13th Conference on Retroviruses and Opportunistic Infections Denver, Colorado - February 5-8, 2006

Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 45

Tomas Cihlar¹, A Ray¹, D Boojamra¹, L Zhang¹, H Hui¹, D Grant¹, K White¹, M Desai¹, N Parkin², and R Mackman^1
1Gilead Sci, Foster City, CA, US and ²Monogram Biosci, South San Francisco, CA, US

BACKGROUND: Long-term clinical benefit of nucleoside(tide) reverse transcriptase inhibitors (NRTI) can be limited by adverse effects, development of resistance, drug-drug interactions, and sub-optimal efficacy against viruses harboring drug resistance mutations. A nucleotide analog GS9148 (phosphonomethoxy-2’-fluoro-2’,3’-dideoxydidehydroadenosine) was selected in a search for novel NRTI with improved pharmacological and resistance profiles.

METHODS: GS9148 and its prodrug were subjected to an extensive in vitro evaluation of antiviral potency, toxicity, and resistance. PhenoSense HIV assay was used to compare the activity of GS9148 and 6 approved NRTI—zidovudine (ZDV), didanosine (ddI), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), and tenofovir (TFV))—against HIV-1 variants with all major types of NRTI-resistance mutations. An ethylalaninyl phenyl ester was identified as a prodrug of GS9148 with the most favorable in vivo pharmacokinetic profile.

RESULTS: The prodrug of GS9148 exhibits potent antiretroviral activity both in primary cells and T cell lines (EC₅₀=25 to 200 nM). Low cytotoxicity (CC₅₀ >100 mM) was observed in multiple cell types including renal cells. The active diphosphate metabolite of GS9148 acts as an obligatory DNA chain terminator and a competitive inhibitor of HIV-1 RT (K_i=0.8 mM). Unlike ddI, d4T, or d4FC, neither GS9148 nor its prodrug showed an effect on mitochondrial DNA or lactate production in HepG2 liver cells. In the PhenoSense assay, the activity of GS9148 was not affected by the presence of K65R, L74V, M184V or their various combinations (EC₅₀ fold change <1). Viruses with 4 or more thymidine analog mutations showed 0.74- to 2.0-fold change in the susceptibility to GS-9148, a shift that was smaller than any other tested NRTI. Passaging of HIV-1 in the presence of GS9148 selected for a primary K70E mutation in RT that conferred <3-fold reduced susceptibility to GS9148. In dogs, the oral bioavailability of GS9148 prodrug exceeded 20%, resulting in an effective and prolonged accumulation of GS9148 diphosphate in blood lymphocytes.

CONCLUSIONS: GS9148 exhibits a favorable in vitro pharmacological profile including lower levels of resistance than approved NRTIs, an indication of potential efficacy against existing NRTI-resistant viruses. The amidate prodrug of GS9148 is an attractive candidate for further development with potential for once daily dosing and activity in both treatment-naïve and NRTI-experienced patients.

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2006-02-05
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