This presentation by Gong and colleagues at Bristol-Myers Squibb provides in vitro and limited in vivo data of a new protease inhibitor in development that promises desirable features of once daily dosing, good tolerability and a resistance profile that appears (at this time) to differ markedly from the existing group of protease inhibitors.

An azapeptide, this protease inhibitor exhibits EC50 values well below the currently licensed group of protease inhibitors, with values of 2 - 5 nM. , which is also well below the concentration of drug that induces cellular toxicity (CC50=2850 microM). Serial passage of virus in the presence of drug (to induce resistance mutations) demonstrated a delayed appearance of mutations (relative to saquinavir and ritonavir) and then the appearance of a different mutation N88S upon genotypic analysis. Cross resistance studies involving 5 other protease inhibitors indicated that BMS-232632 resistant virus remained sensitive to saquinavir while showing some resistance to nelfinavir, ritaonavr, indinavir and amprenavir. In reciprocal cross resistance studies testing the sensitivity to BMS-232632 of strains resistant to nelfinavir, saquinavir and amprenavir, these viruses demonstrated sensitivity to the drug, while indinavir and ritonavir resistant virus displayed partial cross-resistance to BMS-232632.

Limited Phase I data (first in man study) was also presented evaluating the pharmacokinetics of five different doses (once daile doses of either 100mg, 300, 600, 900, 1200) in 40 subjects. Bioavailabilty ranged from 57 - 80 % and was tolerated well, with isolated increases in serum bilirubin seen in the group on the highest dose that was not symptomatic. The group of subjects taking doses above 300mg daily demonstrated serum concentrations of drug that were above the EC50 for HIV for a 24 hour period, distinguishing this agent for once daily dosing. Plans are being made to study this drug further in larger human trials.