GMHC Treatment Issues (Newsletter of Experimental AIDS Therapies) Volume 13, Number 2 - February 1999
Five NNRTIs still under development were presented at the 6th Conference on Retroviruses and Opportunistic Infections. Currently the NNRTIs have cross-resistance to each other. A single mutation (K103N -- a lysine to asparagine at amino acid 103 in HIV's reverse transcriptase enzyme) can occur rapidly and negates the activity of all currently approved NNRTIs. Drug companies are now attempting to develop NNRTIs that either will not trigger this mutation or, even better, will still be potent against HIV with K103N. Such activity would allow the new agent to replace one of the present NNRTIs should treatment failure occur.
DuPont, maker of the NNRTI Sustiva (efavirenz), is hoping to bring a "second generation" NNRTI to market within a few years. The company has two compounds in development, DPC 961 and DPC 963 (S. Erickson-Viitanen et al., slide presentation 13). Both show strong activity in the test tube against wild type HIV. Their activity against the K103N mutant virus is reduced but is greater than that of the established NNRTIs. Initial pharmacokinetic data show a long half-life for both drugs in the body. This will most likely allow once-a-day dosing. DuPont is planning to select the better of these drugs for fast-track development. It hopes to start testing the chosen agent in humans by the end of the year.
Glaxo Wellcome presented GW420867X, one of a family of NNRTIs purchased from Hoescht-Bayer that includes the previously reported HBY097. The GW compound exhibits better antiviral activity than HBY097 and is less affected by binding to blood proteins (JP Kleim et al., poster 599). Test-tube data on the resistance profile of GW420867X found results comparable to efavirenz (JP Kleim et al., poster 600). Based on its pharmacokinetic profile, GW420867X, like the DuPont compounds, should permit once-a-day dosing. Glaxo has done some pharmacokinetic (drug level) studies in healthy HIV-negative adults, and clinical studies in HIV-infected patients are to commence soon.
Agouron, which produces the protease inhibitor Viracept (nelfinavir), also has a new NNRTI, AG1549 (K Potts et al., slide presentation 12). AG1549 remained active in cell cultures against laboratory-generated strains of virus resistant to present NNRTIs. Significant reductions in virus susceptibility to AG1549 did occur when two or more reverse transcriptase mutations arose. Phase I/II clinical trials are underway to determine optimal dosing.
Sarawak Medichem pharmaceuticals has a singular set of related NNRTIs, calanolide A and B (respectively, J Ruckle et al., poster 606 and T Jenta et al., poster 602), derived from the latex of a tree indigenous to Sarawak, Malaysia. In tests that were once again highly preliminary, the calanolides exhibited an attractive resistance mutation profile. Their activity in the test tube against nevirapine-resistant HIV with the Y181C, normally a resistance-conferring mutation, was actually better than against wild type HIV, although the K103N mutation was detrimental. In early dosing trials of calanolide A, the most common reported adverse events were dizziness, headache and an oily taste. Since the calanolides readily combine with fats (are lipophilic), they may penetrate tissue membranes more readily and reach areas difficult to get drugs into, such as the brain.
A word of caution concerning all of these compounds: The data from cell culture experiments look promising, but test-tube data on resistance has often differed in the past from what was observed once an agent is tested in the human body.- MN
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