Background: Long-acting oral antiretrovirals remain an unmet medical need. GS-1720 is an oral integrase strand transfer inhibitor (INSTI) with potent anti-HIV-1 activity. In a phase Ib study in people with HIV-1, GS-1720 was well tolerated and demonstrated antiviral activity (mean reduction in HIV-1 RNA across four dosing cohorts [30, 150, 450 and 900 mg] of 1.74−2.44 log10 copies/ml from baseline to day [D] 11) [1], comparable with approved once-daily INSTIs. We report GS-1720 pharmacokinetics/pharmacodynamics and resistance data from this phase Ib study.

Methods: In this open-label multicohort study, participants, who were treatment-naïve or treatment-experienced but naïve to INSTIs and off antiretroviral therapy for ≥12 weeks, were administered oral GS-1720 on D1 and D2 and followed for 10 days. Participants were tested for genotypic and phenotypic integrase (IN) resistance at baseline and D11. Endpoints included: change in HIV-1 RNA (log10 copies/ml) from baseline to D11 [1], GS-1720 concentrations on D11, correlation between concentrations at D11 versus reduction of plasma HIV-1 RNA, emergence of IN resistance mutations at D11.

Results: Participants were enrolled into 30, 150, 450 and 900 mg cohorts (n = 28; 7/cohort). Median (range) age was 33 (18–62) years; 89.3% were male. Mean GS-1720 concentrations on D11 were 1.64, 5.87, 8.78 and 18.4 µg/ml in 30, 150, 450 and 900 mg cohorts, respectively; mean HIV-1 RNA reductions on D11 were 1.74, 2.18, 2.44 and 2.37 log10 copies/ml, respectively. In participants with GS-1720 concentrations at D11 above two-fold the inhibitory quotient (IQ2; 3.876 µg/ml), robust antiviral activity (≥1.5 log10 copies/ml reduction in HIV-1 RNA from baseline to D11) was observed. No participant had primary resistance-associated mutations (RAMs) in IN at screening. No resistance to the INSTI-class was detected at D11. One individual (lowest dose [30 mg] cohort) had increasing HIV-1 RNA after D7 of the monotherapy period. However, resistance testing showed no INSTI RAMs at D11.

Conclusions: GS-1720 showed robust antiviral activity with D11 concentrations above IQ2. There were no observed cases of treatment-emergent IN resistance, including participants with low GS-1720 concentrations. The robust pharmacokinetics/pharmacodynamics data and lack of resistance support further clinical development and dose selection for GS-1720.

Reference

1. Fichtenbaum CJ, Berhe M, Bordon J, Lalezari JP, Oguchi G, Sinclair G, et al. Antiviral activity, safety, and pharmacokinetics of GS-1720, a novel weekly oral INSTI [CROI Abstract 116]. Top Antivir Med. 2024;32(1):19.