Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta

Fabry Disease Clinical Trial

Official title:

Immune Response in Subjects With Fabry Disease Who Are Switching From Agalsidase Alfa to Agalsidase Beta

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01745185
• Other study ID #: 12-CFCT-03
• Status: Completed
• Phase: N/A
• First received: December 5, 2012
• Last updated: April 3, 2017
• Start date: June 2012
• Est. completion date: August 7, 2016

Study information

• Verified date: April 2017
• Source: O & O Alpan LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: August 7, 2016
• Est. primary completion date: April 7, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Fabry Disease

Locations

Country	Name	City	State
United States	O&O Alpan	Fairfax	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
O & O Alpan LLC

Country where clinical trial is conducted

United States, 

References & Publications (1)

Bénichou 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Monitoring antibody formation against agalsidase alfa and beta	Blood samples will be collected prior to infusion (screening & month 12). At baseline, antibodies against agalsidase alfa and beta measured, and at 12 months, antibodies against agalsidase beta will be measured by ELISA technique and will be isotyped immunoglobulins (IgG, IgA, IgM, or IgE). Positive samples will subsequently tested for enzyme neutralizing activity using an in vitro assay. Antibody measurements will be done by Shire Human Genetics Therapies, INC.	12 months
Secondary	Measurement of plasma/urine Gb3 and plasma lyso-Gb3	Plasma samples collected after at least 8 hours of fasting prior to the blood draw. Plasma and urine samples (Gb3 only) analyzed using mass spectrometry. Gb3 measurements will be performed by Shire HGT.	12 months

External Links

•   O&O Alpan LLC