Brief Title
Personalized Prediction of Tolerance and Immunogenicity in Hemophilia
Official Title
Study of Severe Hemophilia A Patients Who Have Only Received a Single Recombinant FVIII Therapeutic for the Purpose of Identifying the Pharmacogenetic Determinants of Tolerance and Immunogenicity
Brief Summary
This study is designed to accurately identify the pharmacogenetic determinants of risk of
Factor VIII (FVIII) inhibitor development by focusing on only a select group of Hemophilia A
(HA) patients who have: (i) received a recombinant FVIII therapeutic product containing the
same primary amino acid sequence since their original diagnosis; (ii) verifiable FVIII
infusion histories; and (iii) been tested regularly for FVIII inhibitor development.
Detailed Description
We are developing a novel, personalized strategy for assessing immunogenicity of protein
therapeutics using, as our model, the infusion of Factor VIII (FVIII) into hemophilia A (HA)
patients. About 20% of all treated HA patients develop neutralizing FVIII alloantibodies
("inhibitors") that make disease management difficult and expensive. Nowadays, HA is usually
treated with highly purified human recombinant (r)-proteins, an advance in safety from
pathogens not accompanied by a decrease in inhibitor incidence. Current strategies for
upcoming FVIII formulations focus largely on engineering the most immunogenic epitopes in the
hope of forming a universally less immunogenic protein. In contrast, we are pioneering a
pharmacogenetic approach to immunogenicity that takes into account the underlying variability
of the patient population.
This project focuses on defining the role of individual genetic differences on FVIII
immunogenicity. The principles, however, have broader application for protein therapeutics in
general. We have studied non-HA-causing variants in the FVIII gene (F8) and have shown that
(i) nonsynonymous (ns)-single-nucleotide polymorphisms (SNPs) encode several structurally
distinct wild-type FVIII proteins in the human population and (ii) a sequence mismatch
between patients' endogenous FVIII and infused FVIII due to ns-SNPs is a risk factor for
inhibitor development that may explain the high inhibitor incidence in HA patients with black
African ancestry.
The most well established risk factor for inhibitor development is the type of HA-causing F8
gene mutation. As a rule, large alterations in F8 and absence of antigenically cross-reactive
material (CRM) in plasma are associated with inhibitor development. The most common F8
mutation causing severe HA, an intron-22-inversion (I22I), fits that description but is not
associated with a high inhibitor risk. Similarly, while most HA patients with missense
mutations do not develop inhibitors, this alloimmune complication occurs frequently in
patients with one of a few highly recurrent missense mutations.
While not definitively established, population heterogeneity in the repertoires of
HLA-class-II (HLA-II) molecules expressed on the surfaces of the antigen-presenting cells in
individual patients is likely another genetic contributor to inhibitor risk.
This project is a comprehensive assessment of the pharmacogenetics of the immune response to
FVIII leveraging a unique resource comprised of a group of 55 subjects with severe or
moderately-severe HA who were (i) enrolled as previously-untreated patients (PUPs) in the
recently concluded clinical trial known as the Advate PUP study and (ii) have received the
same r-FVIII protein (i.e., Advate) since birth. Prior PUP-study data as well as new blood
samples and data will be obtained from these subjects upon their enrollment into the current
study. In addition to having been treated with only a single FVIII product, this exceptional
patient cohort was (and continues to be) closely monitored for both FVIII infusion history
and inhibitor development, the latter of which by undergoing frequent Bethesda testing. (HA
patients who have been treated with several FVIII products are not ideal for testing the
hypotheses we have proposed.)
Study Type
Observational
Condition
Hemophilia A
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Estimated Enrollment
55
Start Date
June 2012
Completion Date
June 2014
Primary Completion Date
April 2013
Eligibility Criteria
Inclusion Criteria:
- Patients with severe or moderately severe hemophilia A (HA) who have since birth been
treated with only a single Factor VIII product (i.e., FVIII protein molecules
containing only one primary amino acid sequence).
Exclusion Criteria:
- HA patients with severities other than severe or moderately severe.
- Hemophilia B patients.
- HA patients who have been treated with more than one FVIII product.
- HA patients who have been treated with more than one FVIII product.
- HA patients who do not have verifiable infusion histories.
- HA patients who lack documentable inhibitor testing & infusion histories.
Gender
Male
Ages
2 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Victor J. Marder, M.D., 404-597-8014, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01626105
Organization ID
PPTIH No. 1
Responsible Party
Sponsor-Investigator
Study Sponsor
Victor J Marder, M.D.
Collaborators
Baxter Healthcare Corporation
Study Sponsor
Victor J. Marder, M.D., Principal Investigator, The Los Angeles Orthopaedic Hospital and The David Geffen School of Medicine at UCLA
Verification Date
July 2012