S/GSK1265744: a next generation integrase inhibitor (INI) with activity against raltegravir-resistant clinical isolates
Presented by Mark Underwood (United States).
M. Underwood1, M. St Clair1, B. Johns1, A. Sato2, T. Fujiwara2, W. Spreen1
1GlaxoSmithKline Inc., Research Triangle Park, United States, 2Shionogi & Co., Ltd., Osaka, Japan
Background: S/GSK1265744 is a once daily unboosted INI that is being developed as a backup to the once daily unboosted integrase inhibitor, S/GSK1349572. Susceptibility to S/GSK1265744 and raltegravir (RAL) was determined for INI resistant clinical isolates from therapy experienced patients treated with RAL plus optimized background regimen.
Methods: Thirty-nine clinical isolate samples were examined; 30 had IN coding region mutations and 22 of those were longitudinal samples from 9 patients. Mutations included those from the three main RAL resistance pathways as well as more complex mixtures such as E92Q,N155N/H,G140G/S,Q148Q/R; and E138E/K,G140G/S,Q148Q/H,N155N/D. Susceptibility was evaluated using Monogram Biosciences Integrase PhenoSense assay.
Results: Median FC in IC50 against the 30 IN-mutant isolates was 2.26 (range=0.91-40) for S/GSK1265744, and >81 (range=3.74->87) for RAL.
Representative mutant fold change (FC) in IC50 versus wild-type.
[FC IC50 versus wild-type]
Median (Range)||RAL FC
|N155H||1.92 (1.60-2.34)||19.0 (14.0-36.0)||5|
|G140S,Q148H||6.91 (3.52-40)||>87 (58.0->87)||7|
|G140S,Q148R||23 (13-33)||>87 (>87->87)||2|
|T97A,Y143R||1.10 (1.07-1.12)||>81 (>81->81)||2|
High level resistance to RAL was common (18 IN-mutant isolates had RAL FC >50); 10 IN-mutant isolates had S/GSK1265744 FC >5. All longitudinal virologic failure samples were more susceptible (18/21 were >5-fold more susceptible) to S/GSK1265744 than RAL. In human subjects, S/GSK1265744 25mg QD solution dosing produced a mean steady state Ctau of 5.4 ug/mL and IQ of 32 (PAIC90 166 ng/ml against wild-type virus). 32/39 (82%) of the isolates had FCs < 6.4 (5-fold less than IQ).
Conclusions: S/GSK1265744 exhibited in vitro activity against raltegravir-resistant clinical isolates. These data suggest a virologic profile distinct from RAL, and consistent with potential for S/GSK1265744 to treat patients with RAL resistance.
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