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Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies
BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigation...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527132/ https://www.ncbi.nlm.nih.gov/pubmed/23176611 http://dx.doi.org/10.1186/1750-1172-7-91 |
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author | Germain, Dominique P Giugliani, Roberto Hughes, Derralynn A Mehta, Atul Nicholls, Kathy Barisoni, Laura Jennette, Charles J Bragat, Alexander Castelli, Jeff Sitaraman, Sheela Lockhart, David J Boudes, Pol F |
author_facet | Germain, Dominique P Giugliani, Roberto Hughes, Derralynn A Mehta, Atul Nicholls, Kathy Barisoni, Laura Jennette, Charles J Bragat, Alexander Castelli, Jeff Sitaraman, Sheela Lockhart, David J Boudes, Pol F |
author_sort | Germain, Dominique P |
collection | PubMed |
description | BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. METHODS: Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. RESULTS: Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. CONCLUSIONS: Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing. TRIAL REGISTRATION: Clinicaltrial.gov: NCT00283959 and NCT00283933 |
format | Online Article Text |
id | pubmed-3527132 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-35271322012-12-21 Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies Germain, Dominique P Giugliani, Roberto Hughes, Derralynn A Mehta, Atul Nicholls, Kathy Barisoni, Laura Jennette, Charles J Bragat, Alexander Castelli, Jeff Sitaraman, Sheela Lockhart, David J Boudes, Pol F Orphanet J Rare Dis Research BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. METHODS: Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. RESULTS: Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. CONCLUSIONS: Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing. TRIAL REGISTRATION: Clinicaltrial.gov: NCT00283959 and NCT00283933 BioMed Central 2012-11-24 /pmc/articles/PMC3527132/ /pubmed/23176611 http://dx.doi.org/10.1186/1750-1172-7-91 Text en Copyright ©2012 Germain et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Germain, Dominique P Giugliani, Roberto Hughes, Derralynn A Mehta, Atul Nicholls, Kathy Barisoni, Laura Jennette, Charles J Bragat, Alexander Castelli, Jeff Sitaraman, Sheela Lockhart, David J Boudes, Pol F Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies |
title | Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies |
title_full | Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies |
title_fullStr | Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies |
title_full_unstemmed | Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies |
title_short | Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies |
title_sort | safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase a activity and globotriaosylceramide clearance in fabry disease: report from two phase 2 clinical studies |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527132/ https://www.ncbi.nlm.nih.gov/pubmed/23176611 http://dx.doi.org/10.1186/1750-1172-7-91 |
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