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


METHODS
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.


CONCLUSIONS
Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.
Department of Medicine, Division of Gastroenterology, University of Leuven, Herestraat 49, 3052 Leuven, Belgium. paul.rutgeerts@uz.kuleuven.ac.be
Paul J
PJ
Rutgeerts
Richard N
RN
Fedorak
Daan W
DW
Hommes
Andreas
A
Sturm
Daniel C
DC
Baumgart
Brian
B
Bressler
Stefan
S
Schreiber
John C
JC
Mansfield
Marna
M
Williams
Meina
M
Tang
Jennifer
J
Visich
Xiaohui
X
Wei
Mary
M
Keir
Diana
D
Luca
Dimitri
D
Danilenko
Jackson
J
Egen
Sharon
S
O'Byrne
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D003093:Colitis, Ulcerative / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C559198:etrolizumab