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
Identifieur interne : 001517 ( Pmc/Curation ); précédent : 001516; suivant : 001518Safety 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
Auteurs : Dominique P. Germain [France] ; Roberto Giugliani [Brésil] ; Derralynn A. Hughes [Royaume-Uni] ; Atul Mehta [Royaume-Uni] ; Kathy Nicholls [Australie] ; Laura Barisoni [États-Unis] ; Charles J. Jennette [États-Unis] ; Alexander Bragat [États-Unis] ; Jeff Castelli [États-Unis] ; Sheela Sitaraman [États-Unis] ; David J. Lockhart [États-Unis] ; Pol F. Boudes [États-Unis]Source :
- Orphanet Journal of Rare Diseases [ 1750-1172 ] ; 2012.
Abstract
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.
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.
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
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
Clinicaltrial.gov: NCT00283959 and NCT00283933
Url:
DOI: 10.1186/1750-1172-7-91
PubMed: 23176611
PubMed Central: 3527132
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Germain</name><affiliation wicri:level="1"><nlm:aff id="I1">Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles – St Quentin en Yvelines (UVSQ), Garches, 92380, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles – St Quentin en Yvelines (UVSQ), Garches, 92380</wicri:regionArea></affiliation></author><author><name sortKey="Giugliani, Roberto" sort="Giugliani, Roberto" uniqKey="Giugliani R" first="Roberto" last="Giugliani">Roberto Giugliani</name><affiliation wicri:level="1"><nlm:aff id="I2">Medical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil</nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Medical Genetics Service, HCPA/UFRGS, Porto Alegre</wicri:regionArea></affiliation></author><author><name sortKey="Hughes, Derralynn A" sort="Hughes, Derralynn A" uniqKey="Hughes D" first="Derralynn A" last="Hughes">Derralynn A. 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Boudes</name><affiliation wicri:level="1"><nlm:aff id="I7">Amicus Therapeutics, Cranbury, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Amicus Therapeutics, Cranbury, NJ</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23176611</idno><idno type="pmc">3527132</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527132</idno><idno type="RBID">PMC:3527132</idno><idno type="doi">10.1186/1750-1172-7-91</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001657</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001657</idno><idno type="wicri:Area/Pmc/Curation">001517</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001517</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">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><author><name sortKey="Germain, Dominique P" sort="Germain, Dominique P" uniqKey="Germain D" first="Dominique P" last="Germain">Dominique P. Germain</name><affiliation wicri:level="1"><nlm:aff id="I1">Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles – St Quentin en Yvelines (UVSQ), Garches, 92380, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles – St Quentin en Yvelines (UVSQ), Garches, 92380</wicri:regionArea></affiliation></author><author><name sortKey="Giugliani, Roberto" sort="Giugliani, Roberto" uniqKey="Giugliani R" first="Roberto" last="Giugliani">Roberto Giugliani</name><affiliation wicri:level="1"><nlm:aff id="I2">Medical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil</nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea>Medical Genetics Service, HCPA/UFRGS, Porto Alegre</wicri:regionArea></affiliation></author><author><name sortKey="Hughes, Derralynn A" sort="Hughes, Derralynn A" uniqKey="Hughes D" first="Derralynn A" last="Hughes">Derralynn A. Hughes</name><affiliation wicri:level="1"><nlm:aff id="I3">Royal Free Campus, University College London, London, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Royal Free Campus, University College London, London</wicri:regionArea></affiliation></author><author><name sortKey="Mehta, Atul" sort="Mehta, Atul" uniqKey="Mehta A" first="Atul" last="Mehta">Atul Mehta</name><affiliation wicri:level="1"><nlm:aff id="I3">Royal Free Campus, University College London, London, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Royal Free Campus, University College London, London</wicri:regionArea></affiliation></author><author><name sortKey="Nicholls, Kathy" sort="Nicholls, Kathy" uniqKey="Nicholls K" first="Kathy" last="Nicholls">Kathy Nicholls</name><affiliation wicri:level="1"><nlm:aff id="I4">Royal Melbourne Hospital, Parkville, VIC, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Royal Melbourne Hospital, Parkville, VIC</wicri:regionArea></affiliation></author><author><name sortKey="Barisoni, Laura" sort="Barisoni, Laura" uniqKey="Barisoni L" first="Laura" last="Barisoni">Laura Barisoni</name><affiliation wicri:level="1"><nlm:aff id="I5">New York University School of Medicine, New York, NY, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>New York University School of Medicine, New York, NY</wicri:regionArea></affiliation></author><author><name sortKey="Jennette, Charles J" sort="Jennette, Charles J" uniqKey="Jennette C" first="Charles J" last="Jennette">Charles J. Jennette</name><affiliation wicri:level="1"><nlm:aff id="I6">University of North Carolina, Chapel Hill, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of North Carolina, Chapel Hill, NC</wicri:regionArea></affiliation></author><author><name sortKey="Bragat, Alexander" sort="Bragat, Alexander" uniqKey="Bragat A" first="Alexander" last="Bragat">Alexander Bragat</name><affiliation wicri:level="1"><nlm:aff id="I7">Amicus Therapeutics, Cranbury, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Amicus Therapeutics, Cranbury, NJ</wicri:regionArea></affiliation></author><author><name sortKey="Castelli, Jeff" sort="Castelli, Jeff" uniqKey="Castelli J" first="Jeff" last="Castelli">Jeff Castelli</name><affiliation wicri:level="1"><nlm:aff id="I7">Amicus Therapeutics, Cranbury, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Amicus Therapeutics, Cranbury, NJ</wicri:regionArea></affiliation></author><author><name sortKey="Sitaraman, Sheela" sort="Sitaraman, Sheela" uniqKey="Sitaraman S" first="Sheela" last="Sitaraman">Sheela Sitaraman</name><affiliation wicri:level="1"><nlm:aff id="I7">Amicus Therapeutics, Cranbury, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Amicus Therapeutics, Cranbury, NJ</wicri:regionArea></affiliation></author><author><name sortKey="Lockhart, David J" sort="Lockhart, David J" uniqKey="Lockhart D" first="David J" last="Lockhart">David J. Lockhart</name><affiliation wicri:level="1"><nlm:aff id="I7">Amicus Therapeutics, Cranbury, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Amicus Therapeutics, Cranbury, NJ</wicri:regionArea></affiliation></author><author><name sortKey="Boudes, Pol F" sort="Boudes, Pol F" uniqKey="Boudes P" first="Pol F" last="Boudes">Pol F. Boudes</name><affiliation wicri:level="1"><nlm:aff id="I7">Amicus Therapeutics, Cranbury, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Amicus Therapeutics, Cranbury, NJ</wicri:regionArea></affiliation></author></analytic><series><title level="j">Orphanet Journal of Rare Diseases</title><idno type="eISSN">1750-1172</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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 <italic>in vitro</italic> 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 <italic>in vivo</italic> had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated.</p></sec><sec><title>Conclusions</title><p>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 <italic>GLA</italic> mutations. Phase 3 studies are ongoing.</p></sec><sec><title>Trial registration</title><p>Clinicaltrial.gov: NCT00283959 and NCT00283933</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Germain, Dp" uniqKey="Germain D">DP Germain</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eng, Cm" uniqKey="Eng C">CM Eng</name></author><author><name sortKey="Guffon, N" uniqKey="Guffon N">N Guffon</name></author><author><name sortKey="Wilcox, Wr" uniqKey="Wilcox W">WR Wilcox</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schiffmann, R" uniqKey="Schiffmann R">R Schiffmann</name></author><author><name sortKey="Kopp, Jb" uniqKey="Kopp J">JB Kopp</name></author><author><name sortKey="Austin, Ha" uniqKey="Austin H">HA Austin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alfhadel, M" uniqKey="Alfhadel M">M Alfhadel</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Orphanet J Rare Dis</journal-id><journal-id journal-id-type="iso-abbrev">Orphanet J Rare Dis</journal-id><journal-title-group><journal-title>Orphanet Journal of Rare Diseases</journal-title></journal-title-group><issn pub-type="epub">1750-1172</issn><publisher><publisher-name>BioMed Central</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23176611</article-id><article-id pub-id-type="pmc">3527132</article-id><article-id pub-id-type="publisher-id">1750-1172-7-91</article-id><article-id pub-id-type="doi">10.1186/1750-1172-7-91</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-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</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" equal-contrib="yes" id="A1"><name><surname>Germain</surname><given-names>Dominique P</given-names></name><xref ref-type="aff" rid="I1">1</xref><email>dominique.germain@rpc.aphp.fr</email></contrib><contrib contrib-type="author" equal-contrib="yes" id="A2"><name><surname>Giugliani</surname><given-names>Roberto</given-names></name><xref ref-type="aff" rid="I2">2</xref><email>rgiugliani@hcpa.ufrgs.br</email></contrib><contrib contrib-type="author" id="A3"><name><surname>Hughes</surname><given-names>Derralynn A</given-names></name><xref ref-type="aff" rid="I3">3</xref><email>rmgvdah@ucl.ac.uk</email></contrib><contrib contrib-type="author" id="A4"><name><surname>Mehta</surname><given-names>Atul</given-names></name><xref ref-type="aff" rid="I3">3</xref><email>atul.mehta1@nhs.net</email></contrib><contrib contrib-type="author" id="A5"><name><surname>Nicholls</surname><given-names>Kathy</given-names></name><xref ref-type="aff" rid="I4">4</xref><email>kathy.nicholls@mh.org.au</email></contrib><contrib contrib-type="author" id="A6"><name><surname>Barisoni</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="I5">5</xref><email>Laura.Barisoni@nyumc.org</email></contrib><contrib contrib-type="author" id="A7"><name><surname>Jennette</surname><given-names>Charles J</given-names></name><xref ref-type="aff" rid="I6">6</xref><email>charles_jennette@med.unc.edu</email></contrib><contrib contrib-type="author" id="A8"><name><surname>Bragat</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="I7">7</xref><email>abragat@amicusrx.com</email></contrib><contrib contrib-type="author" id="A9"><name><surname>Castelli</surname><given-names>Jeff</given-names></name><xref ref-type="aff" rid="I7">7</xref><email>jcastelli@amicusrx.com</email></contrib><contrib contrib-type="author" id="A10"><name><surname>Sitaraman</surname><given-names>Sheela</given-names></name><xref ref-type="aff" rid="I7">7</xref><email>ssitaraman@amicusrx.com</email></contrib><contrib contrib-type="author" id="A11"><name><surname>Lockhart</surname><given-names>David J</given-names></name><xref ref-type="aff" rid="I7">7</xref><email>dlockhart@amicusrx.com</email></contrib><contrib contrib-type="author" id="A12"><name><surname>Boudes</surname><given-names>Pol F</given-names></name><xref ref-type="aff" rid="I7">7</xref><email>pboudes@amicusrx.com</email></contrib></contrib-group><aff id="I1"><label>1</label>Division of Medical Genetics, Hôpital Raymond Poincaré (AP-HP), University of Versailles – St Quentin en Yvelines (UVSQ), Garches, 92380, France</aff><aff id="I2"><label>2</label>Medical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil</aff><aff id="I3"><label>3</label>Royal Free Campus, University College London, London, UK</aff><aff id="I4"><label>4</label>Royal Melbourne Hospital, Parkville, VIC, Australia</aff><aff id="I5"><label>5</label>New York University School of Medicine, New York, NY, USA</aff><aff id="I6"><label>6</label>University of North Carolina, Chapel Hill, NC, USA</aff><aff id="I7"><label>7</label>Amicus Therapeutics, Cranbury, NJ, USA</aff><pub-date pub-type="collection"><year>2012</year></pub-date><pub-date pub-type="epub"><day>24</day><month>11</month><year>2012</year></pub-date><volume>7</volume><fpage>91</fpage><lpage>91</lpage><history><date date-type="received"><day>8</day><month>7</month><year>2012</year></date><date date-type="accepted"><day>12</day><month>11</month><year>2012</year></date></history><permissions><copyright-statement>Copyright ©2012 Germain et al.; licensee BioMed Central Ltd.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>Germain et al.; licensee BioMed Central Ltd.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.0"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri xlink:href="http://www.ojrd.com/content/7/1/91"></self-uri><abstract><sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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 <italic>in vitro</italic> 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 <italic>in vivo</italic> had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated.</p></sec><sec><title>Conclusions</title><p>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 <italic>GLA</italic> mutations. Phase 3 studies are ongoing.</p></sec><sec><title>Trial registration</title><p>Clinicaltrial.gov: NCT00283959 and NCT00283933</p></sec></abstract><kwd-group><kwd>Pharmacological chaperone</kwd><kwd>Conformational diseases</kwd><kwd>Protein-misfolding</kwd><kwd>Fabry disease</kwd><kwd>Lysosomal storage disorder</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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