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

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

Study Overview

• Status: Completed
• Conditions: Fabry Disease

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.

• Study Type: Observational
• Enrollment (Anticipated): 30

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • O&O Alpan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

30 subjects of (7 and above) who meet eligibility criteria.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Fabry disease switch group; Subjects will include individuals with Fabry disease who are switching from agalsidase alfa to agalsidase beta
Control Group; Controls will include individuals with Fabry disease who have only received agalsidase beta as treatment in their lifetime.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: O & O Alpan LLC
• Investigators: Principal Investigator: Ozlem Goker-Alpan, MD, O & O Alpan LLC

Publications and helpful links

General Publications

• 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.

Helpful Links

• O&O Alpan LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2012
• Primary Completion (ACTUAL): April 7, 2015
• Study Completion (ACTUAL): August 7, 2016

Study Registration Dates

• First Submitted: December 5, 2012
• First Submitted That Met QC Criteria: December 7, 2012
• First Posted (ESTIMATE): December 10, 2012

Study Record Updates

• Last Update Posted (ACTUAL): April 4, 2017
• Last Update Submitted That Met QC Criteria: April 3, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: antibody; immunity; Fabry Disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease
• Other Study ID Numbers: 12-CFCT-03