Two First-in-Human, Open-Label, Phase I Dose-Escalation Safety Trials of MEDI-528, a Monoclonal Antibody Against Interleukin-9, in Healthy Adult Volunteers

Background: Interleukin-9 (IL-9) is involved in pathogenic aspects of the asthmatic response, including induction of the proliferation of T-helper type 2 lymphocytes, mucus production, and mast-cell differentiation, proliferation, and recruitment to the lung. In preclinical studies in mice, inhibition of IL-9 through neutralizing monoclonal antibody (mAb) treatment partially reduced airway hyperresponsiveness and mast-cell progenitor migration to the lung. Objective: The goal of the present studies was to determine the safety and pharmacokinetic profiles and immunogenicity of MEDI-528, a humanized Immunoglobulin G1(k) anti-IL-9 mAb, in healthy adult volunteers. Methods: In separate open-label, Phase I dose-escalation studies, single doses of MEDI-528 0.3, 1.0, 3.0, or 9.0 mg/kg were administered as an intravenous infusion (20 mg/min administered over 1-40 minutes, depending on dose) and by subcutaneous injection. All subjects were followed for 84 days. Any laboratory test value outside the normal reference range was considered an adverse event (AE). Results: Twenty-four subjects were enrolled in the intravenous Study, and 29 Subjects were enrolled in the subcutaneous study. No deaths or serious or severe AEs occurred in either study The most frequently reported AEs in the intravenous study were laboratory test abnormalities; the most frequently reported AEs in the Subcutaneous study were pharyngolaryngeal pain, palpable lymph nodes, and laboratory test abnormalities. The single-close pharmacokinetics of MEDI-528 were linear and dose proportional over the dose range studied with both routes of administration. The mean t(1/2) after intravenous administration was similar to 26 days (range, 25-28 days); the mean t(1/2) after sub cutaneous administration ranged front 33 to 87 days across doses. A low titer (1:80) of antibodies to MEDI-528 was detected on day 84 in a single volunteer receiving intravenous MEDI-528 3.0 mg/kg. No antibody titers were detected in any of the volunteers receiving Subcutaneous MEDI-528. Conclusions: Administered Intravenously or subcutaneously, MEDI-528 had an acceptable safety profile and exhibited linear pharmacokinetics over the dose range studied in healthy adults in these Phase I studies. The findings support further investigation of MEDI-528 in multiple-dose trials in patients with asthma. ClinicalTrials.gov Identification numbers: NCT001.92296 (intravenous Study); NCT00116168 (Subcutaneous study). (Clin Ther. 2009;31:728-740) (C) 2009 Excerpta Medica Inc.