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BRISTOL-MYERS SQUIBB’s d4T (STAVUDINE) PARALLEL TRACK APPLICATION FILED

Executive Summary

BRISTOL-MYERS SQUIBB's d4T (STAVUDINE) PARALLEL TRACK APPLICATION FILED with FDA, meaning the AIDS drug could be available "by the end of the summer," Bristol-Myers Squibb Anti- Infectives Division Medical Director Lisa Dunkle, MD, announced July 22 at the VIII International AIDS Conference in Amsterdam. The application for an expanded access program for the didehydrothymidine nucleoside analog was filed with FDA on July 17, BMS said. Approval of the application would be the first under the parallel track regulation published in April ("The Pink Sheet" April 13, p. 12). The company does not plan to charge patients in the parallel track program for the compound. Speaking at a session on new antiretroviral therapies, Dunkle summarized data from five studies with d4T including results from a Phase II trial that evaluated the safety and activity of the nucleoside analog at daily doses of 0.1, 0.5 and 2 mg/kg. A total of 259 subjects were enrolled in the five studies. In the randomized Phase II trial (protocol 006), a dose- response effect in p24 antigen (defined as a decrease of 50% or more from baseline) was observed at up to 1 mg/kg of d4T. Regarding d4T's effect on CD4 cell counts, Dunkle said "the profile corroborates the p24 data, showing a dose response up to the range of 0.5 to 1 mg per kilo, and a relative plateau thereafter." CD4 counts in patients receiving clinical doses of 0.5, 1 and 2 mg/kg per day plotted over time showed "a gratifying response that's sustained for most of the first six months of therapy," Dunkle stated. She added that the drug is "relatively well tolerated," with the major dose-limiting toxicity being peripheral neuropathy. Among the 164 patients receiving a clinical dose of d4T, 25 developed peripheral neuropathy, Dunkle said. While 14 of these patients resumed therapy at half of the original dose for an average of six months, 11 patients had to be permanently discontinued from treatment. The expanded access (parallel track) protocol would be a randomized, double-blind study of AIDS patients who are intolerant to or resistant to AZT or ddI (BMS' Videx) and have CD4 counts of 300 or less. Patients would be randomized to receive either 20 mg or 40 mg of d4T orally twice a day. The program would include AIDS patients 12 years of age or older. Future studies of stavudine will focus on evaluating combination therapy with Videx and "ultimately in combination with AZT," Dunkle said. In a discussion following Dunkle's presentation, Lawrence Corey, University of Washington, observed that "we see the maximal antiviral effect as measured by p24...at a dose of 2 mg/kg." He added, however, that the 2 mg/kg/day dose of stavudine results in "a relatively high rate of peripheral neuropathy," and suggested that "further development will be probably at lower dosages [of] either 1 or 0.5 mg/kg." Commenting on the limitations of reverse transcriptase inhibitors in stabilizing the effects of HIV, Corey said that "at current levels, monotherapy with all these RT inhibitors is only partially effective in blocking new infections" and suggested that "even combination therapy may have only limited effects." He noted that recent data from an AIDS Clinical Trials Group study show that AZT/ddI combination therapy has a more beneficial effect on CD4 counts compared to AZT monotherapy, but that "at 20 weeks, most patients are below" baseline CD4 levels.

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