Background: Signs and symptoms of the X-linked disorder, Fabry disease (FD), can occur early during childhood with heterogeneous clinical manifestations including potential cardiac and renal dysfunction. Several studies support the efficacy of the enzyme replacement therapy (ERT) agalsidase alfa, in adults with FD, though published data on the long-term safety and efficacy of agalsidase alfa in children are limited. As early treatment with ERT has the potential to reduce complications arising from disease progression, children in particular could benefit. The objective of this study was to evaluate the safety and efficacy of long-term agalsidase alfa ERT in children with FD.
Methods: TKT029 was a 6.5-year open-label, multicenter, extension study of children who completed TKT023 (26-week, open-label, every-other-week, intravenous 0.2 mg/kg agalsidase alfa). TKT029 was divided into two phases (before and after an agalsidase alfa manufacturing process change); only patients who participated in both phases were included in the analysis. Primary endpoints included safety, tolerability, and heart rate variability (HRV). Additional efficacy parameters included left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), and plasma/urine globotriaosylceramide (Gb3).
Results: Eleven patients participated (phase 1 baseline median [range] age: 10.8 [8.6-17.3] years; 10 [90.9%] males). During TKT029 (6.5 years), all patients experienced ≥1 treatment-emergent adverse event (AE); eight patients had ≥1 possibly/probably drug-related AE. Six patients experienced infusion-related AEs, but none discontinued due to AEs. Eight serious AEs arose (two patients); none were deemed drug-related. No deaths occurred. Three patients developed anti-agalsidase alfa antibodies, with IgG antibodies in one patient that were agalsidase alfa neutralizing, but without apparent clinical impact. Renal (eGFR) endpoints remained generally in normal range. Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV, although some patients experienced a reduction in heart rate. Plasma and urinary Gb3 reductions were maintained.
Conclusions: TKT029 represents the longest assessment of ERT in children with FD in a clinical trial setting. Overall, agalsidase alfa was well tolerated and demonstrated a stabilizing clinical effect. Agalsidase alfa may be a useful clinical therapeutic option for long-term treatment initiated during childhood in patients with FD.
Trial Registration: http://ClinicalTrials.gov identifier NCT00084084 .
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260255 | PMC |
| http://dx.doi.org/10.1186/s13023-014-0169-6 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Effects of Current Therapies on Disease Progression in Fabry Disease: A Narrative Review for Better Patient Management in Clinical Practice.
Adv Ther
December 2024
Cardiovascular Department, ASL8 Arezzo San Donato Hospital, Via Pietro Nenni 20, 52100, Arezzo, Italy.
Article Synopsis
- - Fabry disease (FD) is a rare genetic disorder causing issues in the kidneys, nervous system, and heart, with four treatment options: three enzyme replacement therapies (ERTs) and one pharmacological chaperone.
- - Agalsidase beta and agalsidase alfa improve various organ functions and quality of life, with agalsidase beta possibly being more effective long-term; early treatment is crucial for optimal response.
- - Migalastat benefits patients with specific gene variants by stabilizing kidney function and relieving some symptoms, but its neurological effects are unclear and further research is needed for direct treatment comparisons.
A phase III, open-label clinical trial evaluating pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease previously treated with other enzyme replacement therapies.
J Inherit Metab Dis
January 2025
Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
Article Synopsis
- Pegunigalsidase alfa is a new enzyme replacement therapy for Fabry disease, showing a longer half-life and administered every 4 weeks instead of the typical 2-week schedule.
- The BRIGHT study involved 30 adult patients who switched from another ERT to pegunigalsidase alfa, revealing good safety results with mostly mild side effects and no new anti-drug antibodies.
- Although the treatment showed acceptable tolerance, more research is needed due to the small sample size, but it suggests that this 4-week regimen could be a viable new option for managing Fabry disease.
2024 Update of the TSOC Expert Consensus of Fabry Disease.
Acta Cardiol Sin
September 2024
Division of Cardiology, Department of Internal Medicine, Min-Sheng General Hospital, Taoyuan.
Article Synopsis
- Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene, leading to harmful buildup of glycosphingolipids in various tissues and classified into classic and late-onset phenotypes.
- Classic phenotype shows severely reduced enzyme activity, resulting in a progressive disease with multi-organ issues, while late-onset often presents with milder symptoms and mainly affects the heart due to some remaining enzyme activity.
- Early diagnosis through enzyme testing, imaging, and genotyping is crucial for effective treatment, which includes enzyme replacement therapy and new pharmacological options to prevent irreversible damage and optimize patient care based on genetic and gender considerations.
Establishing Treatment Effectiveness in Fabry Disease: Observation-Based Recommendations for Improvement.
Int J Mol Sci
September 2024
Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Article Synopsis
- Fabry disease (FD) results from mutations in a specific gene that lead to a deficiency in the enzyme α-galactosidase A, causing harmful substrate accumulation, with symptoms varying widely between male and female patients.
- Although FD therapies like enzyme replacement therapy (ERT) and chaperone therapy have been available for around 20 years, there is still limited evidence supporting their long-term effectiveness due to diverse patient populations and inconsistencies in study designs.
- To improve future research on FD treatments, the review suggests better patient matching, international collaboration, and standardized approaches for evaluating treatment effectiveness, including clear recommendations for study outcomes and duration.
Comparative study on incorporation of three recombinant human α-galactosidase A drugs (agalsidases) into cultured fibroblasts and organs/tissues of Fabry mice.
Mol Genet Metab Rep
September 2024
Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.
Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (α-Gal A) drugs (agalsidases) has been successfully used for treatment of Fabry disease, and three kinds of agalsidases are now available in Japan. To compare the biochemical characteristics of these drugs, especially focusing on their incorporation into cultured fibroblasts and organs/tissues of Fabry mice, we performed in vitro, cell, and animal experiments. The results revealed that there were no differences in the kinetic parameters and enzyme activity between these agalsidases.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!