Pharmacokinetic and Pharmacodynamic Properties of TRU-015, a CD20-Directed Small Modular Immunopharmaceutical Protein Therapeutic, in Patients with Rheumatoid Arthritis: A Phase I, Open-Label, Dose-Escalation Clinical Study

Background: TRU-015 is a small modular immunopharmaceutical protein drug that binds to CD20 and effectively depleted B cells in nonhuman primates. Objective: The aim of this clinical study was to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties, immunogenicity, and tolerability of TRU-015 in patients with rheumatoid arthritis (RA). Methods: This Phase 1, open-label, dose-escalation clinical study was conducted at 4 medical centers in the United States. Patients with RA who were receiving stable-dose methotrexate were enrolled in 1 of 8 dose groups and received TRU-015 as a single IV dose of 0.015, 0.05, 0.15, 0.5, 1.5, 5, or 15, or 2 IV doses of 15 mg/kg, administered 7 days apart (30 mg/kg). Patients were enrolled in the next higher dose cohort based on the tolerability observed in the prior cohort. Prior to TRU-015 infusion, patients were premedicated with an antihistamine and acetaminophen and may have received a corticosteroid at the investigator's discretion. Serum samples were collected for analysis of PK properties (serum t(1/2)) and neutralizing antibodies to TRU-015; enzyme-linked immunosorbent assays and a cell-based neutralizing assay were used to evaluate samples from patients. PD response was measured using B-cell (CD19(+)-cell) count using flow cytometry at prespecified time points. Tolerability was assessed during drug infusion and at prespecified time points after infusion using physical examination and laboratory analysis. Patients were followed for >= 4 weeks and until B-cell recovery. Results: Thirty-seven patients were enrolled. Most were female (81%) and white (95%); the mean age was 53 years. Serum t(1/2) ranged from 12 to 19 days. B-cell depletion generally increased in degree and duration with increasing doses. No neutralizing antibodies to TRU-015 were detected. Mild adverse events (AEs) included back pain, headache, peripheral edema, and upper respiratory infection (5 patients each). Mild urticaria occurred in 1 patient. Grade 3 AEs included hypertension, arthralgia, and urticaria and bronchospasm (1 patient each). No dose-limiting toxicity was found. Conclusions: In this small population of patients with RA, the C-max and the AUC appeared to increase in a dose-proportional manner. The mean t(1/2) ranged from 12 to 19 days. TRU-015 was associated with dose-dependent B-cell depletion and an acceptable tolerability profile. (Clin Ther. 2008;30:1806-1816) (C) 2008 Excerpta Medica Inc.