544. Pharmacokinetic Profile of Ibalizumab From a Phase 3 Trial

Background Ibalizumab (IBA) is a long-acting humanized monoclonal antibody that binds domain 2 of the CD4 receptor and blocks HIV-1 infection of host cells. TMB-301 was a 24-week, Phase 3 clinical trial conducted in 40 heavily treatment-experienced patients with multidrug-resistant (MDR) HIV-1 investigating the safety, efficacy and tolerability of IBA. Patients received a 2,000 mg IBA loading dose followed by 800 mg every 2 weeks by intravenous infusion plus an optimized background regimen. Viral load <50 and <200 HIV RNA copies/mL was achieved in 43% and 50% of patients, respectively, at Week 25. We determined the pharmacokinetic profile of IBA, i.e., serum concentrations, CD4 receptor occupancy (RO), and CD4 receptor density (RD), in these patients with MDR HIV-1. Methods Pre- and post-dose blood samples collected at various time points during trial were used to determine IBA serum concentrations, CD4 RO and RD at trough. IBA serum concentrations were measured using a validated ELISA. IBA bound to CD4+ T cells (RO) and cell surface CD4 levels (RD) were measured simultaneously by flow cytometry using the Molecules of Equivalent Soluble Fluorescence approach. Results The maximum IBA serum concentrations were observed immediately after the end of the 2,000 mg infusion with mean (SD) of 567 (235) μg/mL. Steady state was reached at Week 4 after the loading dose. The mean IBA concentrations were >30 μg/mL throughout the dosing period. Both Cpeak and Ctrough (Day 7 and Week 25 IBA concentrations) were decreased with increased body weight. The median Ctrough in the high body weight group (≥85 kg) was 0.23 μg/mL. The mean RO was >85% throughout the dosing period. The 2,000 mg loading dose helped to reach >85% RO after the initial dose and maintain high levels of RO throughout the dosing period. Elevation in RO was generally associated with increased IBA serum concentrations; concentrations ≥0.13 μg/mL supported ≥85% CD4 RO. After IBA administration, down-modulation of surface CD4 receptors by up to 20% was observed. There was no apparent association between IBA serum concentration and RD probably due to high inter-individual variation. Conclusion Dosing regimen of 2,000 mg loading dose followed by 800 mg every 2 weeks was sufficient to support high levels of RO and to maintain the drug concentration above the therapeutic level. Disclosures P. N. Kumar, TheraTechnologies: Consultant and Investigator, Consulting fee and Research grant. ViiV: Consultant, Investigator and Shareholder, Research grant and Speaker honorarium. Merck: Investigator and Shareholder, Research grant. Gilead: Consultant, Investigator and Shareholder, Consulting fee and Research grant. S. Weinheimer, TaiMed Biologics: Employee, Salary. Z. Cohen, Theratechnologies Inc.: Employee, Salary. C. Marsolais, Theratechnologies Inc.: Employee, Salary. K. L. Kuo, TaiMed Biologics Taiwan: Employee, Salary. S. Lewis, TaiMed Biologics: Employee, Salary.