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Recent advances in antiretroviral therapy have allowed the creation of highly active antiretroviral therapies (HAART). For the therapy-naïve individual infected with wild type HIV-1, these drug combinations provide a high probability of initial viral suppression. However, it is estimated that 40 to 80% of patients currently receiving antiretroviral therapy are beyond their initial regimen. It is also well established that the probability of achieving full virological suppression decreases with each new regimen following virological failure. The DuPont Pharmaceuticals Company (DPC) has focused its discovery and development efforts in HIV to the creation of
second generation compounds through improved antiviral activity (Potency), improved free drug levels (Protein binding) or improved total drug availability (Pharmacokinetics). Improvements of any or all of these 3 P’s could lead to compounds highly active against single or multiple mutations which confer resistance to existing antiretroviral agents. DPC is actively pursuing such agents in all 3 classes of drugs active against HIV-1: the non-nucleoside analog reverse transcriptase inhibitors (NNRTI), the protease inhibitors (PI) and the nucleoside analog reverse transcriptase inhibitors (NRTI). DPC 083 is a quinazolinone NNRTI. Its antiviral activity is similar to efavirenz against single mutant variants with substitutions at positions 98,
101, 106, 108, 181 and 188. DPC 083 is 2- to 5-fold more potent than efavirenz against mutant virus with single substitutions of K103N (which confers cross-class resistance to all currently available NNRTIs), or L100I. DPC 083 is 2- to 4-fold more potent than efavirenz against virus with 2 or 3 amino acid substitutions, including clinically relevant mutants prevalent in NNRTI-failure such as K103N+V108I, K103N+P225H, Y188L, and K103N+K101E. In vitro selection experiments indicate that high level resistance requires several mutations. Free drug concentrations of DPC 083 are approximately 4- to 10-fold higher than those for efavirenz (2.0% free drug versus 0.21 to 0.55% free drug, respectively). The combination of greater potency and higher free
fraction results in DPC 083 having an overall improvement in antiviral activity of 10- to 20-fold relative to efavirenz. Additionally, DPC 083 has a half-life in humans of approximately 90 hours (3.8 days) which translates to low peak to trough ratios at steady state. DPC 083 is currently in Phase II development and is expected to enter Phase III in the fall of 2001. DPC is also developing novel protease inhibitors (PIs) with antiviral activity against mutant virus resistant to currently available PIs. DPC 681 and DPC 684 are potent and selective inhibitors of HIV protease. Both are active against all single and most multiple mutations conferring resistance and cross-resistance to currently available PIs. These agents are 1.6 to 1.9% free in
plasma. It is anticipated that total drug concentrations at trough approaching 1 uM will be sufficient to suppress greater than 90% of multi-PI resistant clinical isolates selected for by existing agents in this class. At the time of submitting this abstract, these agents are in Phase I development. Finally, DuPont is actively searching for new nucleoside analogs with activity against mutants conferring resistance to currently available agents. The first such candidate is DPC 817 which began dosing in humans earlier this year.
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