Antiviral agent – KNI-272
The rapid rate at which the HIV is able to mutate into resistant forms means a constant stream of new antiviral agents is needed if the arsenal of drugs is to remain effective. The earliest antiviral drugs used against HIV, the reverse transcriptase inhibitors like AZT, are now invariably used in combination with the newer protease inhibitors in a cocktail of drugs to attack the virus. But there is no guarantee that the drug cocktail will remain effective as the virus mutates.
A novel protease inhibitor, KNI-272, or kynostatin, is being developed by Japan Energy as a treatment for primary HIV infection1. It is highly potent against HIV protease, and shows minimal inhibition of other aspartic processes in in-vitro HIV strains.
Thirty-seven patients with AIDS or symptomatic HIV infection, and 100–400 CD4 cells per ml, were given the drug four times a day for up to 12 weeks in an escalating dose Phase I study. The maximum tolerated dose was 40mg/kg/day, and at this dose there was some evidence of an anti-HIV effect, and an upward trend in the CD4 count2.
In a Phase I/II trial in 18 patients with symptomatic HIV disease, a microsphere formulation of the drug was given in escalating doses of up to 60mg/day. It was rapidly absorbed, but had only a very short half-life, probably a result of its rapid metabolism. Perhaps because of this, no consistent effect on plasma HIV RNA levels or CD4+ lymphocyte counts was seen in patients3. However, animal studies indicate that coadministering the drug with antiviral agents such as nelfinavir and indinavir that inhibit cytochrome P450-mediated metabolism could improve its pharmacokinetics by slowing down this metabolism, and hence make it more viable as an oral protease inhibitor.