Background
Integrase strand transfer inhibitors (INSTIs) are the cornerstone of current HIV therapies, but their oral dosing remains limited to once-daily administration. Herein we describe the in vitro resistance profile for GS-1720, a potent and selective investigational INSTI with Phase 1 clinical pharmacokinetic, safety and antiviral efficacy data supportive of once-weekly oral dosing.
Methods
GS-1720 activity against HIV-1 reporter viruses containing integrase (IN) substitutions associated with INSTI class resistance was assessed at Monogram Biosciences. In vitro resistance barrier was studied by serial passage of HIV-1 IIIb- and HXB2-infected MT-2 cells in the presence of increasing concentrations of GS-1720. GS-1720 was also evaluated in a 35-day fixed-dose viral breakthrough assay in HIV-1 BaL-infected human PBMCs. Emergent viral variants were characterized genotypically and phenotypically.
Results
GS-1720 retained potent antiviral activity, defined as an EC50 fold-change (FC) < 10, against 91% of INSTI-resistant isolates tested (n=55), as compared to 96% and 75% for bictegravir (BIC) and cabotegravir, respectively. Reduced virus susceptibility to GS-1720 (FC>10) required 3 IN mutations (G140A/S+Q148H/K+L74I, T97A or E138A/K) previously defined as primary or secondary drivers of INSTI class resistance. In vitro dose escalation resistance selections with GS-1720 against IIIb virus progressed at a rate comparable to BIC and significantly slower than elvitegravir (EVG), with the emergence of IN variants S153F (GS-1720), S153S/Y (BIC) and P145S (EVG) after >300, 140 and 119 days in culture, respectively. The S153Y variant also emerged in two dose escalation selections with HXB2 virus at GS-1720 concentrations equal to 16-fold its EC50 after 112 days in culture. Site-directed mutants of S153 variants showed high susceptibility to GS-1720 and all 5 approved INSTIs (FC<2.7). In a fixed-dose viral breakthrough assay, clinically relevant concentrations of GS-1720 or BIC prevented viral breakthrough while EVG and raltegravir, when tested at their equivalent clinical trough plasma concentrations, showed breakthrough with resistance in 45% and 18% of PBMC cultures (n=44-48/condition), respectively.
Conclusions
GS-1720 exhibits an in vitro resistance profile comparable to the best-in-class INSTI bictegravir, including high barrier to resistance and minimal cross-resistance within the INSTI class. These observations support the ongoing clinical development of GS-1720 as a novel once-weekly oral INSTI.
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