Presentation Abstract

Session: 073-New Antiretroviral Therapy: Bench to Bedside
Monday, Sep 10, 2012, 8:30 AM -11:00 AM
Presentation Title: H-552 - Virological Profiling of GS-7340, a Next-generation Tenofovir Prodrug with Superior Potency over TDF
Location: Room 104
Presentation Number: H-552
Pres. Time: Monday, Sep 10, 2012, 9:00 AM - 9:15 AM
Category: H2
Keywords: GS-7340; HIV; Tenofovir prodrug
Author(s): C. Callebaut, PhD - Sr Scientist, N. Margot, MS - Associate Scientist, G. Stepan, BS - Associate Scientist, Y. Tian, PhD - Research Scientist, M. Miller, PhD - Sr Director;
Gilead Sci., Foster City, CA.
Financial Disclosures:  C. Callebaut,
Gilead Role(s): Employee, Shareholder (excluding diversitied mutual funds).
N. Margot,
Gilead Role(s): Employee, Shareholder (excluding diversitied mutual funds).
G. Stepan,
Gilead Role(s): Employee, Shareholder (excluding diversitied mutual funds).
Y. Tian,
Gilead Role(s): Employee, Shareholder (excluding diversitied mutual funds).
M. Miller,
Gilead Role(s): Employee, Shareholder (excluding diversitied mutual funds).
Abstract: Background: Tenofovir (TFV) is an HIV-1 nucleotide reverse transcriptase inhibitor (NtRTI), metabolized intracellularly to its active metabolite TFV-diphosphate (TFV-DP). Tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, is widely used for treatment of HIV-1 infection. GS-7340 is a novel oral prodrug of TFV that is more stable in human serum leading to enhanced delivery and conversion to TFV in lymphoid cells and increased TFV-DP in PBMCs. Phase 1 clinical studies showed that GS-7340 has more potent antiviral activity than TDF. Virological profiling of GS-7340 is described here. Methods: Antiviral activity was evaluated in PBMCs against HIV-1 clinical isolates; compounds were also evaluated against a panel of other human viruses. Antiretroviral (ARV) drug combination studies were performed in MT-2 cells in a 384-well automated format. Potency experiments were performed in the presence of ARV drugs pre-incubated at 37ºC in human serum. Results: GS-7340 showed high potency against a panel of 26 HIV-1 isolates from multiple subtypes (mean EC50 = 3.6 nM) and 3 HIV-2 isolates (mean EC50 = 1.8 nM). GS-7340 activity was highly specific for retroviruses with no significant activity detected against other viruses. Combination studies of GS-7340 or TFV with other ARV drugs, as well as the pharmaco-enhancer cobicistat, showed additive-to-synergistic interactions, and no antagonism. Although potency of the two prodrugs was similar without pretreatment, TDF potency was significantly reduced in the presence of human serum. Unlike TDF, GS-7340 maintained its potency after prolonged serum treatment, reflecting the greater plasma stability of GS-7340.Conclusions: The next generation prodrug of TFV, GS-7340, has a virological profile similar to that of TFV regarding spectrum of activity and has in vitro synergy with other ARVs. GS-7340 demonstrated superior antiviral potency to TDF in vitro in the presence of human serum, consistent with the higher intracellular TFV-DP levels and greater antiviral potency seen in the clinical setting as compared to TDF.

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