GS-7340, a pro-drug of tenofovir that reaches higher concentrations in
cells, had superior efficacy and may be more suitable for inclusion in
co-formulations, researchers reported on 7 March at the 19th Conference on Retroviruses and
Opportunistic Infections in Seattle.
tenofovir is among the most potent nucleoside/nucleotide reverse transcriptase
inhibitors. Tenofovir disoproxil fumarate (TDF), marketed as Viread and also contained in the Truvada, Atripla and Eviplera combination pills, is a preferred agent in European and US
antiretroviral treatment guidelines. GS-7340, a pro-drug of tenofovir that is
converted into the active form in the body, was designed to better target
lymphoid tissues and cells.
14-day monotherapy study (GS-US-120-1101) presented at last year's Retrovirus
conference showed that GS-7340 at doses of 50 and 150mg demonstrated favourable
pharmacokinetics and good antiviral activity. The 50mg dose produced an 88%
lower plasma tenofovir concentration, but fourfold higher intracellular
concentration compared with 300mg TDF.
these findings, Peter Ruane and colleagues conducted a randomised, controlled
dose-finding trial (GS-US-120-0104) comparing three doses of the GS-7340: 8, 25
and 40mg taken once daily for ten days. Control patients received either
open-label TDF (active control) or placebo (inactive control).
The analysis included 38
HIV-positive participants with viral load of at least 2000 copies/ml. They
could be either antiretroviral-naive or experienced, but had no genotypic drug
resistance at baseline. Almost all (97%) were men, about half were white and
the average age was 38 years. The mean CD4 cell count was 444 cells/mm3.
At day 11, all doses of
GS-7340 produced time-weighted average decreases in
HIV RNA (0.76, 0.94 and 1.08 log10 copies, respectively, in the
three dose arms) greater than the reduction seen with TDF (0.48 log10)
or placebo (0.01 log10).
Median drops in viral load were likewise larger with GS-7340 (1.08,
1.46 and 1.73 log10, respectively) than with TDF (0.97 log10)
or placebo (0.07 log10). In both comparisons, differences
from TDF and placebo were statistically significant for the two higher GS-7340
Plasma tenofovir levels (AUC
and Cmax) were 79% to 98% lower with GS-7340 than with TDF. As in the pilot
study, intracellular tenofovir diphosphate levels were higher with GS-7340 than with TDF
– about seven times
higher with the 25mg dose and more than 20 times higher with the 40mg dose.
GS-7340 was generally well-tolerated, with no premature drug discontinuations, drug-related serious
adverse events or clinically significant laboratory abnormalities. No tenofovir
resistance mutations were detected.
The researchers said that
GS-7340 at doses of 25 and 40mg demonstrated "superior antiviral efficacy"
compared with 300mg TDF, "achieving higher intracellular [tenofovir diphosphate] concentration with lower
systemic [tenofovir] exposure".
"GS-7340 has the
potential to be more efficacious with an improved safety margin, and to be
easier to co-formulate, compared with TDF," they concluded, noting that an
adequate dose of GS-7340 has one-tenth the mass of 300mg TDF.
No signals of kidney toxicity
were reported in this study, a concern with TDF. Ruane said there has been no
evidence of bone toxicity in dogs, but human studies are ongoing.
Based on these findings,
Gilead has elected to proceed with the 25mg dose, which the researchers said
provided "near maximal" antiviral activity. Ruane said this dose was
chosen over the more potent 40mg dose because the smaller amount would be
easier to put in single-tablet regimens.
To date, Gilead has announced
two such products: a new version of the Quad pill containing GS-7340, the
experimental integrase inhibitor elvitegravir, the novel boosting agent
cobicistat and emtricitabine, as well as a protease inhibitor-based tablet
containing GS-7340 plus darunavir (Prezista), cobicistat and emtricitabine.
Studies of both new single-tablet regimens are underway.