The Body Covers: The 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy
Early Pre-Clinical Development of GW8248 Promising
September 14, 2003
GW8248 is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed for treatment of NNRTI-resistant virus. NNRTIs such as nevirapine (NVP, Viramune) and efavirenz (EFV, Sustiva) have assumed a central position in HIV therapy in recent years because of their efficacy, low pill burden, convenience, limited effects on lipids and body fat and their tolerability. However, the weakness of the class has been the cross resistance to the entire class conferred by single mutations in reverse transcriptase. Another concern is the increasing frequency of NNRTI resistance due to sexual transmission of HIV by persons with resistant virus, which is being seen in newly infected patients in studies from the United States and Europe.Reference
Against this background, new NNRTIs that are active against virus resistant to the first generation NNRTIs are going to be crucial. Several candidates are in early development, including GW8248, TMC 125 and capravirine. This presentation from the drug development team at GlaxoSmithKline added to the information on GW 8248 presented this summer at the Paris IAS meeting and provided more important information on resistance patterns.
GW8248 is a benzophenone derivative that is active at very low concentrations against "wild type" (drug sensitive) HIV and against virus with the most important mutations that develop after use of nevirapine, efavirenz and delavirdine (DLV, Rescriptor) (which include K103N, G190A and Y181C), as well as against many viruses with two of these mutations. Mutations at position 188 had modest resistance, but so far, these have been uncommon mutations. GW8248 showed very little toxicity in some of the lab experiments designed to predict if a drug may be toxic in humans.
In experiments combining GW8248 with other licensed drugs, it appears to be synergistic as an additive. This suggests that it will be effective in combination.
GW8248 may not be well absorbed as a pill, however, since it is not very water soluble. A pro-drug of GW 8248 is being explored, dubbed GW8635 (see Abstract H-872), that is metabolized to GW 8248 but is likely to be much better absorbed. Preliminary studies in rats using the prodrug are presented at this meeting and look good. This might allow lower doses and smaller tablets.
An important set of experiments was presented in which the researchers intentionally created resistant virus by exposing virus to steadily increasing concentrations of the drug in cell culture, starting at low enough levels of drug so as to not suppress replication. Two patterns emerged when resistance was induced in wild type virus. In the first, development of V106A and P236L mutations in combination led to significant resistance. The other pattern was a triple mutation with V106I, E138K and P236L. Perhaps more importantly, when the same experiment was conducted with nevirapine and resistant virus with the K103N mutation, the development of V106A led to resistance to GW 8248. How this will play out remains to be seen when the drug is used in patients who have developed NNRTI resistance.
In conclusion, the early pre-clinical development looks quite promising but we have learned to be cautious. At every stage of drug development, roadblocks can appear. Unexpected side effects, easy development of resistance, variable blood levels and drug interactions are just some of the things that can go wrong. We are still waiting for that crucial second generation NNRTI to make it.
Authored by: R. J. Hazen, R. Harvey, R. Ferris, K. Creech, M. St. Clair, K. Romines, G. Freeman, L. Schaller, J. Chan, R. Dornsife, L. Boone
Affiliations: GlaxoSmithKline, Research Triangle Park, NC
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