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GS-7340 Stronger Than TDF in Human Serum, Synergistic With Other ARVs
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52nd ICAAC, September 9-12, 2012, San Francisco
Mark Mascolini
GS-7340, the investigational oral prodrug of tenofovir, had stronger antiviral activity than tenofovir disoproxil fumarate (TDF) in vitro in the presence of human serum [1]. The new agent was additive to synergistic with other antiretrovirals, including the three non-TDF components of QUAD.
TDF, the widely used reverse transcriptase inhibitor, and GS-7340 (tenofovir alafenamide, TAF) are both prodrugs of tenofovir, which is metabolized inside cells to the active metabolite tenofovir diphosphate. Because GS-7340 is more stable in human serum than TDF, it may hold advantages over TDF. Research in humans indicates that GS-7340 achieves enhanced delivery of tenofovir to the lymphatic system, higher intracellular concentrations of tenofovir, greater viral load suppression at doses lower than TDF, and lower circulating tenofovir levels, which may improve safety and tolerability [2,3].
Gilead Sciences investigators evaluated the antiviral activity of GS-7340 against HIV-1 and HIV-2 isolates in peripheral blood mononuclear cells and against a panel of other human viruses. These experiments showed that GS-7340 had high potency against 26 HIV-1 isolates representing 7 subtypes, averaging a 50% effective concentration (EC50) of 3.6 nM. GS-7340 had an average EC50 of 1.8 nM against three HIV-2 isolates.
While antiviral potency of TDF was significantly reduced in the presence of human serum, GS-7340 maintained its antiviral potency after prolonged serum exposure, a finding consistent with the greater stability of GS-7340 than TDF in plasma.
The investigational prodrug had no significant activity against other viruses studied, including CMV, HSV-1, or VZV. It had moderate activity against HSV-2.
When combined with other antiretrovirals and with the boosting agent cobicistat, GS-7340 had strong synergistic activity with emtricitabine (FTC), elvitegravir, raltegravir, and dolutegravir and moderately synergistic activity with efavirenz, atazanavir, and darunavir. GS-7340 had slight synergy or was additive with tenofovir, nevirapine, and cobicistat. No antagonist interactions with other agents were identified. If development of GS-7340 proceeds smoothly, Gilead will probably coformulate it with elvitegravir, cobicistat, and FTC in a second-generation QUAD.
The Gilead team concluded that GS-7340 "has a virological profile similar to that of tenofovir regarding spectrum of activity." But the investigational agent had stronger antiviral activity than TDF in the presence of human serum, "consistent with the higher intracellular tenofovir diphosphate levels and greater antiviral potency seen in the clinical setting as compared to TDF."
One question always arises after GS-7340 penetrations: Does the drug's better cell penetration compared with TDF mean it will heighten toxicity in kidney and bone cells? Christian Callebaut, who presented these Gilead findings, said studies in kidney cells disclosed no evidence of heightened toxicity, while studies in bone cells are under way.
References
1. Callebaut C, Margot N, Stepan G, Tian T, Miller M. Virological profiling of GS-7340, a next-generation tenofovir prodrug with superior potency over TDF. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-552.
2. Ruane P, DeJesus E, D Berger D, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir disoproxil fumarate 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 103. http://www.natap.org/2012/CROI/croi_29.htm.
3. Markowitz M, Zolopa A, Ruane P, et al. GS-7340 Demonstrates greater declines in HIV-1 RNA than TDF during 14 days of monotherapy in HIV-1-infected subjects. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 152LB.
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