Background
The development of integrase strand transfer inhibitors (INSTIs) compatible with long-acting injectable (LAI) lenacapavir (LEN) dosing would provide significant unmet need to people with HIV-1 (PWH) who struggle to take pills. Herein we describe the nonclinical virology and safety profile of GS-3242, an investigational INSTI with PK supportive of at least once every 3 months injectable dosing.
Methods
Inhibition of integrase (IN) strand transfer activity was evaluated using a biochemical assay. Anti-HIV-1 activity and cytotoxicity were determined in human cell lines and primary cells. Antiretroviral 2-drug combinations and drug resistance selections by dose escalation were assessed in HIV-1-infected MT2 and SupT1 cells, respectively. Safety pharmacology and toxicology profiles were evaluated in nonclinical species following injectable administration.
Results
GS-3242 inhibited recombinant HIV-1 IN strand transfer activity with a 50% inhibitory concentration (IC50) of 19 nM and HIV-1 replication in MT4 cells, primary human macrophages and CD4+ T-lymphocytes with mean 50% effective concentration (EC50) and selectivity index values of 0.23 to 0.82 nM and >25,000, respectively. In human PBMCs, GS-3242 was 2-fold more potent than bictegravir (BIC) against a multiclade panel of 20 HIV-1 clinical isolates, with median EC50 values of 0.21 nM and 0.44 nM, respectively. When tested against 14 HIV-1 mutants encoding 1 to 3 INSTI resistance-associated mutations, the EC50 fold-change (FC) range relative to wild-type virus for GS-3242, cabotegravir (CAB), BIC, and elvitegravir (EVG) was 1.0 to 16, 1.0 to 25, 0.6 to 3.7, and 3.2 to >576, respectively. Similarly, in vitro resistance selections with GS-3242, CAB, and EVG resulted in the emergence of G193E (FC=1.4), S153F (FC=1.9), and E138K/Q148R IN variants (FC=68), respectively, after 224 days in culture. GS-3242 maintained full potency against LEN-resistant HIV-1 mutants and demonstrated additive-to-synergistic antiviral activity and no antagonism when combined with other ARVs, including LEN. In nonclinical safety studies, GS-3242 was nongenotoxic, and no systemic adverse effect was observed in 13-week rat and monkey toxicity studies where the highest achievable exposures were also the no-observed-adverse-effect-levels in both species.
Conclusions
GS-3242 is a novel, potent and selective INSTI with a favorable nonclinical pharmacology profile. These data support the ongoing clinical testing of GS-3242 as a component of a LAI treatment regimen for PWH.