AIDSWEEKLY Plus, 5 August 1996
Daniel J. DeNoon, Senior Editor

Early data from clinical trials show that the drug, nicknamed U89, carries as strong an initial anti-HIV punch as the new protease inhibitors.

It remains to be seen whether this intense effect can be maintained.

"U89 has potent antiviral activity, potent CD4 effects, and good safety," said Gabriel Torres of St. Vincent's Hospital, New York.

Torres described the findings in a report to the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

Unlike most other nucleoside analogs, U89 is a prodrug that is converted intracellularly to carbovir triphosphate, the active form of the guanosine analog carbovir. The chemical name for U89 is (1S,4R)-4-[2-amino-6- (cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate.

An earlier study by Wellcome researcher W.B. Mahony (1995 Proc Annu Meet Am Assoc Cancer Res; 36:A2211) showed that U89 and carbovir structurally differ only at the 6-position of the nucleobase where U89 has a cyclopropylamino group and carbovir has an oxy moiety.

But U89 is far more active than carbovir. Preclinical studies showed that the drug:

• has synergy with AZT, ddC, and ddI.
• has good oral bioavailability.
• penetrates the blood/brain barrier without toxicity.

In the first part of the 12-week trial reported by Torres, participants with CD4 counts between 200 and 500 cells/mL and with fewer than 12 weeks of prior AZT therapy received oral U89 at doses of 200, 400, and 600 mg three times per day or 300 mg twice a day for four weeks.

In the second part of the trial participants continued U89 therapy and also received either AZT or placebo for eight weeks.

Torres said there were no significant differences in antiviral effect between the 200 TID, 400 TID, or 300 BID doses (data from the 600 mg TID dose group were not available as of July 1996).

Because the trial was still blinded at the time of Torres's report, the U89/AZT and U89/placebo groups were considered together. After 12 weeks of treatment, participants had a decrease in HIV viral load ranging from 1.5 to 2.2 log10 and a mean increase in CD4 cell count of about 100 cells/mL.

Nausea was more common at the highest dose, and some patients reported headaches. Four patients had to discontinue therapy: two who had allergic reactions, one with persistent nausea, and one with paresthesia.

"The positive virologic and immunologic responses to 1592U89, alone and in combination with AZT, and its safety profile demonstrate the potential for 1592U89 as an effective and safe HIV therapy," wrote University of Alabama researcher Michael Saag, Torres, and colleagues in the presentation abstract.

Currently the most effective antiretroviral therapy is the combination of a protease inhibitor with AZT and lamivudine (3TC).

Because U89 appears to be at least as effective as the AZT/3TC combination, a small trial of U89 plus a protease inhibitor is planned.

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