Introduction\nNerve growth factor plays a key role in the pathology of osteoarthritis (OA) related chronic pain. The aim of these studies was to evaluate the safety, tolerability, pharmacokinetics, and clinical response of AMG 403, a human anti-nerve growth factor monoclonal antibody, in healthy volunteers and subjects with knee OA.\n\nMethods\nTwo phase I, randomized, placebo-controlled, double-blind studies were conducted. The single-ascending dose study randomized healthy volunteers (n�=�48) 3:1 to receive AMG 403 (1, 3, 10, or 30 mg intravenously; or 10 or 30 mg subcutaneously; n�=�8 per group) or placebo. The multiple-ascending dose study randomized knee OA subjects (n�=�18) 3:1 to receive AMG 403 (3, 10, or 20 mg subcutaneously once monthly for four doses) or placebo. Safety, tolerability, and pharmacokinetics (PK) were assessed for both studies. Patient�s and physician�s disease assessments and total WOMAC score were determined in knee OA subjects.\n\nResults\nAMG 403 appeared to be well-tolerated after single and multiple doses, except for subject-reported hyperesthesia, pain, and paresthesia (mild to moderate severity). These treatment-emergent neurosensory events showed evidence of reversibility and a possible dose-dependence. Three serious adverse events were reported in AMG 403 treated subjects, but were not considered treatment related. AMG 403 PK was linear with an estimated half-life of 19.6 to 25.8 days. After multiple doses, AMG 403 PK showed modest accumulation (�2.4-fold increase) in systemic exposure. Knee OA diagnosis, body weight, and anti-drug antibody development did not appear to affect AMG 403 PK. Patient�s and physician�s disease assessments and total WOMAC score showed improvement in AMG 403 treated knee OA subjects compared with placebo.\n\nConclusions\nAMG 403 was generally safe and well-tolerated in both healthy volunteers and knee OA patients, and exhibited linear pharmacokinetics. Preliminary clinical efficacy was observed in knee OA subjects.
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