A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis

• Published in: Gut Vol. 62; no. 8; pp. 1122 - 1130
• Main Authors: Rutgeerts, Paul J, Fedorak, Richard N, Hommes, Daan W, Sturm, Andreas, Baumgart, Daniel C, Bressler, Brian, Schreiber, Stefan, Mansfield, John C, Williams, Marna, Tang, Meina, Visich, Jennifer, Wei, Xiaohui, Keir, Mary, Luca, Diana, Danilenko, Dimitri, Egen, Jackson, O'Byrne, Sharon
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.08.2013; BMJ Publishing Group LTD; BMJ Group
• Series: Original article
• Subjects: Adolescent; Adult; Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; antibody targeted therapy; Apoptosis; arthritis; autoimmune disease; Cell adhesion & migration; cell cycle; Chronic illnesses; Colitis, Ulcerative - blood; Colitis, Ulcerative - drug therapy; Crohn's disease; cytokines; Dendritic cells; Dose-Response Relationship, Drug; Double-Blind Method; drug development; Etrolizumab; Female; Gastrointestinal Agents - administration & dosage; Gastrointestinal Agents - adverse effects; Gastrointestinal Agents - blood; Gastrointestinal Agents - therapeutic use; genetics; Headache; Humans; IBD; IBD basic research; IBD clinical; IBD models; IBD–genetics; Immunoglobulins; immunology; Inflammation; Inflammatory Bowel Disease; inflammatory bowel disorders; Infusions, Intravenous; Injection; Injections, Subcutaneous; Integrins; Intravenous administration; Lymphocytes; Male; Middle Aged; Migration; Monoclonal antibodies; Pharmacokinetics; Remission; Retention; rhuMAb β7; safety; Severity of Illness Index; signal transduction; Studies; Treatment Outcome; Ulcerative colitis; Wound healing; Young Adult; United States > US; IBD basic research; cell cycle; rhuMAb β7; signal transduction; IBD clinical; IBD models; drug development; Etrolizumab; apoptosis; Crohn's disease; IBD; autoimmune disease; antibody targeted therapy; integrins; dendritic cells; genetics; arthritis; safety; inflammatory bowel disorders; pharmacokinetics; cytokines; ulcerative colitis; immunology; IBD–genetics
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2011-301769

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.