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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (388)	2/2/2000 7:40:00 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 1169

SOURCE: Glaxo Wellcome Studies Assess Safety, Efficacy and Resistance Profile of Agenerase SAN FRANCISCO, Feb. 2 /PRNewswire/ -- Two new studies about the resistance profile of Agenerase(TM) (amprenavir) were presented at a major scientific meeting in San Francisco today. The first study evaluated the cross resistance to Agenerase in protease inhibitor (PI) treated patients and the second study evaluated safety and efficacy of two doses of Agenerase in PI-naive and experienced children. The first study, presented by Barbara Schmidt, M.D., principal investigator, Institute of Clinical Molecular Virology, National Reference Centre for Retroviruses, Erlangen, Germany, was designed to evaluate the extent of cross-resistance to Agenerase among patients treated with other marketed PIs. The study examined the in vitro sensitivity against Agenerase, indinavir (Merck), saquinavir (Hoffman-LaRoche), ritonavir (Abbott) and nelfinavir (Agouron). The study found that more than two thirds of samples from patients with previous therapeutic experience of at least one PI were still fully sensitive to Agenerase in these laboratory tests. Furthermore, more than one third of the samples with complete phenotypic cross-resistance to the other four PIs were still sensitive to Agenerase in the phenotypic analysis. The study analyzed 155 samples from 132 patients. Treatment history was available for 127 patients. Of those, 16 were not PI-experienced and 111 were pretreated with one to four PIs. Drug sensitivity against the PIs was determined by an investigational recombinant virus (phenotypic) assay. The phenotypic assay showed that 105 samples (68 percent) were sensitive to Agenerase, 25 were intermediately resistant (4 to 8 fold) and 25 were highly resistant (>8 fold). Of the 62 samples with complete cross-resistance to the other four PIs, 23 were still sensitive to Agenerase. Resistance against Agenerase was more frequently associated with previous treatment with indinavir or ritonavir than saquinavir or nelfinavir. The second study, presented by J. Church, M.D., Children's Hospital, Los Angeles, CA, evaluated the safety and efficacy of two doses of Agenerase oral solution in PI-naive and experienced children, ages two to 12 years. Subjects were randomized to receive 20 mg/kg BID or 15 mg/kg TID Agenerase oral solution in combination with NRTIs. The study found that both Agenerase regimens were generally well-tolerated. Of the 40 subjects (25 PI-naive, 15 PI-experienced) who were evaluated, 84 percent were symptomatic and 48 percent had HIV-1 RNA >100,000c/mL. Two of 23 (9 percent) PI-naive and 11 of 15 (73 percent) PI-experienced subjects had baseline virus with PI-resistant mutations. Only one PI-experienced subject (3 percent) showed reduced susceptibility to Agenerase compared with 11 subjects (78 percent) demonstrating phenotypic resistance to one or more of ritonavir, saquinavir, nelfinavir and indinavir. Twenty three (60 percent) subjects exhibited reverse transcriptase mutations associated with resistance to at least one of the NRTIs co-administered with Agenerase. ``These studies demonstrate a resistance profile of Agenerase that apparently differs from the profiles of other protease inhibitors,' said Lynn Smiley M.D., vice president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome. ``However, the potential for protease inhibitor cross resistance with HIV-1 isolates from Agenerase-treated patients has not been fully evaluated.' In vitro and genotypic analysis of isolates from Agenerase-treated patients showed mutations at 46I/L, 47V, 50V, 54L/V and 84V. The clinical relevance of the genotypic and phenotypic changes associated with Agenerase therapy has not been established. Varying degrees of cross-resistance among protease inhibitors have been observed. The potential for protease inhibitor cross-resistance in HIV-1 isolates from Agenerase-treated patients has not been fully evaluated. Agenerase in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies up to 24 weeks in duration. At present, no results from controlled trials evaluating long-term suppression of HIV RNA or disease progression with Agenerase have been submitted to the FDA for evaluation. The safety of Agenerase was studied in 736 adult patients. In patients receiving protease inhibitors, diabetes mellitus, hyperglycemia, acute hemolytic anemia and redistribution/accumulation of fat have been reported. Severe and life-threatening drug interactions could be associated with therapy with Agenerase (see full prescribing information for specific drug interactions). Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, have been associated with Agenerase. There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors.