UPJOHN ANTI-HIV AGENTS U-90,152 AND U-87,201 ARE IN PHASE II

UPJOHN ANTI-HIV AGENTS U-90,152 AND U-87,201 ARE IN PHASE II clinical trials, both in combination with zidovudine (Burroughs Wellcome's Retrovir/AZT) and didanosine (Bristol-Myers Squibb's Videx/ddI) and as monotherapies. The two non-nucleoside reverse transcriptase inhibitors are in clinical trial programs sponsored by Upjohn, as well as in trials through the National Institute of Allergy and Infectious Diseases and the AIDS Clinical Trial Group (ACTG) network. U-90,152 and U-87,201 (ateviridine), members of the bisheteroarylpiperazines (BHAP) class of compounds, have shown evidence of greatly increased potency against the AIDS virus compared to other non-nucleoside RTIs and appear to have overcome problems with viral resistance that can develop after six to 12 months with R71s. This cross-resistance has been stumbling block to further development of some RTIs and has strengthened the argument that combination regimens are a better approach to HIV treatment. 90,152 has shown a 50-100 fold increase in potency compared to its precedessor compound, ateviridine. Upjohn will begin a Phase II combination trial of 90-152 and AZT in Kalamazoo April 1. The dosing regimen trial is expected to enroll approximately 40-50 HIV- positive individuals with CD4 cell counts in the 100-300 range at each of two centers. Within about eight to 10 weeks, Upjohn expects to proceed with a monotherapy trial of 90,152. The company also hopes to begin a study of 90,152 and AZT in Europe this summer in about 150 patients. NIAID announced March 22 that it has launched a study of 90,152, ddI and AZT at the NIH Clinical Center. The study will be conducted in two 24-week phases with HIV-infected individuals whose CD4 cell counts range from 100 to 300. The first phase will include 40 patients who will receive either a three-drug combination of 90,152, AZT and ddI or a two-drug combo of AZT and ddI. The second phase will enroll an additional 40 patients who will receive 90,152 alone or in combination with AZT. The second phase will also assess the combination regimen in patients with CD4 cell counts of less than 100. A report at the recent ACTG mid-year meeting on ateviridine found that in a 20-patient trial, resistance to the compound did not develop. A 120-patient ACTG trial (ACTG 199) of ateviridine in combination with AZT is scheduled to start in the next few weeks, and an ACTG monotherapy trial is also in the works. Upjohn has committed to a clinical trial of ateviridine, ddI and AZT. The company is looking at ateviridine for AIDS-related dementia due to the compound's high concentration in brain tissues. Upjohn has met with AIDS activist groups to discuss expanded access to the compounds. The company said it is prepared to go to expanded access as soon as it sees that the drugs are safe enough to do so and have some activity. NIAID's launch of the 90,152 trial follows the institute's March 3 announcement regarding plans for a combination trial that evaluates ddI, AZT and Boehringer-Ingelheim's non-nucleoside transcriptase inhibitor nevirapine. That trial, in patients with advanced AIDS, is expected to begin later this spring. Boehringer is currently conducting Phase II clinical trials of nevirapine as a monotherapy and in combination with AZT. Although there was concern with patients developing resistance to nevirapine, the company said it has changed dosages and will continue testing the compound.