Skip Navigation LinksHome > June 2009 - Volume 51 - Issue > 167 Update on Gilead Sciences Anti-HIV Development Programs
JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/01.qai.0000351127.48912.09
Abstracts

167 Update on Gilead Sciences Anti-HIV Development Programs

Cihlar, Tomas PhD

Free Access
Collapse Box

Author Information

Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404

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.

© 2009 Lippincott Williams & Wilkins, Inc.

Login