NRTI GS-9131 Resurfaces at CROI 2017: In Vitro Sensitivity to Nuke-Resistant HIV
February 16, 2017
A poster presented in vitro results of an NRTI compound from Gilead that appears has been in preclinical development for at least a decade.1
GS-9131 is a prodrug of GS-9148 -- and early animal and in vitro drug resistance studies on GS-9148 were presented at CROI in 2006.2
Other previously published studies have highlighted the potential for low risk of toxicity in animal studies. The compound retains in vitro phenotypic sensitivity to broad NRTI resistance including mutations at K65R, L74V and M184V and multiple TAMS.
The poster at CROI 2017, confirms results from previously published studies (from 2007) into the activity against common NRTI mutations. The compound has good potency (EC50: 25 to 200 nM) with activity against HIV-1 subtypes A, B, C, D, E, F, group O and N (EC50: 0.29 to 113 nM), and also against HIV-2.3
Serial passaging of HIV-1 in the presence of GS-9148 selected two resistance pathways: (i) a primary K70E mutation plus D123N and T165I; or (ii) Q151L with K70E, L74I, and L187F/M. These variants conferred reduced susceptibility to GS-9131 of <3-fold and 50-fold, respectively.
Of note, synergistic activity was reported for GS-9131 in combination with AZT, FTC, abacavir, efavirenz, bictegravir, dolutegravir and lopinavir, and additive activity with TFV and TAF.
The poster concludes: "GS-9131 is an attractive candidate for further clinical development with a potential for once daily dosing and efficacy in patients with NRTI resistance" which seems slightly incongruous given how long this compound has been with the company.
This early data is interesting -- and questions how many other potentially useful compounds are in Gilead's stockroom. It would also be good to know plans for how this compound would fit with other compounds produce by the company.
This article was provided by HIV i-Base. It is a part of the publication The 24th Conference on Retroviruses and Opportunistic Infections. Visit HIV i-Base's website to find out more about their activities, publications and services.
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