Just 10 days ago the first two HIV-1-positive patientsreceived their initial doses of a new kind of anti-AIDSchemotherapy at San Francisco General Hospital.
The novel compound infused into their veins has no nameyet, just a number _ AR-177. Those letters stand forAronex Pharmaceuticals Inc., The Woodlands, Texas,whose virologists, Robert Rando and Joshua Ojwang,discovered the novel oligonucleotide three years ago. AR-177 is not just new but novel, Ojwang points out, becauseit attacks the AIDS virus at a quite different Achilles heelthan are targeted by current drugs, AZT, ddi, and anti-proteases.
When Ojwang and Rando came up with their compound,it received a different designation, T30177, becauseAronex, then known as Triplex Pharmaceutical Corp., ofThe Woodlands, had not yet merged with TheWoodlands-based Argus Pharmaceuticals Inc. andOncologix Inc., of Gaithersburg, Md. (See BioWorldToday, Feb 24, 1995, p. 1.)
"We were looking at the oligonucleotides of antivirals ingeneral," Ojwang said. "One variant of those compoundswas very active, so we tried to optimize it."
During the ensuing three years, a lot of rats and mice putthe compound through its toxicology andpharmacokinetic hoops, while virology labs on both sidesof the Atlantic, and both U.S. coasts, checked out its anti-HIV-1 efficacy against established human cell lines, plusfresh cultures from current AIDS and pre-AIDS patients.
"Our lab, where we discovered 177," Ojwang said, "thenTriplex, now Aronex, didn't do the live-virus work. Wecontracted those studies to multiple laboratories that workwith HIV."
Their work came together today in the November issue ofAntimicrobial Agents and Chemotherapy. Ojwang andRando are respectively, first and senior authors of thejust-published paper, titled: "T30177, an oligonucleotidestabilized by an intramolecular guanosine octet, is apotent inhibitor of laboratory strains and clinical isolatesof human immunodeficiency virus type 1."
That research led the FDA to approve an investigationalnew drug application for the Phase I trial now begun.Aronex President James Chubb told BioWorld Today thatthis study aims to enroll "up to 24 HIV-positive patientsto document safety and potential efficacy."
The open-label, dose-escalation regimen requiresintravenous infusion of AR-177 every other day, butChubb mentioned a very recent "unusual finding that thecompound, unlike most known oligonucleotides, is orallyavailable," and may at some future date be soadministered.
Although Aronex initially synthesized the compound,Chubb observed, "for these Phase I studies, we havecontracted its production to the DNA-synthesis group atPerSeptive Biosystems Inc., of Cambridge, Mass."
"HIV integrase," Ojwang explained, "is the enzyme thatthe virus uses to integrate proviral DNA into thechromosome of the host's target cell. Integrase," he wenton, "is the central protein required to process that proviralDNA. Then, after it's transported into the cell's nucleus,that enzyme causes the nick in the cell's chromosomeinto which the viral DNA is integrated, inserted."
Integrase is not a protease (which HIV-1 uses to make itsprotective protein coat). This sets its inhibitor _ AR-177_ apart from HIV protease inhibitors, now a mainstay ofanti-AIDS chemotherapy.
"It seems to have a unique mechanism of action," Ojwangobserved, "as opposed to reverse transcriptase inhibitors,such as AZT, by which the virus replicates its geneticcode."
Just how AR-177 blocks the activity of HIV integrase isthe subject of very recent research, as yet unpublished. Invitro studies have shown that HIV-1-infected cellsexposed to the compound for four days, continue toprevent viral proliferation for 21 days or longer. Cells sotreated with AZT return to pre-treatment levels of HIVwithin two days.
Other laboratories now are hunting HIV-integraseinhibitors, both Chubb and Ojwang said, but none to theirknowledge is anywhere near the stage of human trials.
Aronex's flagship anti-HIV compound does have itslimitations. For one thing, it must be administered duringa narrow window of time, "in the early-late stage ofinfection," as Ojwang put it. For another, it is potentiallyvulnerable to resistance factors that might nullify itsintegrase-inhibiting prowess. "We are now sequencing amutant HIV-1 genome," he said. "Knowing that mutationwill in the future help us to make other compounds thatmight avert that shortcoming.
"AR-177 is a very exciting compound," Ojwangconcluded. "The clinical trials will of course tell us theultimate." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.