Ibalizumab (IBA) is a humanized monoclonal antibody that binds to a conformational epitope on the domain 2 region of human CD4 receptors thereby blocking entry of HIV into CD4 lymphocytes. It is a long-acting HIV entry inhibitor currently in Phase 3 development for the treatment of multi-drug resistant (MDR) HIV infection via intravenous (IV) administration. In this ongoing adaptive design study, we aimed to investigate the pharmacokinetics (PK), safety, antiretroviral activity, and pharmacodynamics (PD) of intramuscular (IM) administration of different doses of IBA. This report presents results of the 800 mg IM dose group as it offers the most direct comparison to the previous IV administration trial in patients with MDR HIV.
A Phase 1/2, randomized study of IBA injection was conducted, which enrolled HIV positive patients with HIV-1 RNA ≥5000 copies/mL who have not received antiretroviral (ARV) treatment for the preceding year. Injections of 800 mg IBA were administrated intramuscularly every two weeks with no other ARVs on three occasions.
All eight patients enrolled in the 800 mg dose group were males with a mean age of 28 years. At Baseline (BL), mean viral load (VL) was 55,000 copies/mL and mean CD4+T cell count was 314 cells/µL. Starting ~3 days post-injection, after serum concentrations peaked, the PK profile of 800 mg IM IBA was comparable to that of IV IBA infusions (from study TMB-202, Figure 1). The terminal half-life (T1/2) was 0.86 day and distribution T1/2 was 3.47 days. The mean trough concentration was 5-14 µg/mL and the mean CD4 receptor occupancy (RO) was greater than 80% during the dosing period. The mean maximum VL reduction was 1.23 log10 at Day 7 following the first administration, followed by a return toward BL at the end of dosing. After three doses, CD4+ T cell counts were 51% higher than Baseline, on average. No serious adverse events or discontinuations were reported during the study period. No injection site reactions were reported.
The PK profile of biweekly 800 mg IBA administered IM was comparable to the IV PK profile from a previous study. IBA at 800 mg was safe, well tolerated, and produced clinically significant viral load reductions at Day 7 as monotherapy.