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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<author><name sortKey="Boudes, Pol F" sort="Boudes, Pol F" uniqKey="Boudes P" first="Pol F" last="Boudes">Pol F. Boudes</name>
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<series><title level="j">Orphanet Journal of Rare Diseases</title>
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<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 sortKey="Sirrs, S" uniqKey="Sirrs S">S Sirrs</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fan, Jq" uniqKey="Fan J">JQ Fan</name>
</author>
<author><name sortKey="Ishii, S" uniqKey="Ishii S">S Ishii</name>
</author>
<author><name sortKey="Asano, N" uniqKey="Asano N">N Asano</name>
</author>
<author><name sortKey="Suzuki, Y" uniqKey="Suzuki Y">Y Suzuki</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ishii, S" uniqKey="Ishii S">S Ishii</name>
</author>
<author><name sortKey="Chang, Hh" uniqKey="Chang H">HH Chang</name>
</author>
<author><name sortKey="Kawasaki, K" uniqKey="Kawasaki K">K Kawasaki</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yam, Gh" uniqKey="Yam G">GH Yam</name>
</author>
<author><name sortKey="Zuber, C" uniqKey="Zuber C">C Zuber</name>
</author>
<author><name sortKey="Roth, J" uniqKey="Roth J">J Roth</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Benjamin, Er" uniqKey="Benjamin E">ER Benjamin</name>
</author>
<author><name sortKey="Flanagan, Jj" uniqKey="Flanagan J">JJ Flanagan</name>
</author>
<author><name sortKey="Schilling, A" uniqKey="Schilling A">A Schilling</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Khanna, R" uniqKey="Khanna R">R Khanna</name>
</author>
<author><name sortKey="Soska, R" uniqKey="Soska R">R Soska</name>
</author>
<author><name sortKey="Lun, Y" uniqKey="Lun Y">Y Lun</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mayes, Js" uniqKey="Mayes J">JS Mayes</name>
</author>
<author><name sortKey="Scheerer, Jb" uniqKey="Scheerer J">JB Scheerer</name>
</author>
<author><name sortKey="Sifers, Rn" uniqKey="Sifers R">RN Sifers</name>
</author>
<author><name sortKey="Donaldson, Ml" uniqKey="Donaldson M">ML Donaldson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wu, X" uniqKey="Wu X">X Wu</name>
</author>
<author><name sortKey="Katz, E" uniqKey="Katz E">E Katz</name>
</author>
<author><name sortKey="Della Valle, C" uniqKey="Della Valle C">C Della Valle</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Roddy, Tp" uniqKey="Roddy T">TP Roddy</name>
</author>
<author><name sortKey="Nelson, Bc" uniqKey="Nelson B">BC Nelson</name>
</author>
<author><name sortKey="Sung, Cc" uniqKey="Sung C">CC Sung</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fuller, M" uniqKey="Fuller M">M Fuller</name>
</author>
<author><name sortKey="Sharp, Pc" uniqKey="Sharp P">PC Sharp</name>
</author>
<author><name sortKey="Rozaklis, T" uniqKey="Rozaklis T">T Rozaklis</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Thurberg, Bl" uniqKey="Thurberg B">BL Thurberg</name>
</author>
<author><name sortKey="Rennke, H" uniqKey="Rennke H">H Rennke</name>
</author>
<author><name sortKey="Colvin, Rb" uniqKey="Colvin R">RB Colvin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Barisoni, L" uniqKey="Barisoni L">L Barisoni</name>
</author>
<author><name sortKey="Jennette, Jc" uniqKey="Jennette J">JC Jennette</name>
</author>
<author><name sortKey="Colvin, R" uniqKey="Colvin R">R Colvin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fan, Jq" uniqKey="Fan J">JQ Fan</name>
</author>
<author><name sortKey="Ishii, S" uniqKey="Ishii S">S Ishii</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Germain, Dp" uniqKey="Germain D">DP Germain</name>
</author>
<author><name sortKey="Fan, Jq" uniqKey="Fan J">JQ Fan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Banikazemi, M" uniqKey="Banikazemi M">M Banikazemi</name>
</author>
<author><name sortKey="Bultas, J" uniqKey="Bultas J">J Bultas</name>
</author>
<author><name sortKey="Waldek, S" uniqKey="Waldek S">S Waldek</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kitagawa, T" uniqKey="Kitagawa T">T Kitagawa</name>
</author>
<author><name sortKey="Ishige, N" uniqKey="Ishige N">N Ishige</name>
</author>
<author><name sortKey="Suzuki, K" uniqKey="Suzuki K">K Suzuki</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schiffmann, R" uniqKey="Schiffmann R">R Schiffmann</name>
</author>
<author><name sortKey="Waldek, S" uniqKey="Waldek S">S Waldek</name>
</author>
<author><name sortKey="Benigni, A" uniqKey="Benigni A">A Benigni</name>
</author>
<author><name sortKey="Auray Blais, C" uniqKey="Auray Blais C">C Auray-Blais</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Auray Blais, C" uniqKey="Auray Blais C">C Auray-Blais</name>
</author>
<author><name sortKey="Millington, Ds" uniqKey="Millington D">DS Millington</name>
</author>
<author><name sortKey="Barr, C" uniqKey="Barr C">C Barr</name>
</author>
<author><name sortKey="Young, Sp" uniqKey="Young S">SP Young</name>
</author>
<author><name sortKey="Mills, K" uniqKey="Mills K">K Mills</name>
</author>
<author><name sortKey="Clarke, Jt" uniqKey="Clarke J">JT Clarke</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Najafian, B" uniqKey="Najafian B">B Najafian</name>
</author>
<author><name sortKey="Svarstad, E" uniqKey="Svarstad E">E Svarstad</name>
</author>
<author><name sortKey="Bostad, L" uniqKey="Bostad L">L Bostad</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Whybra, C" uniqKey="Whybra C">C Whybra</name>
</author>
<author><name sortKey="Kampmann, C" uniqKey="Kampmann C">C Kampmann</name>
</author>
<author><name sortKey="Willers, I" uniqKey="Willers I">I Willers</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wilcox, Wr" uniqKey="Wilcox W">WR Wilcox</name>
</author>
<author><name sortKey="Oliveira, Jp" uniqKey="Oliveira J">JP Oliveira</name>
</author>
<author><name sortKey="Hopkin, Rj" uniqKey="Hopkin R">RJ Hopkin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kuznetsov, G" uniqKey="Kuznetsov G">G Kuznetsov</name>
</author>
<author><name sortKey="Nigam, Sk" uniqKey="Nigam S">SK Nigam</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bradbury, J" uniqKey="Bradbury J">J Bradbury</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cohen, Fe" uniqKey="Cohen F">FE Cohen</name>
</author>
<author><name sortKey="Kelly, Jw" uniqKey="Kelly J">JW Kelly</name>
</author>
</analytic>
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<pmc article-type="research-article" xml:lang="en"><pmc-dir>properties open_access</pmc-dir>
<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>
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