Dose-Ranging, Three-Day Monotherapy Study of the HCV NS3 Protease Inhibitor GS-9256

Dose-Ranging, Three-Day Monotherapy Study of the HCV NS3 Protease Inhibitor GS-9256

Reported by Jules Levin
EASL Apr 14-18 2010 Vienna Austria
E Lawitz,1 T Marbury,2 B Vince,3 N Grunenberg,4 M Rodriguez-Torres,5 M DeMicco,6 J Tarro,7 M Shelton,8 S West,8 J Zong,8 A Bae,8 K Wong,8 H Mo,8 D Oldach,8 W Delaney,8 and F Rousseau8

Author Summary

• Subject characteristics were generally well-balanced across regimens (Table 1)

• GS-9256 was well-tolerated, with no safety concerns (Table 2)

• Median HCV RNA declines were -1.1, -2.6 or -2.7, and -2.9 log10 IU/mL for the 25 mg, 75 mg, and 200 mg BID regimens, respectively, and -2.6 log10 IU/mL for 300 mg QD (Figure 1)

• Despite low numbers of pateints with genotype 1b in some dose groups, HCV RNA decline was similar for genotype 1a and 1b (data not shown)

• GS-9256 plasma exposure was greater than dose proportional between 25 and 200 mg BID (Tables 3 and 4), with Day 3 Ctau > 10-fold above the protein-binding adjusted EC50 for all regimens except 25 mg BID (Figure 2)

• GS-9256 pharmacokinetics were comparable for capsule and solution

(Table 5)

• A strong correlation was observed between maximum HCV RNA decline from baseline and plasma exposure of GS-9256 following 3-day monotherapy

(Figure 3)

• Detection of NS3 resistance mutations was more common in subjects receiving higher dose GS-9256 regimens (Table 6) and with more profound viral declines suggesting greater suppression of WT virus revealed preexisting

resistant quasispecies

• GS-9256 resistant isolates were not uniformly resistant to other PIs tested and were not cross-resistant to other classes of HCV agents (Table 7)

AUTHOR CONCLUSIONS

• GS-9256 was well-tolerated over three days of dosing in treatment naïve subjects with chronic Genotype 1 HCV infection

• GS-9256 demonstrated robust dose-dependant antiviral activity

• GS-9256 trough concentrations were well in excess of protein-binding adjusted EC50

• GS-9256 is an attractive candidate for further clinical development in combination with pegylated-interferon/ribavirin and other direct-acting HCV agents

• Phase 2 evaluation of GS-9256 in combination with GS-9190 with or without ribavirin is currently underway