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141W94 (VX-478)
Marty St. Clair, Ph.D.
Glaxo Wellcome
141W94 or VX-478 is a potent HIV protease inhibitor licensed by Glaxo Wellcome from Vertex Pharmaceuticals. It has an inhibitor constant (Ki) for HIV protease of 0.6 nM. 141W94 is active against a variety of HIV strains including AZT resistant mutants. Preclinical studies have demonstrated good oral bioavailability of the compound in animal models (35 to 90+%) with oral half-life of 2 to 10 hours.
141W94 is synergistic with AZT, ddI and other nucleoside analogs in development at Glaxo Wellcome (935U83, 524W91, 1592U89). Resistance to 141W94 has been detected in cell culture experiments. Mutation at codon 50 of the protease gene seems to be the primary resistance mutation conferring a 3-fold decline in viral sensitivity to 141W94. Two additional mutations at codon 46 and 47 usually follow the development of mutation at codon 50. A virus with mutations at 46, 47 and 50 is about 20-fold less sensitive to 141W94. Mutation at codon 50 is an unique resistance profile, suggesting that 141W94 may possibly be used in combination with other protease inhibitors.
There was a great deal of concern about protein binding by protease inhibitors which lead to rapid clearance of drug and loss of antiviral effect. In the presence of 45% human serum or plasma, a 1.4 to 2 fold decrease in viral sensitivity to 141W94 were observed. When 1.2 mg/ml of alpha-1 acid glycoprotein is added to 45% human serum in order to approximate the concentration of proteins found in HIV-infected people, a 3 to 4 fold less viral sensitivity were seen. Based on these findings, Dr. St. Clair concluded that human serum or plasma causes small shift in 141W94 antiviral activity and will probably not reduce the overall efficacy of the compound.
Mutation at codon 50 is an unique resistance profile...that 141W94 may possibly be used in combination with other protease inhibitors.
Studies in rats have shown that 141W94's accumulation in the brain approximates that found in the blood. In addition, amounts of 141W94 were found to be 11-fold higher in rats' mesenteric lymph nodes than those in the blood. There were no cardiovascular or respiratory effects in rats and dogs.
A total of 18 HIV-infected people (15 males and 3 females) were enrolled in a phase I, placebo-controlled, single escalating dose study. Participants were randomized to receive single doses of 150, 300, 600, 900, or 1,200 mg of 141W94. The amounts of 141W94 found in those received the 900 or 1,200 mg dose at 8 and 12 hour post dosing were significantly higher than those required to inhibit both laboratory strains or clinical isolates of HIV in cell cultures. In this study, the compound produced a 70 to 78% oral bioavailability with half life of 7 to 10 hours.
Based on both preclinical and early clinical data, further evaluation of 141W94 in HIV-infected people is warranted. Prior to the initiation of pivotal studies, Glaxo Wellcome plans to conduct phase I/II efficacy and dose finding studies of 141W94 alone or in combination with nucleoside analogues.
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