Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta
| Status: | Completed |
|---|---|
| Conditions: | Hematology, Metabolic |
| Therapuetic Areas: | Hematology, Pharmacology / Toxicology |
| Healthy: | No |
| Age Range: | 7 - Any |
| Updated: | 4/5/2017 |
| Start Date: | June 2012 |
| End Date: | August 7, 2016 |
This study is a prospective active comparator study to assess the immune response elicited
by human recombinant agalsidase therapy in subjects who are switching from agalsidase alfa
to agalsidase beta with Fabry disease. Fabry disease is an X-linked lysosomal storage
disorder, due to deficient alpha-galactosidase A activity. The progressive accumulation of
globotriaosylceramide (GL-3) in the lysosomes of the vascular endothelial cells of multiple
organ systems like the kidneys, heart, skin, and brain, leads to a microvascular disease. In
Fabry disease, nephropathy dominates and renal function impairment occurs as a result of
accumulation of GL-3 in renal cells
by human recombinant agalsidase therapy in subjects who are switching from agalsidase alfa
to agalsidase beta with Fabry disease. Fabry disease is an X-linked lysosomal storage
disorder, due to deficient alpha-galactosidase A activity. The progressive accumulation of
globotriaosylceramide (GL-3) in the lysosomes of the vascular endothelial cells of multiple
organ systems like the kidneys, heart, skin, and brain, leads to a microvascular disease. In
Fabry disease, nephropathy dominates and renal function impairment occurs as a result of
accumulation of GL-3 in renal cells
Clinically, the development of an immune response is anticipated in a number of patients
treated with any recombinant human proteins and suggested to be more common especially when
the native protein is deficient or absent as many male patients with Fabry disease.
The immune response that results in the development of antibodies against the infused
proteins may affect the clinical outcome of enzyme replacement therapy by the development of
hypersensitivity, anaphylactoid, or febrile reactions, or may lead to the development of
cytokine release and a generalized inflammatory response or immune complex formation.
Furthermore, the mounted immune response may lead to inactivation or degradation of the
recombinant enzyme or may change the pharmacokinetic and pharmacodynamic properties of the
therapeutic protein.
The different rates of antibody formation with agalsidase alfa and agalsidases beta are
often attributed to differences in techniques used to measure antibody formation. However,
other factors such as host, structural similarity of the infused protein and tertiary
structural difference such as glycosylation may lead to differences in the immune response.
Among the factors that may affect host response are also the dose and the infusion
frequency. Although agalsidase alfa and beta are derived from the same complementary DNA
sequence there are minor differences in glycosylation patterns, and different dosing is
used, 0.2 mg per kg every other week for agalsidase alfa, 1.0 mg per kg for agalsidase beta.
The investigator hypothesize that although the observation that the antibodies exhibit in
vitro neutralizing capacity may suggest the presence of a single immunogenic epitope for
both human recombinant alpha-galactosidases, the immunogenicity may not be similar for both
agalsidase alfa and beta, and thus the differences in immune response will be determined by
the host factors and the escalating dose of infused protein.
treated with any recombinant human proteins and suggested to be more common especially when
the native protein is deficient or absent as many male patients with Fabry disease.
The immune response that results in the development of antibodies against the infused
proteins may affect the clinical outcome of enzyme replacement therapy by the development of
hypersensitivity, anaphylactoid, or febrile reactions, or may lead to the development of
cytokine release and a generalized inflammatory response or immune complex formation.
Furthermore, the mounted immune response may lead to inactivation or degradation of the
recombinant enzyme or may change the pharmacokinetic and pharmacodynamic properties of the
therapeutic protein.
The different rates of antibody formation with agalsidase alfa and agalsidases beta are
often attributed to differences in techniques used to measure antibody formation. However,
other factors such as host, structural similarity of the infused protein and tertiary
structural difference such as glycosylation may lead to differences in the immune response.
Among the factors that may affect host response are also the dose and the infusion
frequency. Although agalsidase alfa and beta are derived from the same complementary DNA
sequence there are minor differences in glycosylation patterns, and different dosing is
used, 0.2 mg per kg every other week for agalsidase alfa, 1.0 mg per kg for agalsidase beta.
The investigator hypothesize that although the observation that the antibodies exhibit in
vitro neutralizing capacity may suggest the presence of a single immunogenic epitope for
both human recombinant alpha-galactosidases, the immunogenicity may not be similar for both
agalsidase alfa and beta, and thus the differences in immune response will be determined by
the host factors and the escalating dose of infused protein.
Inclusion Criteria:
- Confirmed diagnosis of Fabry disease
- Have been treated with ERT using recombinant human agalsidase A.
Exclusion Criteria:
- If the diagnosis of Fabry disease is not confirmed
- If the subject or guardian is not able to provide consent
- Any chronic immunosuppressive state or therapy such as patients on dialysis or
post-transplantation immunosuppressive therapy.
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