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Co-receptor Tropism, ENV Genotype, and in vitro Susceptibility to CCR5 Antagonists during a 14-Day Monotherapy Study with INCB9471
Susan Erickson-Viitanen*1, K Abremski1, K Solomon1, R Levy1, E Lam2, J Whitcomb2, R Lloyd, Jr.3, R Mathis3, J Reeves2, and D Burns3
1Incyte Corp, Wilmington, DE, US; 2Monogram Biosci, South San Francisco, CA, US; and 3Res Think Tank, Buford, GA, US
Background: Study INCB 9471-201 was a 14-day monotherapy
study of the once-daily CCR5 antagonist INCB9471 in naïve or
therapy-experienced subjects who were R5-tropic by Trofile assay at screen. Of
the 49 subjects enrolled, 9 received placebo, 9 received 100 mg, 19 received 200
mg, and 12 received 300 mg of INCB9471.
Methods: Trofile assay, susceptibility (PhenoSense Entry
Assay) and ENV genotype (HIV-1 GeneTanker® C2V3-gp41HR1 domain Select
assay) were determined at screening, baseline, day 14 and day 28; clonal sequencing
was determined by GeneSeq HIV ENV assay.
Results: Virus present at screening and day 28 was highly
susceptible to full inhibition by INCB9471 (Screening IC50 = 12.1±1.5
nM, n = 49, day 28 IC50 = 8.0±1.5 nM, n = 32),
indicating a lack of resistance emerging in this short study. Plasma-derived
viral RNA genotypes were obtained and compared to V3 polarity relative to 11 of
25 basic prediction rules; modified prediction analysis, MuTanker™ was also performed.
Of 39 subjects receiving 14 days of INCB9471 treatment, 30 achieved viral load
declines >1.5 log10 relative to baseline: representing 5 of 9, 16
of 19, and 9 of 11 subjects receiving 100 mg, 200 mg, or 300 mg INCB9471,
respectively. Circulating virus remained R5 tropic in 35 of 39 INCB9471-treated
subjects. Dual/mixed tropic virus was observed on day 14 and/or day 28 for 2
subjects each, who received 200 mg or 300 mg INCB9471. These subjects exhibited
attenuated viral load responses; 3 of 4 had prior therapy experience. Clonal
analysis (Trofile, sequencing, susceptibility) has been completed on 2 of these
subjects. In subject A, receiving 200 mg, dual tropic phenotype was observed in
~13% of clones examined at baseline; corresponding V3 loop sequences revealed
lysine at position 25 relative to other viruses in the swarm with glutamic
acid. Circulating virus was again R5 tropic subsequent to study completion. In
subject B, receiving 200 mg, circulating virus was dual/mixed at day 14,
returning to R5 tropic at day 28. At day 14, the CXCR4-using viruses formed a
monophyletic group, and were distinct from R5 viruses, suggesting that the dual
virus present at day 14 likely arose via outgrowth from an unidentified
ancestral virus present at baseline.
Conclusions: As shown with other CCR5 antagonists, the data
from a 14-day monotherapy study with once-daily INCB9471 suggests that
emergence of CXCR4-using viral variants in a minority of the treated patients
reflects outgrowth from pretreatment viral reservoirs.
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