Session Title: Category 13. LATE-BREAKERS
Presentation Date: Apr 15, 2010
DOSE-RANGING, THREE-DAY MONOTHERAPY STUDY OF THE HCV NS3 PROTEASE INHIBITOR GS-9256
E.J. Lawitz1*, T.C. Marbury2, B.D. Vince3, N. Grunenberg4, M. Rodriguez-Torres5, M.P. De Micco6, J.N. Tarro7, M.J. Shelton8, S. West8, J. Zong8, A. Bae8, K. Wong9, H.-M. Mo9, D. Oldach8, W. Delaney9, F. Rousseau8
1Alamo Medical Research, San Antonio, TX, 2Orlando Clinical Research Center, Orlando, FL, 3Vince & Associates Clinical Research, Inc., Overland Park, KS, 4Charles River Clinical Services Northwest, Tacoma, WA, USA, 5Fundacion De Investigacion De Diego, Santurce, Puerto Rico, 6Advanced Clinical Research Institute, Anaheim, CA, 7Columbia Research Group, Portland, OR, 8Gilead Sciences, Inc, Durham, NC, 9Gilead Sciences, Inc, Foster City, CA, USA. *email@example.com
Background and aims: GS-9256 is a novel HCV NS3 protease inhibitor (in-vitro EC50 of ~20 nM in HCV 1b replicon assays). The aims of this study were to evaluate the safety, antiviral activity, pharmacokinetics (PK), and resistance outcomes of GS-9256 monotherapy in genotype 1 (GT1) HCV subjects.
Methods: A randomized, double-blind, placebo-controlled multiple ascending dose study was conducted in treatment-naïve HCV subjects (GT1). GS-9256 or placebo was administered for 3 days at 25mg, 75mg, and 200mg BID and 300mg QD as capsule or oral solution.
Results: GS-9256 was well tolerated, with significant activity even at the lowest dose studied. 53/54 enrolled subjects completed dosing. There were no SAEs or Grade 3/4 laboratory abnormalities. All treatment-emergent AEs were mild to moderate in severity (headache and diarrhea were most common, occurring in < 20% of subjects). Median HCV RNA declined sharply through Day 2 in a dose-dependent manner. Median changes from baseline in HCV RNA at Day 4 were -1.1, ‑2.7, -2.6, and -2.9 log10 IU/mL for the 25mg (capsule), 75mg (capsule), 75mg (solution), and 200mg (solution) BID regimens respectively. Median HCV RNA change from baseline at Day 4 was -2.6 log10 IU/mL for 300mg QD (solution). GS-9256 exposure was greater than dose proportional and median half life ranged from ~7 to 14 hours. For 75mg BID, 200mg BID and 300mg QD, Day 3 mean Ctau was >10-fold above protein-binding adjusted mean EC50 for GT1. PK was similar for capsule and solution. PK correlated well with HCV RNA suppression. Genotypic analyses identified the NS3 protease mutations R155K, D168G/E/N/V or A156V. At the end of the 3-day dosing period, these mutations were more common in subjects with the most profound HCV RNA reductions and there was no evidence of HCV RNA rebound during the 3-day dosing period. In vitro, these mutations displayed reduced GS-9256 susceptibility, but wild-type sensitivity to IFN-α, ribavirin, and Gilead's non-nucleoside NS5B inhibitor, GS-9190.
Conclusions: GS-9256 is an attractive candidate for development in combination with PEG/RIBA and other direct-acting HCV agents. Phase 2 evaluation of GS-9256 in combination with GS-9190 with or without ribavirin is currently underway.