March 3, 2011

New Version of Tenofovir Is Much More Potent and Hopefully Safer

A new formulation of the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir, currently dubbed GS-7340, achieves far higher concentrations inside of the cells targeted by HIV for infection than the current version of tenofovir (found in Viread, Truvada and Atripla). These data, which were presented Monday, February 28, at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, suggest that the drug could be simultaneously more potent and safer than the current prodrug formation of tenofovir (Viread).

Tenofovir is a potent antiretroviral drug that in its base form is not well absorbed into the blood stream and is quickly eliminated from blood. To overcome this problem, Gilead Sciences made a prodrug version of tenofovir called tenofovir disoproxil fumarate (TDF). Prodrugs are typically inactive chemical compounds that turn into an active drug when they interact with the body’s metabolic system.

TDF allows for slower elimination of the tenofovir, because it takes a while for the body to transform TDF into tenofovir. That way it can reach and maintain adequate blood levels of the active drug. Unfortunately, boosting the amount of drug in the blood can also increase the amount that gets into the kidneys, which can lead to one of the most common side effects—damage to the tubules that help the kidney filter blood.

In an attempt to overcome this problem, and to increase the potency of the drug, Gilead experimented with stripping away the additional molecules present in Viread. In their place, the company added other molecules that result in substantial increases of tenofovir inside of the cells targeted by HIV, such as CD4 cells, but not in the blood or in organs such as the kidneys. This was accomplished by building a new chemical chain (GS-7340) that doesn't turn into tenofovir until it is transformed by cathepsin A2, which is produced predominately by a white blood cell called a lymphocyte.

Andrew Zolopa, MD, from Stanford University in Palo Alto, California, reported on the first study in humans of GS-7340. The study randomized HIV-positive people who’d never taken ARV drugs and placed them in one of three arms. In one arm, people took 300 milligrams (mg) of standard tenofovir (in the form of Viread) once-daily for 14 days. In the second arm, people received 50 mg of GS-7340 once-daily, and in the third arm people received 150 mg of GS-7340 once-daily.

The groups were evenly matched in most characteristics. Most of the participants were in their mid-30s, 90 percent were male, and the group was racially diverse. The average CD4 count was about 400, and the average viral load was just under 5 logs.

The primary aim of the study was to determine the change in HIV levels over 14 days of therapy, and the secondary aim was to establish safety and the degree to which the drug accumulated in cells versus blood.

Zolopa reported that his team found GS-7340 to be far more potent than Viread and to make it into cells at much higher concentrations.

While people taking Viread had a 0.94 log drop in virus over 14 days, people taking 50 mg of GS-7340 had a 1.57 log drop and those taking 150 mg had a 1.71 log drop. In terms of the speed with which the virus dropped, both doses of GS-7340 caused viral loads to drop about twice as fast as those taking Viread.

What’s more, the hope of achieving much higher levels of tenofovir in cells rather than blood was achieved. While GS-7340 resulted in intracellular levels of tenofovir that ranged from 4 to 33 times higher than Viread—exactly what you would want to control HIV reproduction—it accomplished this with less than half the amount getting into the blood—what you would want in order to reduce side effects.

The drug was found to be well tolerated and safe. There were no serious side effects, and the most common side effects—headache and nausea—were mild and didn’t differ between the three arms of the study.

There is one important caveat in regard to safety brought up by Joseph Eron, from the University of North Carolina in Chapel Hill, during the question and answer period of the presentation. Given that GS-7340 is designed to get taken up into cells that have a type of enzyme called cathepsin A2—the process that results in high levels accumulating inside white blood cells—Eron wondered whether more of the drug might get taken up into osteoblasts, a type of cell that helps with bone formation. Osteoblasts produce other types of cathepsins (such as cathepsin K), so the question is whether these other types of cathepsin could help cells take in tenofovir. If so, GS-7340 could theoretically harm bones. William Lee, PhD, from Gilead replied that the company has not yet looked into this, but that they would do so in the future.

Zolopa closed by noting the efficacy of the drug and apparent safety. He also commented that because the drug will likely be cheaper to manufacture than Viread, it could result in lower prices in resource-poor nations.

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