Hemophilia Inhibitor Genetics Study HIGS Hemophilia Inhibitor PUP Study HIPS

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Hemophilia Inhibitor Genetics Study
(HIGS)Hemophilia Inhibitor PUP Study (HIPS)

• Deborah Brown, M.D.
• University of Texas - Houston

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Hemophilia Inhibitor Genetics Study (HIGS)

• Investigator-initiated study funded by grants
  from Baxter, NIH, NCI.
• Principal Investigator
• Erik Berntorp
• Co-Principal Investigator
• Jan Astermark
• Data and Statistics
• Sharyne Donfield, Rho., Inc.

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Objectives

• Determine genetic factors associated with the
  development of inhibitors and response to
  antigenic challenge by factor VIII.
• Identify environmental factors that might
  increase the risk of inhibitor development.
• Explore genetic/environmental interactions that
  might increase the risk of inhibitor development.

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Study Population

• Phase I Brother pairs, either both with
  inhibitor or discordant (one with, one without),
  and their parents.
• Phase II A patient with an inhibitor and his
  parents.
• Phase III Unrelated hemophilia patients with
  and without inhibitors.

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Countries Represented in HIGS

• Argentina
• Austria
• Canada
• Chile
• Colombia
• Finland
• France
• Germany
• Hungary
• Iceland
• Ireland
• Italy
• Lithuania
• Peru
• Poland

• Russia
• Serbia
• South Africa
• Spain
• Sweden
• Switzerland
• The Netherlands
• Turkey
• United Kingdom
• England
• Scotland
• Wales
• United States
• Venezuela

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Clinical Data

• Date of birth and age at onset of treatment
• Race/ethnicity
• Presence of an infection or other illness at time
  first dose of factor was given
• Current type of treatment (prophylaxis vs. on
  demand)
• History of HIV or hepatitis C
• History of hospitalization for
• Surgical procedure
• Injury
• Infection

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Inhibitor-related Data

• Number of exposure days prior to development
• Type(s) of clotting factor used prior to
  development of inhibitor
• Date and method of detection of inhibitor
• Titer at detection, peak and current titer
• Initiation of immune tolerance?
• Type of regimen
• Successful?

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Genotyping

• An Illumina iSelect custom panel was used
• Data include 14,626 single nucleotide
  polymorphisms (SNPs) from 1,081 genes
• Immune response and immune modifier genes
• Cytokines and their receptors
• Chemokines and their receptors
• Pathway genes involved in inflammatory and immune
  responses
• HLA
• Polymorphisms in the FVIII gene

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Recruitment (10 September 2009)
Family members from 91 Phase I and 201 Phase II
families.
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Hemophilia Inhibitor PUP Study (HIPS)

• Investigator-initiated study funded by Baxter.
• Co-Principle Investigators
• Deborah Brown, Elena Santagostino
• Data and statistics
• Sharyne Donfield
• Central laboratory
• Birgit Reipert

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Objectives

• Understand the mechanisms of immune response in
  previously untreated patients with severe factor
  VIII deficiency.
• Specific Aims
• Analyze and functionally characterize
  FVIII-specific T-cells during the first 50
  exposure days to a single FVIII product.
• Monitor Treg cells during the first 50 E.D.s.
• Analyze antibody subclasses of anti-FVIII
  antibodies.

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Y
BCR
co-stimulation
Y
TCR
MHC- class II
Y
activated B cell
activated T cell
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antigen-presenting cell
T cell
Y
BCR
co-stimulation
Y
TCR
MHC- class II
Y
activated B cell
activated T cell
14
antigen-presenting cell
T cell
Y
BCR
co-stimulation
Y
TCR
MHC- class II
Y
activated B cell
activated T cell
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Hypotheses

• The type of FVIII-specific T cell that is
  activated during the first days of exposure to
  FVIII determines the decision of the immune
  system to either develop inhibitors to FVIII or
  not.
• Those patients who do not develop FVIII
  inhibitors have a high proportion of regulatory T
  cells (Treg) during early exposure days compared
  to those who develop inhibitors.
• Infections and immunizations at the time of
  treatment with FVIII reduce the proportion of
  Treg and favor the induction of FVIII-specific T
  cells that drive antibody responses.
• The type of FVIII mutation is related to the type
  of T cell that is activated during early exposure
  days.
• The subclass of anti-FVIII antibodies that
  develops is associated with the type of
  FVIII-specific T cell that is activated during
  early exposure days.

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Study Design

• Multi-center, international, prospective natural
  history study
• A single type of recombinant FVIII replacement
  therapy will be used (Advate)
• Type of treatment regimen will be selected by the
  investigator.
• Participants will be followed for 50 exposure
  days or three years, whichever comes first.

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Study population

• Previously untreated infants with hemophilia A
• Baseline FVIII level lt 1.
• N 50

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Clinical Data Collection

• Ethnic/racial background
• Family history of hemophilia, inhibitors,
  immunological diseases
• Medications, immunizations, illnesses,
  infections, hospitalizations, injuries, surgeries
• Infusion history dates, reason, dose, product,
  method of administration
• Bleeding episodes dates, site, cause, treatment
• Adverse events

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Laboratory studies

• Pre-exposure
• Post-exposure 1st 5 exposure days 3 days (/-
  24 hours) after each exposure
• Post-exposure gt 5 E.D.s 3 days (/- 24 hours)
  after each 7th exposure
• Hospitalizations every 3rd exposure day
• Convenience sample FVIII mutation analysis and
  candidate gene testing

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Inhibitor testing

• Bethesda titer
• Positive if gt 0.4
• Central laboratory (Baxter lab, Vienna)
• Elisa assay for anti-FVIII antibodies (IgM IgG1
  IfG2 IgG3 IgG4 IgA)
• Reipert laboratory
• Screening positive/negative
• If positive Antibody titer will be quantified.
• Competitive assays will be performed for
  specificity

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Steering Committee

• Deborah Brown, Co-Chair TX, USA
• Elena Santagostino, Co-Chair Milan, Italy
• Brigit Reipert, Senior Scientist Vienna,
  Austria
• W. Keith Hoots, Scientific Cunsultant D.C., USA
• Sharyne Donfield, Data Statistics N.C., USA
• Bruce Ewenstein, Baxter CA, USA
• Jean-Marie Saint-Remy Leuven, Belgium
• Jan Astermark Malmo, Sweden
• Erik Berntorp Malmo, Sweden
• Donna DiMichele New York, USA
• Amy Shapiro Indiana, USA
• George Rivard Montreal, Canada
• Johannes Oldenburg Bonn, Germany
• Edward Gomperts California, USA