Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine produced in response to pro-inflammatory stimuli, drives allergic inflammatory responses mostly through its effect on dendritic and mast cells. TSLP reportedly is increased in the airways of asthmatic subjects. AMG 157 is a human anti-TSLP monoclonal antibody that blocks interaction between TSLP and its receptor. The goal of this study was to evaluate AMG 157 effects on asthma biomarkers in mild atopic asthmatic subjects after an inhaled allergen challenge. The study consisted of 31 subjects who received three doses, at monthly intervals, of 700mg AMG 157 (n=16) or placebo (n=15). Allergen challenges were performed pre-dose, and 6 and 12 weeks after initiation of dosing. Sputum eosinophil counts, blood mRNA and fractional exhaled nitric oxide (FeNO) were collected before and after allergen challenge and blood eosinophil counts and Th2/Th1 ratio were followed prior to allergen challenge through the treatment period. AMG 157 attenuated allergen-induced airway responses. Pre-allergen FeNO and blood and sputum eosinophil counts decreased significantly with AMG 157. In whole blood transcript analysis, genes highly expressed in eosinophils were elevated after allergen challenge. Pre-dose gene expression and eosinophil count were well-correlated. However, no AMG 157 effects on blood transcript profiles were detected. Treatment with AMG 157 was associated with a decreased Th2/Th1 cell ratio, driven mostly by a decrease in Th2 cells. The reduction in these markers of airway and systemic inflammation in AMG 157-treated subjects supports a role of TSLP in allergen-induced responses in patients with allergic asthma.

AIMS:AMG 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.METHODS:Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α4 β7 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.RESULTS:Following s.c. dosing, AMG 181 was absorbed with a median tmax ranging between 2-10 days and a bioavailability between 82% and 99%. Cmax and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70-210 mg s.c. and 70-420 mg i.v. ranges. The linear β-phase t1/2 was 31 (range 20-48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml(-1) . The PD effect on α4 β7 RO showed an EC50 of 0.01 μg ml(-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.CONCLUSIONS:AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.