Building a Better Tenofovir: Oral Prodrug GS-7340 Outperforms "Old" Tenofovir, Research Finds

A new oral prodrug form of tenofovir (Viread), GS-7340 (also known as tenofovir alafenamide, TAF), showed greater antiviral potency and stability than the currently marketed form of the drug, according to study results presented at ICAAC 2012.

It should be noted that the NRTI sold under the brand name Viread and used in single-tablet combinations such as Atripla (efavirenz/tenofovir/FTC) and Stribild (elvitegravir/cobicistat/FTC/tenofovir) is actually tenofovir disoproxil fumarate (TDF), which is already a prodrug -- a medication that breaks down into tenofovir when metabolized in the blood. GS-7340 marks an effort to improve upon the previous prodrug formulation.

The study, conducted by Gilead Sciences, analyzed GS-7340's performance against HIV isolates in blood cells. It found that GS-7340 had high potency against 26 HIV-1 isolates representing 7 subtypes. It also showed high potency against three HIV-2 isolates. In addition, GS-7340 maintained its viral potency longer than TDF, showing its better stability.

An earlier phase-1 study showed that GS-7340 was well tolerated and showed improved initial antiviral activity at lower doses than TDF (25 mg vs. 300 mg). After 10 days of monotherapy, study volunteers on GS-7340 had a median HIV RNA reduction of 1.46 log, while those on TDF had a median HIV RNA change of -0.97 log.

Reporting on the ICAAC 2012 study results, Mark Mascolini wrote the following for NATAP:

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.

The researchers also evaluated GS-7340's response against a panel of other human viruses, including influenza A, rhinovirus and varicella zoster virus. There was no significant response, except for moderate activity against herpes simplex virus 2 (HSV-2).

There are two ongoing phase 2 studies analyzing GS-7340's efficacy when used in combination with elvitegravir/cobicistat/emtricitabine and darunavir/cobicistat/emtricitabine.