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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 l.jpg

HemacordBLA 125397

Hematopoietic Progenitor Cells, Cord

(HPC-C)

CTGT Advisory Committee Meeting

September 22, 2011


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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


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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.


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Efficacy Review


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Indications Being Considered

  • Hematological Malignancies

  • Hurler Syndrome

  • Krabbe Disease

  • X-Linked Adrenoleukodystrophy

  • Primary Immunodeficiency Diseases

  • Bone Marrow Failure

  • Beta-Thalassemia


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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


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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


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Hematological Malignancies


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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


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Survival after UCB vs. BMT (Laughlin 2004)


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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


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Non-Malignant Indications


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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


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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


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Specified Indications:Lysosomal Storage and Peroxisomal Enzyme Deficiency Disorders and Beta-Thalassemia


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Bone Marrow Failure


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Primary Immunodeficiency Diseases


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Hurler Syndrome


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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


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Survival (with CI) Following UCB Transplant for 71 Hurler Patients – Docket Data

At Risk: 28 24 20 15 98 5 3


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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


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


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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


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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


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Krabbe Disease


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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


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

At Risk: 23 18 12 9 6 4 2


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Krabbe Disease – Historical Data

  • Hunter’s Hope Krabbe Family Database

  • Based on Questionnaires

  • Survival highly dependent on age at symptom onset


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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


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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


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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


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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


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Adrenoleukodystrophy (ALD)


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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


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Survival (with CI) Following UCB Transplant in 21 ALD Patients – Docket Data

At Risk: 13 12932


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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%


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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


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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


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Severe Combined Immunodeficiency (SCID)


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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


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Survival (with CI) Following UCB Transplant for 47 SCID Patients – Docket Data

At Risk: 26 16 12 10 3


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Age Distribution for SCID Patients – Docket Data


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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.


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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


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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


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Fanconi Anemia (FA)


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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


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

At Risk:11 732


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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


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Mortality in Fanconi Anemia – IFAR (Kutler 2003)

Cumulative Mortality


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


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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 x107/kg

    • Median dose 4.5 x107/kg, range 0.8 - 16


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Severe Aplastic Anemia (SAA)


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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


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Survival (with CI) Following UCB Transplant for 37 SAA Patients – Docket Data

At Risk: 8 32


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SAA – Historical Data

  • Multiple sources available

  • Prognosis has changed over time

  • Role of immunosuppressive therapy (IST)

  • Untreated vs. IST failures?


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Survival Following Sibling BMT or No BMT in SAA Patients (Camitta 1979)

Transplanted

Nontransplanted

Years: 0 1.3 2.5 3.8

Years: 0 0.8 1.7 2.5 3.3 4.2


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Survival in SAA Patients by Response to Antithymocyte Globulin (Rosenfeld 2003)

Response at 3 mo.

n=74

Survival

(censored for transplant)

No Response at 3 mo.

n=31

Years: 0 2.7 5.5 8.2 11


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Survival in IST Non-Responders (Valdez 2011)

2002 – 2008

5-yr survival = 57%

Survival

(censored for transplant)

1996 – 2002

5-yr survival = 35%

1989 – 1996

5-yr survival = 23%


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

Years: 0 0.8 1.7 2.5 3.3 4.2 5.0


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SAA Observations

  • Survival with UCB overlaps older controls and appears worse than recent controls

  • May be worse survival with dose < 2.5 x107/kg

    • Median dose 3.8 x107/kg, range 1.3 - 19


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Beta-Thalassemia


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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


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


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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


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Beta-Thalassemia – Historical Data

  • Prognosis has changed over time

  • Evolution of transfusion and chelation therapies

  • Currently > 95% probability of surviving to adulthood


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


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Estimated Overall Survival Following UCB Transplant for Beta-Thalassemia (Ruggeri 2011)

Thalassemia (n=35) 62%

Overall Survival

0 1 2 3

Years


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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 x107/kg, range 2.5 - 18


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