing live human cord blood cells for unrelated allogeneic use.

4 Efficacy Review

5 Indications Being Considered Hematological Malignancies Hurler Syndrome Krabbe Disease X-Linked Adrenoleukodystrophy Primary Immunodeficiency Diseases Bone Marrow Failure Beta-Thalassemia

6 Sources of Efficacy Information Dockets Datasets –Individual data –Lack diagnostic criteria –Variable completeness and quality Docket Summaries and Case Reports Published Historical Control Data Published Studies of UCB

7 Dose Consideration: TNC dose > 2.5 x 10 7 /kg Total nucleated cell (TNC) dose Gibbons (Institute of Medicine (IOM)) –Pooled dataset of 755 patients –Competing risk survival model –Assessed effect of TNC by 5 –Found that when using a TNC dose < 2.5, the 2-year survival was markedly lower and graft failure rate higher with an HLA mismatch

8 Hematological Malignancies

9 Review Strategy for Hematological Malignancies Focus on acute leukemias – ALL & AML –Focus on overall survival outcomes Compare to bone marrow transplant (BMT) –There are controlled comparisons of BMT to conventional chemotherapy –Recent published comparisons of UCB vs. BMT

10 Survival after UCB vs. BMT (Laughlin 2004)

11 Hematological Malignancies Observations UCB transplant appears generally comparable to BMT for acute leukemia Feasibility of assessing each hematological malignancy is limited May be worse survival with dose < 2.5 x10 7

12 Non-Malignant Indications

13 Review Strategy for Non-Malignant Indications Focus on the 4 specified indications + diseases with greatest representation in docket for the 2 broad indications Focus on survival outcomes –Docket data provided little other than survival –Good endpoint for cross-study comparisons, historical data have little objective data on other outcomes –Important in light of treatment-related mortality –Misses other relevant outcomes

14 Review Strategy for Non-Malignant Indications (cont.) Search literature for candidate control populations Compare docket outcomes to control population outcomes Evaluate UCB studies in literature, if available Explore data for evidence of dose effects

15 Specified Indications: Lysosomal Storage and Peroxisomal Enzyme Deficiency Disorders and Beta-Thalassemia DiagnosisDocket Cases Hurler Syndrome72 Krabbe Disease38 Adrenoleukodystrophy21 Beta-Thalassemia8

16 DiagnosisDocket Cases Fanconi anemia39 Severe aplastic anemia37 Osteopetrosis16 Amegakaryocytic thrombocytopenia4 Diamond-Blackfan anemia4 Dyskeratosis congenita2 Shwachman-Diamond syndrome1 Bone Marrow Failure

17 DiagnosisDocket Cases SCID47 Wiskott-Aldrich syndrome14 Kostmann disease4 Lymphocyte adhesion disorder4 Chronic granulomatous disease3 Chediak-Higashi syndrome2 Combined immunodeficiency (not SCID)1 Common variable immunodeficiency1 Nezelof syndrome1 Other/unknown4 Primary Immunodeficiency Diseases

18 Hurler Syndrome

19 Hurler Syndrome – Docket Findings N = 72, median age 1.3 years 30% mortality in first 2 years, stable thereafter Heavy censoring over first 6 years Concerns about accuracy of follow-up time reporting Increased enzymes measured in blood

20 Survival (with CI) Following UCB Transplant for 71 Hurler Patients – Docket Data At Risk:

21 Hurler Syndrome – Historical Data UK registry Patients seen at small number of centers, so had nearly complete capture For those w/o HSCT (n=140) –Median survival ~ 8 years –More than 20% survived 10 years

22 Survival from Birth for Hurler Syndrome in the UK (Moore 2008)

23 Comparisons to Control Moore BMT vs. Control –Relative hazard 0.58 UCB vs. Control –Relative hazard 2.0 – 2.6 Crossover feature Shorter F/U with UCB

24 Hurler Syndrome Observations Early mortality –Break even point projected to be in range of 5 to 9 years UCB survival looks similar to BMT, but has shorter follow-up experience Enzyme elevations occur –Clinical meaningfulness is unclear No dose response seen for survival –median dose 11 x10 7 /kg, range

25 Krabbe Disease

26 Krabbe Disease – Docket Findings N = 38, median age 0.7 years 37% mortality in first 2 years Additional deaths and progressive censoring in later years Concerns about accuracy of follow-up time reporting Increased enzymes measured in blood

27 Survival (with CI) Following UCB Transplant in 38 Krabbe Disease Patients – Docket Data At Risk:

28 Krabbe Disease – Historical Data Hunter’s Hope Krabbe Family Database Based on Questionnaires Survival highly dependent on age at symptom onset

29 Survival by Age of Symptom Onset in Krabbe Disease – Hunter’s Hope Database (Duffner 2009) Onset ≥ 13 Months n = 11 Onset 7 – 12 Months n = 22 Onset 0 – 6 Months n = Survival Probability Years

30 Survival after UCB for Krabbe Disease (Escolar 2005) Asymptomatic n = 11 Symptomatic n = 14 Untreated Control Survival Probability Years:

31 Issues in Assessing Pre-symptomatic Krabbe Disease Transplantation Age of symptom onset correlates strongly with prognosis –Not known in a pre-symptomatic patient Post hoc analysis, possible selection bias Peri-transplant experience less favorable with additional experience Most pre-symptomatic transplanted patients still appear to be severely affected

32 Krabbe Disease Observations Survival in general patient population appears to overlap candidate controls Variable phenotype makes it hard to identify appropriate control for pre-symptomatic patients – knowing prognosis is critical Enzyme elevations occur –Clinical meaningfulness is unclear No dose response seen for survival –median dose 16.5 x10 7 /kg, range

33 Adrenoleukodystrophy (ALD)

34 ALD – Docket Findings N = 21, median age 8 years 25% mortality in first 2 years, stable thereafter 5-year mortality 75%, lower end of CI 52% Small number of patients (21), limited F/U beyond 5 years Concerns about accuracy of follow-up time reporting

35 Survival (with CI) Following UCB Transplant in 21 ALD Patients – Docket Data At Risk:

36 ALD – Historical Data Primarily from Kennedy Krieger Institute Phenotype highly variable Prognosis relates to MRI findings at presentation and age of onset For those w/o HSCT (n = 283) –Median survival 8.6 years after symptom onset –5-year survival 66%

37 Survival for Early Stage ALD (Mahmood 2007) Transplanted n = 19 Untransplanted n = 30 Survival Probability Years after First Abnormal MRI % 95%

38 ALD Observations Survival appears to overlap experience in controls Variable phenotype makes it difficult to identify appropriate controls No dose response seen for survival –Median dose 4 x10 7 /kg, range

39 Severe Combined Immunodeficiency (SCID)

40 SCID – Docket Findings N = 47, median age 0.6 years 35% mortality in first 2 years, stable thereafter. 2-year survival 65%, lower end of CI 50% Limited F/U after 5 years, but 10 (21%) known alive through 4 years post UCB Some older patients (> 2 years) present

41 Survival (with CI) Following UCB Transplant for 47 SCID Patients – Docket Data At Risk:

42 Age Distribution for SCID Patients – Docket Data

43 SCID – Historical Data In 434 cases published in 1978 (Hitzig), all untreated infants died within the first months of life. In 22 untreated cases reported in 1993 (Stephan), all died by about 18 months of follow-up.

44 Survival in SCID Patients by BMT Type and Without Transplant (Stephan 1993) Years Survival Probability HLA-identical N=30 HLA-non-identical n=50 No transplant n=

45 SCID Observations Rapid fatality in control groups appears distinct from UCB experience In view of age distribution, some question about docket diagnoses (or need for more contemporary controls) No dose response seen for survival –Median dose 13 x10 7 /kg, range

46 Fanconi Anemia (FA)

47 FA – Docket Findings N = 39, median age 8 years 64% mortality at 6 months, 72% in first year Little F/U beyond 3 years Suggestion of worse outcomes with low dose

48 Survival (with CI) Following UCB Transplant for 39 Fanconi Anemia Patients – Docket Data At Risk:

49 FA – Historical Data International Fanconi Anemia Registry (IFAR) established in 1982 Analysis in 2003 had 754 patients with median F/U of 10.6 years –Mortality nearly linear from birth through 50 years – ~2% mortality/year

50 Mortality in Fanconi Anemia – IFAR (Kutler 2003) Cumulative Mortality

51 Overall Survival Time in the Subgroup of FA with BMF, multivariate proportional hazards model (Kutler 2003)

52 Fanconi Anemia Observations UCB survival appears worse than available controls Epidemiology study suggests worse outcomes associated with HSCT – but interpretability is limited May be worse survival with dose < 2.5 x10 7 /kg –Median dose 4.5 x10 7 /kg, range

53 Severe Aplastic Anemia (SAA)

54 SAA – Docket Findings N = 37, median age 7 years 62% mortality in first year Little F/U beyond 2 years 2-year survival 29%, lower end of CI 16% Suggestion of worse outcomes with low dose

55 Survival (with CI) Following UCB Transplant for 37 SAA Patients – Docket Data At Risk: 8 3 2

56 SAA – Historical Data Multiple sources available Prognosis has changed over time Role of immunosuppressive therapy (IST) Untreated vs. IST failures?

57 Survival Following Sibling BMT or No BMT in SAA Patients (Camitta 1979) Nontransplanted Transplanted Years: Years:

58 Survival in SAA Patients by Response to Antithymocyte Globulin (Rosenfeld 2003) Years: Response at 3 mo. n=74 No Response at 3 mo. n=31 Survival (censored for transplant)

59 Survival in IST Non-Responders (Valdez 2011) 1989 – yr survival = 23% 1996 – yr survival = 35% 2002 – yr survival = 57% Survival (censored for transplant)

60 Survival in SAA Following UCB Transplant – Eurocord Registry (Peffault de Latour 2011) Years:

61 SAA Observations Survival with UCB overlaps older controls and appears worse than recent controls May be worse survival with dose < 2.5 x10 7 /kg –Median dose 3.8 x10 7 /kg, range

62 Beta-Thalassemia

63 Beta-Thalassemia – Docket Findings N = 8, median age 4 years Estimated 66% mortality in first year Information on outcomes other than survival from case reports and series

64 Survival (with CI) Following UCB Transplant for 8 Patients with Beta-Thalassemia – Docket Data

65 Information from Case Series A few reports of UCB hemoglobin expression improvement Many series report most surviving patients are no longer transfusion dependant –Reporting subjective and not quantified

66 Beta-Thalassemia – Historical Data Prognosis has changed over time Evolution of transfusion and chelation therapies Currently > 95% probability of surviving to adulthood

67 Survival in Beta-Thalassemia Without Transplant: 1960 through 1997 (Borgna-Pignatti 2004)

68 Estimated Overall Survival Following UCB Transplant for Beta-Thalassemia (Ruggeri 2011) Thalassemia (n=35) 62% Overall Survival Years

69 Beta-Thalassemia Observations UCB appears to improve Hgb expression UCB appears to eliminate transfusion dependence in most survivors Survival after UCB transplant is lower than in available controls Unable to evaluate dose response (n=8) –Median dose 6.4 x10 7 /kg, range