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CROI 2011: New Tenofovir Pro-drug GS-7340 Looks Good in Early Study

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A new pro-drug formulation of tenofovir (currently marketed as Viread, also in the Truvada and Atripla combination pills) produces a higher drug concentration in lymphoid tissues that harbor HIV, offering the prospect of lower doses and new fixed-dose formulations, according to a presentation last week at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston. Further studies are needed to determine whether higher tenofovir concentrations will lead to worse bone or kidney toxicity.

Tenofovir, developed and sold by Gilead Sciences of Foster City, CA, is the most widely used antiretroviral drug in the U.S. It is currently available as a pro-drug called tenofovir disporoxil fumerate (TDF). A pro-drug is a non-active form of a drug that is converted to the active form inside the body.

GS-7340 is a new experimental pro-drug formulation of tenofovir, designed to better target lymphoid tissues and cells, and to remain stable in the body longer. Pre-clinical research showed that it reaches 400 times higher levels of active drug in peripheral blood mononuclear cells (PBMCs) than TDF, and is 200 times more stable in plasma.

In a late-breaker oral presentation at CROI, Andrew Zolopa of Stanford University presented results from a 14-day monotherapy study comparing 2 doses of GS-7340 to the standard dose of TDF, looking at their ability to reduce HIV viral load.

A total of 30 HIV positive treatment-naive participants (27 men) with HIV viral loads greater than 15,000 copies/mL and CD4 T-cell counts above 200 cells/mm3 were randomly assigned to take 300 mg TDF, or either 50 mg or 150 mg GS-7340 once daily for 14 days.

The primary objective of the study was to measure the drugs' effects on viral load. The researchers also looked at drug levels and measures of safety and tolerability.

Results

  • Time-weighted average viral load from baseline through day 14 declined by 0.54 log for TDF, compared to 0.95 log for 50 mg GS-7340 and 1.07 log for 150 mg GS-7340.
  • At 14 days, the mean decrease in HIV viral load was 0.94 log for TDF, compared to 1.57 log for 50mg GS-7340 and 1.71 log for 150 mg GS-7340.
  • There were no serious adverse effects in any arm of the study.
  • Headache was the most commonly reported side effect.
  • There were no significant laboratory abnormalities in any arm of the study.
  • The 2 doses of GS-7340 reached higher drug concentrations in PBMCs compared to plasma.
  • In contrast, TDF reached higher levels in plasma.

Zolopa concluded that GS-7340 is a candidate for a "next generation pro-drug of tenofovir, with the potential to improve efficacy and safety over TDF."

There are, however, unanswered questions about GS-7340. Tenofovir has been shown to affect both kidney and bone tissue. This study was too short to assess GS-7340's effects on kidneys or bones in humans. But animal research showed that the drug concentration in bone tissue was about 3.5 times higher with GS-7340 than with TDF; no difference in drug levels was seen in kidney or liver tissues.

This short monotherapy study suggests promise for a new formulation of tenofovir. GS-7340's ability to selectively target lymphoid or immune system cells raises the hope that it will prove more potent against HIV. Results from this trial suggest that this might be the case. GS-7340's superior stability and penetration into lymphoid tissue also suggest it could be given at a significantly lower dose than TDF, opening the door for novel fixed-dose combination pills and greater availability in resource-limited settings.

Investigator affiliations: Rockefeller University, New York, NY; Stanford University, Palo Alto, CA; Lightsource Med, Los Angeles, CA; Thomas Jefferson University, Philadelphia, PA; Gilead Sciences, Foster City, CA.

Reference


M Markowitz, A Zolopa, P Ruane, and others. 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 (CROI 2011). Boston. February 27-March 2, 2011. Abstract 152LB.