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Low-Dose, Cell-Homing Tenofovir Prodrug Outdoes TDF in 10-Day Study
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19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
GS-7340, a tenofovir prodrug that may pack a bigger antiviral punch at a lower dose than tenofovir disoproxil fumarate (TDF, Viread), cleared an early hurdle in a 10-day monotherapy comparison with placebo and standard-dose TDF [1].
Peter Ruane, who presented results of this pilot trial, explained that scientists designed GS-7430 so that "cells will load up faster" with this reverse transcriptase inhibitor than with the now-standard backbone agent TDF. And the lower doses of GS-7430 being tested hold the promise of a kinder toxicity profile.
In a proof-of-concept study presented in 2011, GS-7430 at doses of 50 or 150 mg once daily pushed viral loads down significantly more than TDF at the standard dose of 300 mg once daily [2]. At the 50-mg dose, GS-7430 had 88% lower plasma levels of tenofovir and 4-fold higher intracellular concentrations of tenofovir diphosphate (the drug's active form) than recorded with TDF.
The new partially blinded trial randomized 38 antiretroviral-naive and experienced people with no genotypic resistance to TDF, a viral load of at least 2000 copies, and a CD4 count of at least 200 to standard-dose TDF, to 8 mg, 25 mg, or 40 mg of GS-7430 once daily, or to placebo for 10 days [2].
The study group averaged 38 years in age, 37 were men, 63% white, and 37% African American. Median pretreatment viral load stood at 40,000 copies and median CD4 count at 444.
On day 11 time-weighted average change in HIV RNA was significantly lower with 25 or 40 mg of GS-7430 than with TDF:
Median time-weighted average change in viral load:
Placebo (n = 7): -0.01 log10 copies/mL (P = 0.038 versus TDF)
TDF (n = 6): -0.48
GS-7430 8 mg (n = 9): -0.76 log (P = 0.216 versus TDF)
GS-7430 25 mg (n = 8): -0.94 log (P = 0.017 versus TDF)
GS-7430 40 mg (n = 8): -1.08 log (P = 0.01 versus TDF)
Median viral load changes from baseline were -0.97 log with TDF, -1.08 log with GS-7430 8 mg, -1.46 log with GS-7430 25 mg (P = 0.024 versus TDF), and -1.73 log with GS-7430 40 mg (P = 0.003 versus TDF).
Compared with TDF, tenofovir plasma area under the concentration-time curve and maximum concentration were 96% and 98% lower with GS-7430 8 mg, 86% and 94% lower with GS-7430 25 mg, and 79% and 89% lower with GS-7430 40 mg. Conversely, intracellular tenofovir diphosphate levels were about 7 times higher with GS-7340 25 mg and more than 20 times higher with GS-7340 40 mg than with 300 mg of TDF.
In this brief study there were no discontinuations, no serious adverse events, and no clinically significant lab abnormalities. Two phase 2 trials will compare 40 mg of GS-7340 with TDF combined with either cobicistat-boosted elvitegravir or cobicistat-boosted darunavir plus emtricitabine.
References
1. 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.
2. 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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