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Inflammatory bowel disease
Original article
A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis
  1. Paul J Rutgeerts1,
  2. Richard N Fedorak2,
  3. Daan W Hommes3,
  4. Andreas Sturm4,
  5. Daniel C Baumgart4,
  6. Brian Bressler5,
  7. Stefan Schreiber6,
  8. John C Mansfield7,
  9. Marna Williams8,
  10. Meina Tang8,
  11. Jennifer Visich8,
  12. Xiaohui Wei8,
  13. Mary Keir8,
  14. Diana Luca8,
  15. Dimitri Danilenko8,
  16. Jackson Egen8,
  17. Sharon O'Byrne8
  1. 1Department of Medicine, Division of Gastroenterology, University of Leuven, Leuven, Belgium
  2. 2University of Alberta, Edmonton, Alberta, Canada
  3. 3Center for Inflammatory Bowel Diseases, University of California Los Angeles, Los Angeles, California, USA
  4. 4U Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
  5. 5University of British Columbia, Vancouver, British Columbia, Canada
  6. 6Christian Albrechts University, Kiel, Germany
  7. 7University of Newcastle upon Tyne, Newcastle upon Tyne, UK
  8. 8Genentech Research & Early Development, South San Francisco, California, USA
  1. Correspondence to Professor Paul J Rutgeerts, Department of Medicine, Division of Gastroenterology, University of Leuven, Herestraat 49, 3052 Leuven, Belgium; paul.rutgeerts{at}uz.kuleuven.ac.be

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.

  • Etrolizumab
  • rhuMAb β7
  • ulcerative colitis
  • drug development
  • safety
  • pharmacokinetics
  • IBD clinical
  • IBD basic research
  • IBD
  • IBD models
  • apoptosis
  • cell cycle
  • immunology
  • inflammatory bowel disorders
  • dendritic cells
  • Crohn's disease
  • cytokines
  • genetics
  • signal transduction
  • IBD–genetics
  • antibody targeted therapy
  • arthritis
  • autoimmune disease
  • integrins

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

https://doi.org/10.1136/gutjnl-2011-301769

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    Footnotes

    • Funding This study was sponsored by Genentech, Inc.

    • Competing interests PR: honoraria for participating in scientific advisory boards by Genentech. RF: research grant funding from Genentech. DH: advisory board funding from Genentech. AS: payment for talks or consultancy or scientific research projects from Abbott, ArdeyPharm, Bayer-Schering, Centocor, Essex, Dr. Falk Pharma, Ferring, Fresenius, Shire, Merckle-Recordati, MSD, Travacare, UCB, Vifor and Genentech. DCB: honoraria for participating in scientific advisory boards organised by Genentech. All of his activities and contracts are in conformity with the ‘FSA-Kodex Fachkreise’ (voluntary self-monitoring code for expert consultants to the pharmaceutical industry), have been checked by the Medicolegal Department of Charité and have been approved by the directorate of the Faculty of Medicine. BB: Abbott, Merck, GSK, BMS, Amgen, Millenium Pharmaceuticals and Genentech. SS: Ad board services for Genentech. JM: Ad board services for Genentech. MW, MT, JV, XW, MK, DL, DD, JE and SO are employees of Genentech.

    • Patient consent Obtained.

    • Ethics approval Ethics approval was provided by Institutional review boards at each study site approved the protocol.

    • Provenance and peer review Not commissioned; externally peer reviewed.