Pharmacokinetics (PK) and pharmacodynamics (PD) of AMG 162, a fully human monoclonal antibody to Receptor Activator of NF kappa B Ligand (RANKL), following a single subcutaneous dose to patients with cancer-related bone lesions

8106 Background: RANKL is an essential osteoclastic differentiation/activation factor. AMG 162 PK and PD were evaluated in a phase 1, single dose, randomized, double-blind, double-dummy, active control (pamidronate), dose escalation study, in patients with breast cancer (BC) or multiple myeloma (MM), with lytic or mixed lytic-blastic bone lesions. Methods: Patients (n=54; 3–9/cohort) received a subcutaneous (SC) injection of either AMG 162 (0.1, 0.3, 1.0, or 3.0 mg/kg) or placebo (3:1 ratio) and an intravenous infusion of either 90 mg of pamidronate or saline. Blood and urine samples were collected for determinations of AMG 162 serum concentrations and the bone resorption marker, N-telopeptide levels (uNTx/Cr), respectively. Results: AMG 162 serum levels reached average maximums of 448 ng/mL (0.1 mg/kg) to 19,800 ng/mL (3.0 mg/kg) 14 to 21 days post-dose, and 625 ng/mL (0.1 mg/kg) to 20,100 ng/mL (3.0 mg/kg) 7 to 14 days post-dose in BC and MM patients, respectively. Serum levels were maintained above 100 ng/mL at 0.3 mg/kg and above 3000 ng/mL for 84 days following 3.0 mg/kg in both BC and MM patients. Rapid decreases in uNTx/Cr (within 24 hours) followed AMG 162 administration in BC and MM patients. At 0.3 mg/kg and greater, AMG 162 produced marked suppression in uNTx/Cr with median maximal suppression of greater than 50% in MM and 75% in BC patients. A 1.0 mg/kg dose produced sustained median suppression (>70%) in BC and MM patients for the duration of the study (84 days), while a 3.0 mg/kg dose produced similar suppression in BC yet less suppression in MM patients (∼38%). Conclusions: The favorable PK and PD of AMG 162 potentially allows for infrequent SC dosing in the treatment of bone disorders. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc. Amgen, Inc.