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P225. Pharmacokinetics/pharmacodynamics and safety of AMG 181, a fully human anti-α 4 β 7 antibody for treating inflammatory bowel diseases (IBD)

P225. Pharmacokinetics/pharmacodynamics and safety of AMG 181, a fully human anti-α 4 β 7 antibody for treating inflammatory bowel diseases (IBD)

W.‑J. Pan1, B. Sullivan2, C. Evangelista2, D. Doherty1, C.‑Y. Tam1, S. Patel1, P. Prince1, K. Reynhardt3, W. Rees4, H. Hsu5, K. Zhou6, W. Gu7, M. Yen8, C. Haller9, S. Dodson10, Z. Yu10, L. Wienkers1, D. Borie11

1Amgen Inc., Pharmacokinetics and Drug Metabolism, Seattle, United States; 2Amgen Inc., Clinical Immunology, Thousand Oaks, United States; 3Amgen Inc., Clinical Immunology, Seattle, United States; 4Amgen Inc., Molecular Sciences and Computational Biology, Seattle, United States; 5Amgen Inc., Inflammation, Thousand Oaks, United States; 6Amgen Inc., Biostatistics, San Francisco, United States; 7Amgen Inc., Biostatistics, Thousand Oaks, United States; 8Parexel Early Phase, California Clinical Trials Trials Medical Group, Glendale, United States; 9Amgen Inc., Regulatory, San Francisco, United States; 10Amgen Inc., Early Development, Thousand Oaks, United States; 11Amgen Inc., Inflammation Clinical Research, Thousand Oaks, United States

Background: To evaluate safety, pharmacokinetics/pharmaco­dynamics (PK/PD), and tolerability of single subcutaneous (SC) or intravenous (IV) doses of AMG 181 in healthy or ulcerative colitis (UC) subjects. Registered at ID NCT01290042. On-going study sponsored by Amgen. Inc.

Methods: In this randomized, double-blinded, placebo-controlled, ascending single dose study, 68 healthy male subjects (18–44 yr, 56–121 kg) were randomized and administered single doses of AMG 181 or placebo at dose levels of 0.7, 2.1, 7, 21, 70 mg SC (or IV), 210 mg SC (or IV), and 420 mg IV. Eight UC subjects were randomized to receive a single dose of 210 mg AMG 181 or placebo SC (3:1 ratio). Serum was collected for evaluation of PK and anti-drug antibodies (ADA). Whole blood was collected to assess α 4 β 7 receptor occupancy (RO) and CD4 memory and naïve T cell counts using a validated whole blood 6‑color flow cytometric assay. PK and ADA samples were assayed using validated electrochemiluminescent immunoassay (ECL) methods with a lower limit of quantification (LLOQ) of 10 ng/mL and a lower limit of reliable detection (LLRD) of 20 ng/mL, respectively. Population PK/PD modeling, with demography as covariates, was conducted on AMG 181 concentration and RO data. The follow-up period was based on receptor occupancy, half-life and safety monitoring requirements.

Results: The median time to Cmax (tmax) for AMG 181 was 2–10 days after SC dosing, with a mean bioavailability of 83%. While Cmax was dose-proportional at 21–210 mg SC, both Cmax and AUCinf were dose-proportional at 70–420 mg IV. AMG 181 clearance was low (131 mL/day) and its volume of distribution was 4760 mL. AMG 181 had a linear elimination range half-life of 36 days, with terminal target-mediated disposition occurring below 1 µg/mL. The extent and duration of α 4 β 7 RO increased with AMG 181 dose. The Emax model estimated E0, Emax, and EC50 values for RO were 0.0824, 0.946, and 1.18 ng/mL, respectively. An increase in CD4 T cell counts in peripheral blood was not observed. All subjects tested negative for ADA. Blinded safety data showed a 44% adverse event rate, with no treatment-related ≥ Grade 3 events, serious adverse events, deaths, or dose limiting toxicities. There were no abnormalities in ECGs or neurological exams. No subject discontinued the study due to an adverse event.

Conclusions: AMG 181 is safe and well tolerated with desirable PK/PD properties under fixed dose regimens. It is suitable for further testing in patients with IBD.