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  50th ICAAC
Boston, MA
September 12-15, 2010
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GSK New NNRTI Selects No Resistance Mutations in 7 Days of Monotherapy
  50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
GSK2248761, a nonnucleoside (NNRTI) in phase 2 development at GlaxoSmithKline, selected no mutations in reverse transcriptase in 36 antiretroviral-naive people who took the drug as monotherapy for 7 days [1]. Viral load reductions over the 7 days ranged from 0.97 to 1.87 log with the 5 doses studied.
Called 761 for short, the experimental NNRTI has subnanomolar activity against wild-type (nonmutant) virus and most well-recognized NNRTI mutants. In vitro studies indicated that multiple mutations must be selected to confer resistance to 761. Susceptibility to 761 decreases against a triple combination of three classical NNRTI--K103N, Y181C, and G190A--and against the Y181C plus P277C.
GSK veteran chief virologist Marty St. Clair presented resistance data from two dose-ranging monotherapy studies of 761. Both were double-blind, placebo-controlled trials in antiretroviral-naive people randomized 8-to-2 or 6-to-2 to placebo or 761 for 7 days at doses of 800, 400, 200, 100, or 30 mg. All study participants were 21 to 65 years old, had a viral load at or above 5000 copies, and had a CD4 count at or above 200. No one had AIDS or hepatitis B or C infection. And no one had a major NNRTI resistance mutation when screened for the study.
After 7 days of 761 monotherapy, viral load declines averaged 1.8 log with doses of 100 to 800 mg daily. Responses did not differ in people with subtype B or with subtype B/F. No rash or central nervous system toxicity was noted during treatment.
Among the 38 study participants, 28 had no detectable NNRTI mutations when screened for the study. Ten people had substitutions at reverse transcriptase sites, including K101R, K103R plus V179I, V106I, V179D/E, M41L plus T215E, M184M/L, L210F, and G116L/F.
Two people did not have day 8 genotypes because their viral load was too low to permit genotyping. Genotypes of the people with pretreatment substitutions did not change during 761 therapy. Virologic responses in people with those substitutions did not differ from responses of others in the same dose group without those substitutions. Among people with no substitutions at screening, no mutations emerged during treating.
An L100V substitution evolved during treatment in one person taking 200 mg of 761. St. Clair noted that L100V is not a recognized NNRTI mutation, and this person responded to 761 as well as other people taking 200 mg of the drug. (From Jules: Dr St Clair said phase 2b study is planned to start soon with doses of 100 and 200 mg once daily. ).
1. St. Clair M, Dudas K, You Y, et al. GSK2248761, an NNRTI with activity against common NNRTI resistance mutants, did not select for NNRTI resistance mutations in two seven-day monotherapy studies. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-1814.