Aronex Pharmaceuticals Inc. said it is encouraged by preliminaryresults of its Phase I trials of Zintevir, the first of a new class of HIVintegrase inhibiting compounds tested in HIV-positive patients.
A single-dose escalation study and a two-week, multiple-doseescalation study involving 27 HIV-positive patients indicate thatZintevir, administered at doses up to 6 mg/kg, was well tolerated, JimChubb, president of Aronex, told BioWorld Today.
Results indicated, Chubb said, that Zintevir plasma concentrationsexceeded in vitro inhibitory concentration for the HIV virus forperiods of up to 10 hours, following administration of the higherdoses.
The Phase I single-dose study was initiated at the San FranciscoGeneral Hospital last October. The Phase I multiple-dose study beganin May at Harris Laboratory, in Phoenix, Ariz. Both studies, Chubbsaid, aimed to document safety and potential efficacy.
"We had absolutely no side effects at all, Chubb said. "We started atdoses of .75 mg/kg and increased up to 6 mg/kg. We began with asingle dose, monitored the patient, then gradually increased the doseto a level that is potentially therapeutic."
Based on these results, Chubb said, Aronex is planning follow-onmultiple dose-ranging trials of Zentevir. "Now that we know the drugis well tolerated," said Chubb, "we are going to move forward todemonstrate potential efficacy. We will determine that by looking atdecreases in viral load and changes in CD4."
Zintevir belongs to a class of oligonucleotides discovered by Aronexscientists, Robert Rando and Joshua Ojwang, approximately threeyears ago, Chubb said. "We were originally on a different target," hesaid, "when we screened the molecule in a routine HIV screen andfound that it was active against HIV. It was somewhat serendipitous."
The primary mechanism of action by integrase inhibitors such asZintevir is inhibition of HIV-1 integrase, a key enzyme in catalyzingthe integrations of HIV within human cells, promoting virusreplication.
Reverse transcriptase inhibitors act at the beginning stages of HIVreplication, inhibiting the conversion of viral RNA to DNA, Chubbexplained. Protease inhibitors act at the later stages of virusreplication, inhibiting maturation of infectious virus particles.
Integrase inhibitors act in the middle of the cycle, inhibitingintegration of viral DNA into host DNA.
Patients in the Phase I trials were taking no other drugs, however,Chubb said, assuming that Zentivir is efficacious, it will be used inlater trials in combination with other compounds.
"This is the first HIV integrase inhibitor that has entered a humantrial," Chubb said, "and we believe that it is the most potent integraseinhibitor that has been described to date."
In May, Aronex, of The Woodlands, Texas, completed a publicoffering of 6 million shares at $5 per share, raising gross proceeds of$34 million. The company's burn rate is $10 million a year for 1996,but, Chubb expects the rate to in increase in 1997 as clinical trialsexpand. As of Sept. 30, Aronex had $41 million in cash.
Company stock (NASDAQ:ARNX) closed Tuesday down $0.38 to$7.78. n
-- Frances Bishopp
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