Lack of Resistance Development to the HIV-1 Attachment Inhibitor BMS-626529 during Short-term Mono-therapy with Its Pro-drug BMS-663068
Neelanjana Ray*1, M Wind-Rotolo1, M Healy2, C Hwang1, S-P Huang1, J Whitcomb3, N Zhou2, M Krystal2, and G Hanna1
1Bristol-Myers Squibb, Princeton, NJ, US; 2Bristol-Myers Squibb, Wallingford, CT, US; and 3Monogram Biosci, South San Francisco, CA, US
Background: BMS-626529 is a first-in-class oral HIV-1 attachment inhibitor pro-drug that binds to gp120 and impedes the first step of viral entry by preventing gp120 engagement of the CD4 receptor. In a randomized, open-label multiple-dose 8-day mono-therapy study, BMS-663068, the prodrug of BMS-626529, demonstrated potent antiviral activity. The present analysis examines changes in phenotypic susceptibility and known attachment inhibitor resistance substitutions during this short-term mono-therapy study.
Methods: Phenotypic susceptibility of subjects’ viral quasi-species at days 1 and 8 were assessed from plasma using the PhenoSense Entry assay (Monogram). To minimize inter-assay variability, subjects’ IC50 levels were normalized to that of a control virus to obtain fold-change IC50. Population gp160 sequencing of day 1 and day 8 samples was performed using GeneSeq Env (Monogram).
Results: Of the 48 subjects who completed the study, there were 42 responders (>1.0 log10 copies/mL decline in HIV-1 RNA) and 6 non-responders. All non-responders had baseline IC50 >100 nM. Phenotypic susceptibility to BMS-626529 could be obtained for 46 subjects on day 1, and 38 subjects on day 8. Based on the 38 subjects with both day-1 and day-8 data available, the fold-changes of IC50 from day 1 to day 8 were relatively low (median 1.26; range 0.45 to 4.24). In 34 of 38 subjects (89.5%) the fold changes of IC50 from day 1 to day 8 were <3-fold, which is the fold-change reproducibility cutoff for the PhenoSense Entry assay. In 4 of 38 (10.5%) subjects (2 non-responders and 2 responders), day-8 fold-changes in IC50 were marginally higher than the reproducibility cutoff (>3-fold but <5-fold). However, the 2 non-responders already had high IC50 at baseline (270 nM and 386 nM on day1) and the 2 responders exhibited low IC50 despite the increase (0.2 nM and 3 nM on day 8). Population gp160 sequencing at baseline revealed an association of the known M426L Attachment inhibitor resistance substitution with high IC50 and poor virologic response (5 of 6 non-responders and 2 of 32 responders harbored 426L). Other minor attachment inhibitor resistance substitutions were also present at baseline in certain non-responders with or without M426L. In the 39 subjects with both day 1 and day 8 gp160 population sequencing data available, none demonstrated clear selection of a known attachment inhibitor resistance mutation at day 8.
Conclusions: Monotherapy with BMS-663068 for as long as 8 days did not appear to select for BMS-626529 resistance.