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CROI 2012: Tenofovir Pro-drug GS-7340 Shows Good Efficacy, Safety, and Suitability for Coformulation

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GS-7340, a pro-drug of tenofovir that reaches higher concentrations in cells, was shown to have superior efficacy and may be more suitable for inclusion in coformulated regimens, researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this week in Seattle.

Gilead Sciences' tenofovir is among the most potent nucleoside/nucleotide reverse transcriptase inhibitors. Tenofovir disoproxil fumerate (TDF), marketed as Viread and also contained in the Truvada and Atripla combination pills, is a preferred agent in U.S. and European 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.

A prior 14-day monotherapy study (GS-US-120-1101) presented at last year's CROI showed that GS-7340 at doses of 50 mg and 150 mg demonstrated favorable pharmacokinetics and good antiviral activity. The 50 mg dose produced an 88% lower plasma tenofovir concentration, but a 4-fold higher intracellular tenofovir diphosphateconcentration compared with 300 mg TDF.

Based on these findings, Peter Ruane and colleagues conducted a randomized, controlled dose-finding trial (GS-US-120-0104) comparing 3 doses of GS-7340, 8 mg, 25 mg, and 40 mg taken once-daily for 10 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 antiretroviral-naive or experienced, but had no genotypic drug resistance at baseline. Almost all (97%) were men, half were white, and the average age was 38 years. The mean CD4 T-cell count was 444 cells/mm3.

Results

 

  • After the last day of treatment, GS-7340 at all doses produced greater time-weighted average decreases in HIV RNA than TDF or placebo:

o               8 mg GS-7340: 0.76 log;

o               25 mg GS-7340: 0.94 log;

o               40 mg GS-7340: 1.08 log;

o               300 mg TDF: 0.48 log;

o               Placebo: 0.01 log.

  • Median drops in viral load were likewise larger with all doses of GS-7340 compared with TDF or placebo:

o               8 mg GS-7340: 1.08 log;

o               25 mg GS-7340: 1.46 log;

o               40 mg GS-7340: 1.73 log;

o               300 mg TDF: 0.97 log;

o               Placebo: 0.07 log.

  • In both comparisons, differences from TDF and placebo were statistically significant for the 2 higher GS-7340 doses.
  • Plasma tenofovir levels (AUC and Cmax) were 79% to 98% lower with GS-7340 compared with TDF.
  • Intracellular tenofovir diphosphatelevels were higher with GS-7340 compared with TDF:

o               About 7 times higher with the 25 mg dose;

o               More than 20 times higher with the 40 mg dose.

  • No tenofovir resistance mutations were detected.
  • GS-7340 was generally well tolerated.

o               There were no premature drug discontinuations, drug-related serious adverse events, or clinically significant laboratory abnormalities.

o               No signals of kidney toxicity were reported, a concern with TDF.

o               There was no evidence of bone toxicity in dogs, but human studies are ongoing.

The researchers concluded that GS-7340 at doses of 25 mg and 40 mg demonstrated "superior antiviral efficacy" compared with 300 mg 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 added, noting that an adequate dose of GS-7340 has one-tenth the mass of 300 mg TDF.

Based on these findings, Gilead has elected to proceed with the 25 mg dose, which the researchers said provided "near maximal" antiviral activity. Ruane said this dose was chosen over the more potent 40 mg dose because the smaller amount is easier to include in single-tablet regimens.

Gilead has announced 2 such products:

  • New version of the Quad pill also containing the experimental integrase inhibitor elvitegravir, the novel boosting agent cobicistat, and emtricitabine;
  • A protease inhibitor-based tablet containing GS-7340 plus darunavir (Prezista), cobicistat, and emtricitabine.

Studies of both new single-tablet regimens are currently underway.

3/8/12

Reference

P Ruane, E DeJesus, D Berger, et al. GS-7340 25 mg and 40 mg demonstrate superior efficacy to tenofovir 300 mg in a 10-day monotherapy study of HIV-1+ patients. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 103.