A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis
Identifieur interne : 000428 ( Main/Exploration ); précédent : 000427; suivant : 000429A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis
Auteurs : Paul J. Rutgeerts [Belgique] ; Richard N. Fedorak [Canada] ; Daan W. Hommes [États-Unis] ; Andreas Sturm [Allemagne] ; Daniel C. Baumgart [Allemagne] ; Brian Bressler [Canada] ; Stefan Schreiber [Allemagne] ; John C. Mansfield [Royaume-Uni] ; Marna Williams [États-Unis] ; Meina Tang [États-Unis] ; Jennifer Visich [États-Unis] ; Xiaohui Wei [États-Unis] ; Mary Keir [États-Unis] ; Diana Luca [États-Unis] ; Dimitri Danilenko [États-Unis] ; Jackson Egen [États-Unis] ; Sharon O'Byrne [États-Unis]Source :
- Gut [ 0017-5749 ] ; 2013-08.
Abstract
Objective Etrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. Design In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). Results In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. Conclusion Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.
Url:
DOI: 10.1136/gutjnl-2011-301769
Affiliations:
- Allemagne, Belgique, Canada, Royaume-Uni, États-Unis
- Berlin, Californie, Schleswig-Holstein
- Berlin, Kiel
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type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Egen, Jackson" sort="Egen, Jackson" uniqKey="Egen J" first="Jackson" last="Egen">Jackson Egen</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech Research & Early Development, South San Francisco, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="O Byrne, Sharon" sort="O Byrne, Sharon" uniqKey="O Byrne S" first="Sharon" last="O'Byrne">Sharon O'Byrne</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Genentech Research & Early Development, South San Francisco, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Gut</title><title level="j" type="abbrev">Gut</title><idno type="ISSN">0017-5749</idno><idno type="eISSN">1468-3288</idno><imprint><publisher>BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><date type="published" when="2013-08">2013-08</date><biblScope unit="volume">62</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="1122">1122</biblScope></imprint><idno type="ISSN">0017-5749</idno></series><idno type="istex">D5F156BE9F0AFD95EB8DA29F415CE0F8BC601F7F</idno><idno type="DOI">10.1136/gutjnl-2011-301769</idno><idno type="href">gutjnl-62-1122.pdf</idno><idno type="ArticleID">gutjnl-2011-301769</idno><idno type="PMID">22717454</idno><idno type="local">gutjnl;62/8/1122</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0017-5749</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Objective Etrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. Design In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). Results In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. Conclusion Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Belgique</li><li>Canada</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Berlin</li><li>Californie</li><li>Schleswig-Holstein</li></region><settlement><li>Berlin</li><li>Kiel</li></settlement></list><tree><country name="Belgique"><noRegion><name sortKey="Rutgeerts, Paul J" sort="Rutgeerts, Paul J" uniqKey="Rutgeerts P" first="Paul J" last="Rutgeerts">Paul J. Rutgeerts</name></noRegion><name sortKey="Rutgeerts, Paul J" sort="Rutgeerts, Paul J" uniqKey="Rutgeerts P" first="Paul J" last="Rutgeerts">Paul J. Rutgeerts</name></country><country name="Canada"><noRegion><name sortKey="Fedorak, Richard N" sort="Fedorak, Richard N" uniqKey="Fedorak R" first="Richard N" last="Fedorak">Richard N. Fedorak</name></noRegion><name sortKey="Bressler, Brian" sort="Bressler, Brian" uniqKey="Bressler B" first="Brian" last="Bressler">Brian Bressler</name></country><country name="États-Unis"><region name="Californie"><name sortKey="Hommes, Daan W" sort="Hommes, Daan W" uniqKey="Hommes D" first="Daan W" last="Hommes">Daan W. Hommes</name></region><name sortKey="Danilenko, Dimitri" sort="Danilenko, Dimitri" uniqKey="Danilenko D" first="Dimitri" last="Danilenko">Dimitri Danilenko</name><name sortKey="Egen, Jackson" sort="Egen, Jackson" uniqKey="Egen J" first="Jackson" last="Egen">Jackson Egen</name><name sortKey="Keir, Mary" sort="Keir, Mary" uniqKey="Keir M" first="Mary" last="Keir">Mary Keir</name><name sortKey="Luca, Diana" sort="Luca, Diana" uniqKey="Luca D" first="Diana" last="Luca">Diana Luca</name><name sortKey="O Byrne, Sharon" sort="O Byrne, Sharon" uniqKey="O Byrne S" first="Sharon" last="O'Byrne">Sharon O'Byrne</name><name sortKey="Tang, Meina" sort="Tang, Meina" uniqKey="Tang M" first="Meina" last="Tang">Meina Tang</name><name sortKey="Visich, Jennifer" sort="Visich, Jennifer" uniqKey="Visich J" first="Jennifer" last="Visich">Jennifer Visich</name><name sortKey="Wei, Xiaohui" sort="Wei, Xiaohui" uniqKey="Wei X" first="Xiaohui" last="Wei">Xiaohui Wei</name><name sortKey="Williams, Marna" sort="Williams, Marna" uniqKey="Williams M" first="Marna" last="Williams">Marna Williams</name></country><country name="Allemagne"><region name="Berlin"><name sortKey="Sturm, Andreas" sort="Sturm, Andreas" uniqKey="Sturm A" first="Andreas" last="Sturm">Andreas Sturm</name></region><name sortKey="Baumgart, Daniel C" sort="Baumgart, Daniel C" uniqKey="Baumgart D" first="Daniel C" last="Baumgart">Daniel C. Baumgart</name><name sortKey="Schreiber, Stefan" sort="Schreiber, Stefan" uniqKey="Schreiber S" first="Stefan" last="Schreiber">Stefan Schreiber</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Mansfield, John C" sort="Mansfield, John C" uniqKey="Mansfield J" first="John C" last="Mansfield">John C. Mansfield</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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