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

Abstract

ObjectiveEtrolizumab (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.DesignIn 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).ResultsIn 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.ConclusionEtrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.

Current and emerging therapeutic targets for IBD

“…Prospective studies comparing vedolizumab with TNF blockers such as infliximab in anti TNF agent naive patients will determine the precise position ing of vedolizu mab in the treatment algorithm for IBD. On the basis of the success of the anti α4β7 integrin approach with vedolizumab, further therapies target ing T cell homing are currently tested in clinical trials including anti MAdCAM1 antibodies (PF 00547659) and the anti β7 integrin antibody etrolizumab [66][67][68] (FIG. 1).…”

The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions

“…Etrolizumab is a humanized antibody targeting the b-7 subunit of a-4-b-7 and a-E-b-7 integrins delivered by self-injection. It is efficacious and safe for ulcerative colitis according to phase I and II studies [87,88]. It is now in phase III clinical trials for Crohn's disease (NCT02394028) and ulcerative colitis (NCT02165215, NCT02171429, NCT02100696).…”

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

“…To improve efficiency and reduce the costs associated with drug development, pharmacodynamic (PD) biomarkers have demonstrated promise in aiding in the rational design of clinical trials 2, 3, 4, 5, 6.…”

“…RO assays have been developed and applied in both nonclinical and clinical studies to provide insight into PKPD relationships. For example, RO on circulating cells has been utilized as a PD biomarker for a number of therapeutic antibodies, such as anti‐PD‐1 2, anti‐PD‐L1 3, AMG479 4, ATR‐107 5, and Etrolizumab 6.…”