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Hemacord BLA 125397

Hemacord BLA 125397. Hematopoietic Progenitor Cells, Cord (HPC-C). CTGT Advisory Committee Meeting September 22, 2011. CMC Steven Bauer, PhD Joydeep Ghosh, PhD Bharat Joshi, PhD Safa Karandish, BS, MT Brenton McCright, PhD Mercy Quagraine, PhD DMPQ Mohammad Heidaran, PhD

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Hemacord BLA 125397

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  1. HemacordBLA 125397 Hematopoietic Progenitor Cells, Cord (HPC-C) CTGT Advisory Committee Meeting September 22, 2011

  2. 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 Hemacord FDA Review Team

  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 107/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 < 2.5, 2.5 - 5, > 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 forHematological 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 x107

  12. Non-Malignant Indications

  13. Review Strategy forNon-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 forNon-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

  16. Bone Marrow Failure

  17. 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: 28 24 20 15 98 5 3

  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 of5 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 x107/kg, range 3.4 - 30

  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: 23 18 12 9 6 4 2

  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 Survival Probability Onset 7 – 12 Months n = 22 Onset 0 – 6 Months n = 81 0 8.3 16.7 25 33.3 41.7 Years

  30. Survival after UCB for Krabbe Disease (Escolar 2005) Asymptomatic n = 11 Survival Probability Symptomatic n = 14 Untreated Control Years: 0 1 2 3 4 5 6 7 8 9

  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 x107/kg, range 2.4 - 50

  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: 13 12932

  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 95% 54% Untransplanted n = 30 Survival Probability 0 5 10 15 20 Years after First Abnormal MRI

  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 x107/kg, range 1.7 - 14

  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: 26 16 12 10 3

  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) HLA-identical N=30 Survival Probability HLA-non-identical n=50 No transplant n=22 0 4.2 8.3 12.5 16.7 20.8 25 Years

  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 x107/kg, range 2.9 - 74

  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:11 732

  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

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