Gilead Sciences has two current development programs for anti-HIV small molecule inhibitors. Elvitegravir (EVG, GS-9137) is an HIV-1 integrase inhibitor (INI) which has completed a phase 2 dose-ranging study (Study GS-US-183-0105). Patients were randomized to 20 mg, 50 mg or 125 mg QD doses of ritonavir-boosted EVG (EVG/r) plus optimized background therapy (OBT) comprised of NRTIs +/− T-20. Study 0105 patients were highly experienced with a median of 3 TAMs and 11 PI-R mutations at baseline. Patients receiving EVG 125 mg had rapid viral load declines (mean decline in HIV-1 RNA of 2.1 log10 copies/mL at week 24); those with ≥1 active drug(s) in their background therapy had durable responses. Among patients with virologic failure on EVG/r 125 mg, the most common integrase mutations detected were E92Q, E138K, Q148R/K/H and N155H (observed in 11/28, 39%), S147G (9/28, 32%) and T66I/A/K (5/28, 18%), some of which have been selected by raltegravir (MK-0518) in vivo. RC declined from a median of 108% at baseline to 54% at virologic failure. EVG is currently entering phase 3 studies.
In another program, a novel nucleotide analog, phosphonomethoxy-2'-fluoro-2', 3'-dideoxydidehydroadenosine (GS-9148), was selected as an NRTI with an improved pharmacological and resistance profile. The prodrug of GS-9148 (GS-9131) exhibits potent antiretroviral activity both in primary cells and T-cell lines (EC50 = 25-200 nM), low cytotoxicity (CC50 > 50 iM) in multiple cell types, and shows no effect on mitochondrial DNA or lactate production in HepG2 cells. In phenotypic assays, the activity of GS-9148 was not affected by the K65R, L74V, or M184V mutations in RT (EC50 fold change <1). Viruses with 4 or more thymidine analog mutations showed 0.74 to 2.0-fold change in the susceptibility, a shift that was smaller than that of any other tested NRTI. Passage of HIV-1 in the presence of GS-9148 selected for a primary K70E mutation and two other RT mutations that together conferred <3-fold resistance to GS-9148. Oral administration of GS-9131 in dogs resulted in high and persistent levels of GS-9148 diphosphate in PBMCs and lymph nodes. Overall, GS-9131 exhibits a favorable in vitro virological and in vivo pharmacological profile and is entering phase I trials for once daily dosing in NRTI-experienced patients.