AEGiS-GMHC: The First Integrase Inhibitor

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

The First Integrase Inhibitor

GMHC Treatment Issues, Volume 10, Number 1 - January 1996
Theo Smart

The first clinical trials of an HIV "integrase inhibitor," Aronex Pharmaceuticals' AR-177, are in progress at San Francisco General Hospital. Like reverse transcriptase and protease, integrase is an essential HIV enzyme. It binds to HIV DNA, which is created by the reverse transcriptase enzyme, and integrates that DNA into the host cell's chromosomes. AR-177 does not inhibit this integrating activity (compounds that do so are years away) but rather appears to keep the enzyme from binding to the newly processed DNA in the first place.

The drug is an oligonucleotide (string of nucleotides -- the building blocks of DNA). Most oligonucleotides cannot be administered systemically, because they breakdown and rapidly pass from the body. But AR-177 is unique -- formed by seventeen nucleotides (mostly guanine), it folds upon itself to form a stable structure less prone to destruction in the blood. In animal studies, the compound was not easily metabolized and was excreted very slowly. Some drug remained in the animals' bodies a week after a single dose.

Work on this compound began because similar oligonucleotides were found to bind to the V3 loop on the HIV envelope protein gp120, potentially interfering with entry of the virus into cells. But after adding AR-177 and HIV to cell cultures with HIV, researchers were still able to detect viral DNA in the cells. Nevertheless, the drug blocked viral replication, and the HIV DNA within the cells disappeared after several hours.

This observation suggested that HIV was getting into cells, but that AR-177 was keeping the viral DNA from being integrated into the cell's DNA. Subsequent studies showed that the drug blocked binding to and early processing of viral DNA by integrase.

The phase I single dose escalation study of AR-177, directed by James Kahn, M.D, began in October. The study has reached its second dose level (1.5 mg/kg of body weight) and has already achieved blood levels that correlate with activity in laboratory cell cultures. Higher doses will be evaluated. A subsequent study evaluating the pharmacokinetics, safety and antiviral effect of multiple dosing will begin in the second quarter of this year.

At present, AR-177 is an injectable drug. The company hopes that the compound's half-life will be long enough to allow for infrequent dosing. Meanwhile, preliminary data in rodents show that the drug does have some oral bioavailability. The company is now studying an oral formulation in primates.

Testosterone for Wasting

Unimed Pharmaceuticals is starting a clinical trial of its new, rub-on testosterone gel in twenty HIV-positive men with wasting associated with low testosterone levels (hypogonadism). The ten-week dose comparison study will begin at Beth Israel Hospital in Boston, and an additional site may be added in San Francisco or Los Angeles. Call Richard Spark, M.D., at 617/667-2471 if interested.

Two testosterone patches -- Androderm, marketed by Smith- Kline Beecham, and Testoderm, from Alza -- already are approved for use in hypogonadal wasting. Testoderm must be applied to a shaved scrotum, while Androderm (just approved by the FDA in October) can be placed anywhere on the body. There is no data available to date on the use of either patch in people with AIDS, but results from at least one study should be released within the next few months.

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Copyright © 1996 - Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 fredg@gmhc.org http://www.gmhc.org

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