Broadly neutralizing antibodies (bNAbs) are being developed for long-acting HIV-1 therapy. VH3810109 (N6LS) is a CD4-bs antibody with broad and potent neutralization activity in vitro, which is currently being evaluated in the Phase 2a BANNER study.
BANNER is a randomized, open-label, 2-part, multicenter study in treatment-naive viremic (viral load [VL] ≥5000 c/mL) adults to evaluate safety, pharmacokinetics, and antiviral activity of VH3810109. In part 1, VH3810109 was evaluated during monotherapy after a single IV infusion of 40mg/kg or 280mg (~4mg/kg) followed by 48 weeks of standard-of-care ART. Monotherapy duration was determined by either virologic non-response (VL < 0.5 log10 by Day 11) or rebound (VL ≥1.0 log10 over nadir or < 0.5 log10 from baseline [BL]). Antibody sensitivity of pre-dose and rebound viruses was determined retrospectively, using the PhenoSense mAb assay. Here we report the impact of BL viral and participant factors, on maximum VL decline (VLD) and time to virologic rebound following infusion of VH3810109.
Fourteen participants enrolled, 13 were male, median (range) BL VL was 4.31 (3.13-5.24) log10 c/mL and median (range) BL CD4+ count was 369 (190-700) cells/mm3. Virologic response was observed in 13 participants; median (range) viral nadir from BL was 1.72 (0.60-2.60) and 1.18 (0.30-2.18) log10 c/mL for 40mg/kg and 280mg, respectively. In a post hoc analysis, BL VH3810109 IC80 and CD4+ cell count were moderately correlated with maximum VLD and time to viral rebound in both treatment arms. The 2 participants with the highest BL IC80s (1.512 and >50 µg/mL) had the smallest VLD (0.60 and 0.30 log10 c/mL) and the shortest time to rebound (12 days and virologic non-response). The longest time to rebound (78 days) was observed in the participant with the lowest IC80 (0.091 µg/mL). A weak correlation between lower BL log10 HIV-1 RNA and virologic response was apparent only in the 280mg dose group.
In BANNER part 1, a single IV infusion of VH3810109 was well tolerated, with few drug-related AEs and robust antiviral efficacy at both doses studied. In this small study, viral sensitivity to VH3810109 and BL CD4+ cell count correlated with magnitude and duration of antiviral response. However, other factors may impact virologic outcome, including pre-treatment VL, serum antibody concentration, and an individual’s inherent control of viral replication. BANNER part 2 is ongoing to evaluate alternate dosing options and modalities for VH3810109.
FIgure. Viral Responses and Baseline Antibody Sensitivity of Plasma Viruses