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Executive Summary

Roche's TAT antagonist Ro 24-7429 will enter Phase I/II clinical trials this month under the auspices of the AIDS Clinical Trial Group. Participants are now being accrued for the AIDS Clinical Trial Group study (ACTG 213) at four sites: the University of California-San Diego, Case Western Reserve University in Cleveland, Johns Hopkins and Harvard/Massachusetts General Hospital. As currently designed, the ACTG 213 protocol features arms of 25, 50 and 100 mg of Ro 24-7429 and a nucleoside control group. The addition of Ro 24-7429 to the nucleoside group after 12 weeks of study is tentatively scheduled, Mass. General investigators said. The protocol calls for the enrollment of 24 individuals per site with HIV and CD4 lymphocyte counts between 50 and 500 mm. At least 50% of the enrollees will be positive for p24 antigens. Roche Director of Virology Ming-Chu Hsu, PhD, presented preclinical and Phase I data on Ro 24-7429 Oct. 12 in Anaheim at the American Society for Microbiology's Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Hsu, who helped discover the TAT (transactivator for transcriptase) antagonist class of compounds, said completed Phase I studies of Ro 24-7429 at four different dosage levels showed "no adverse events versus control groups." Another long Phase I study is now under way, Hsu said. The inhibition of TAT, which facilitates and elongates viral transcription, affords the possibility of "preventing new rounds of infection" and therefore keeping HIV in a dormant stage, Hsu told ICAAC. The drug has shown activity in vitro against HIV strains resistant to AZT (Burroughs Wellcome's Retrovir) and could be useful in treating both acute and chronic infection, she noted. The Roche investigator emphasized Ro 24-7429's ability to restore CD4 cell expression by chronically infected cells -- a quality "unique to this class of compound." Because TAT antagonists attack HIV at an earlier point in the replication process than nucleosides, Hsu said Roche eventually hopes to use its TAT inhibitor in combination with other AIDS drugs, including the nucleoside analogs and protease inhibitors. She added that Ro 24-7429 use "did not produce resistance in the lab." The compound also demonstrated "synergy with AZT and with ddC [Roche's Hivid] in vitro," Hsu observed. Data from two Phase I/II dose-escalating studies of Glaxo's 3TC ('3 thiacytidine or lamivudine) nucleoside analog were presented to ICAAC on Oct. 13. One study was performed in Europe and one was conducted in the U.S. and Canada. Presenting results of the North American 3TC study, James Pluda, MD, National Cancer Institute, concluded that "the data reflecting the anti-viral activity of 3TC at doses of 8 and 12 mg/kg give cause for a certain degree of cautious optimism." In addition, Pluda said, "the absence of substantial toxicity is very encouraging." The trial divided 82 patients with CD4 cell counts below 300 cells per mm into six groups receiving 3TC doses ranging from .5 mg/kg to 12 mg/kg per day. Most of the patients had advanced AIDS-related complex and had received prior nucleoside therapy for one-and-one-half to two years. Pluda reported that "no consistent elevation in CD4 counts was observed at the lower doses." However, he added, "at the higher dose levels, an initial increase in the mean CD4 count was consistently seen" in the first four weeks of therapy. The increase in CD cell counts ranged from 35 cells for the 4 mg/kg per day dose to 49 cells in the 12 mg/kg dose group. In most patients, CD4 counts returned to baseline levels by the 12th week of the study. Pluda noted, however, that the CD4 counts of the 8 mg/kg group rose again in week 20 of the study. He said the decline in CD4 counts "does not appear" to be caused by the development of HIV strains resistant to 3TC. A European trial of 3TC had very similar results, investigator C. Katlama, MD, University of Paris, told ICAAC. In that study, "CD4 [cell counts] exhibited a small initial rise and then were maintained around baseline levels for the remainder of the trial," Katlama said. NCI's Pluda said patients are currently being enrolled for further study of 3TC at doses "as high as 20 mg/kg." He concluded that "the place of 3TC [in AIDS treatment] needs to be clarified in a randomized trial." Pluda also pointed out that in vitro data suggest that 3TC is "synergistic with AZT" and "additive with ddC and ddl [Bristol- Myers Squibb's Videx]." He recommended further studies in combination with other nucleosides and as monotherapy. Glaxo said the company hopes to begin large-scale safety and efficacy trials with 3TC in 1993. At the opening session of the conference, Douglas Richman, MD, V-A Medical Center, San Diego, noted that all of the currently licensed nucleoside analogs "have distinctive toxicity profiles that limit their therapeutic benefit." He suggested that "what we truly need is a nucleoside analog that is analogous to acyclovir in that it is sufficiently non-toxic that it can be given in higher doses and hopefully we can get better effectiveness." Richman indicated that 3TC might be such a compound, saying that "it is very interesting that...the positive enantiomer has the toxicity characteristics...and you can separate these two [enantiomers]." Glaxo licensed 3TC's parent compound, 2'-deoxy-3'-thiacytidine, from the Canadian firm Biochem Pharma ("The Pink Sheet" Dec. 16, 1991, p. 19). Lamivudine is the negative enantiomer of the licensed compound. Data on another class of AIDS drug candidates, protease or proteinase inhibitors, were presented to ICAAC members by Abbott, Searle, Roche and Upjohn. Of the compounds discussed at the conference, Roche's Ro 31- 8959, currently in Phase I/II dose-ranging studies in Europe, is the farthest along in the development process. Roche U.K. investigator Noel Roberts, PhD, said "over 200 patients are on drug" in the ongoing study and efficacy data should be available "in early 1993." At a meeting in Florida earlier this year, Roche Director of Chemistry Peter Machin, PhD, said the company was considering "a wide range" of surrogate markers to use in the efficacy trials of Ro 31-8959, including p24, CD4 and viremia measured by polymerase chain reaction (PCR) ("The Pink Sheet" March 23, T&G-6). Abbott Project Leader of Antiviral Research Daniel Norbeck, PhD, said his company's lead oral protease inhibitor, A-80987, is currently undergoing preclinical safety assessment and should enter the clinic in 1993. He highlighted the compounds "50% oral bioavailability" and "good in vitro activity against HIV." A-80987 was the result of "extensive" chemical manipulation of earlier drug candidates, which either lacked anti-HIV activity or had unacceptably low bioavailability, Norbeck explained. Abbott is already conducting early clinicals on its intravenous protease inhibitor, A-77003, at the Amsterdam Medical Center. At the VIII International Conference on AIDS in Amsterdam earlier this year, Norbeck said that trial would evaluate the ability of A-77003 to dissolve in and diffuse through lipid barriers ("The Pink Sheet" July 27, T&G-9). Searle intends to begin clinical studies of its oral SC-52151 protease inhibitor early in 1993.

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