Ibalizumab (IBA) is a long-acting post-attachment inhibitor approved for the treatment of multi-drug resistant HIV-1 infection in heavily treatment-experienced (HTE) adults. IBA is diluted in 250 mL of saline and administered via intravenous infusion (IVI) as a loading dose of 2000 mg followed by 800 mg maintenance doses, every 2 weeks. We sought to evaluate administration of IBA maintenance doses as undiluted IV push (IVP) over 30 seconds (s).
In TMB-302, an open-label non-randomized phase 3 study, clinically stable people with HIV (PWH) on IBA-containing ARV regimens and HIV-uninfected individuals (UI) were administered IBA at progressively increasing concentrations over shortening intervals and then as IVP. Blood samples were collected at various times pre- and post-dosing via IVI and IVP to estimate PK parameters. A PK bridge between IVI and IVP was demonstrated if the proportion of subjects with IBA serum trough concentrations (Ctrough) ? 300 ng/mL was comparable by two one-sided tests of significance (TOST), and the 90% confidence interval (CI) of area under the curve (AUC) geometric mean ratios was within 0.80-1.25. All subjects were followed for safety throughout and monitored for development of anti-drug antibodies (ADA). IBA efficacy was assessed in PWH by measuring viral load (VL).
A total of 22 subjects, 9 HIV+ and 13 HIV-, predominantly male (81.8%) and white (95.5%) were enrolled. All PWH and 10/13 UI completed the study. Reasons for discontinuation were: adverse events (AEs) unrelated to IBA, consent withdrawal and protocol noncompliance. The proportion of subjects with average Ctrough ? 300 ng/mL was 18/19 (94.7%) for both IVI and IVP and the 90% CI of the AUC ratio of IVP to IV Infusion was within the target value (0.9478-1.1226). Among PWH, median VL at baseline and end of study was <20 copies/mL, with no virologic failures observed. One subject experienced virologic rebound following the last IVP dose, which was linked to non-adherence to the oral antiretroviral regimen. All AEs were mild to moderate, with no serious AEs recorded and ADA were not detected for any subjects.
Administration of IBA as an undiluted IVP over 30s was safe and well tolerated in all participants, and remained effective among PWH. Bioequivalence between IVI and IVP administration was demonstrated and supports IVP as a potential alternative for delivery of IBA. Assessment of IM injection as an additional option for HTE patients is ongoing in this study.