Table 4.
Number of clones with the indicated amino acid substitutions in NS5A genotype 1aa
| Variant | No. of clones for indicated concn of BMS-790052 (nM) |
MAD dose cohort (mg)c | |||||
|---|---|---|---|---|---|---|---|
| 0b | 1 | 10 | 100 | 250 | 500 | ||
| WT | 58 | 4 | 5 | 3 | 1 | ||
| M28T | 15 | 8 | 1 | 1, 30, 60, 100 | |||
| Q30D | 1 | 1 | |||||
| Q30E | 1 | 2 | 23 | 51 | 22 | 10, 30, 60, 100 | |
| Q30H | 17 | 12 | 1, 10, 30, 60, 100 | ||||
| Q30K | 1 | 10 | 30, 60 | ||||
| Q30R | 5 | 6 | 1, 10, 30, 60, 100 | ||||
| Q30G/L/P | 1/1/1 | ||||||
| L31M | 6 | 3 | 1, 10, 30, 100 | ||||
| L31V | 2 | 10, 30, 60 | |||||
| L31P/Q/R | 1/1/1 | ||||||
| P32L | 1 | ||||||
| H58D | 1 | 100 | |||||
| Y93C | 1 | 2 | 1, 30, 60, 100 | ||||
| Y93H | 5 | 6 | 12 | 10, 30, 60, 100 | |||
| Y93N | 5 | 30, 60, 100 | |||||
| M28T/Y93H | 15 | ||||||
| Q30E/Y93H | 1 | 1 | 3 | ||||
| Q30H/Y93C | 1 | ||||||
| Q30H/Y93H | 1 | 60 | |||||
| Q30K/Y93H | 1 | ||||||
| Q30R/H58D | 3 | 100 | |||||
| Q30R/Y93H | 1 | ||||||
| Total clones | 58 | 60 | 47 | 58 | 55 | 46 | |
a
NS5A cDNA clones were isolated from H77c replicon cells following 7 days of exposure to BMS-790052 at the indicated doses. WT, wild type.
b
DMSO-treated control cells.
c
Monotherapy multiple ascending dose study in which subjects received once-daily doses of BMS-790052 for 14 days; mutations were identified in virus from one or more subjects at the indicated doses.