Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody, for treating inflammatory bowel diseases

AimsAMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study. MethodsHealthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70mg s.c. (or i.v.), 210mg s.c. (or i.v.), 420mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male:female 2:2) received 210mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), (47) receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3-9 months after dose. ResultsFollowing s.c. dosing, AMG 181 was absorbed with a median t(max) ranging between 2-10 days and a bioavailability between 82% and 99%. C-max and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210mg s.c. and 70-420mg i.v. ranges. The linear -phase t(1/2) was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1gml(-1). The PD effect on (47) RO showed an EC50 of 0.01gml(-1). Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed. ConclusionsAMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.