Clinical trial NCT01745185: Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta
Official title: Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Fabry Disease
Keywords: Fabry Disease
immunity
antibody
Lead sponsor: O & O Alpan LLC
Sponsor class: OTHER
First posted: 2012-12-10
Enrollment: 30
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 30 subjects of (7 and above) who meet eligibility criteria.

Brief summary: 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

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Monitoring antibody formation against agalsidase alfa and beta
timeFrame: 12 months
Secondary outcomes:
measure: Measurement of plasma/urine Gb3 and plasma lyso-Gb3
timeFrame: 12 months
Other outcomes:
Locations:
city: Fairfax
country: United States
facility: O&O Alpan
state: Virginia
Study officials:
affiliation: O & O Alpan LLC
name: Ozlem Goker-Alpan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Benichou B, Goyal S, Sung C, Norfleet AM, O'Brien F. A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease. Mol Genet Metab. 2009 Jan;96(1):4-12. doi: 10.1016/j.ymgme.2008.10.004. Epub 2008 Nov 20.