icon-folder.gif   Conference Reports for NATAP  
  58th Annual Meeting of the American Association
for the Study of Liver Diseases
November 2-6, 2007
Boston, MA
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Antiviral, pharmacokinetic and safety data for GS-9190, a non-nucleoside HCV NS5B polymerase inhibitor, in a phase-1 trial in HCV genotype 1 infected patients
  Reported by Jules Levin
AASLD, Nov 2-6, 2007, Boston, MA
Bavisotto L, Wang C, Jacobson I, Marcellin P, Zeuzem S, Lawitz S, Lunde NM, Sereni P, O'Brien C, Oldach D, Rhodes G and the GS-9190 Study Team
- GS-9190 generally well tolerated
- Dose proportionality observed between 40 and 120mg
- Multiple dose PK confirms T _ OF 10-13 hours, bid dosing
- Antiviral activity achieved and sustained at both doses administered over 8 - days, average 1.5 log reductions in 8 day dosing.
- Focused QT study underway, anticipate completion by the end of the year.
- Novel non-nucleoside HCV NS5B polymerase inhibitor
- Potent in-vitro activity against HCV genotype 1 (0.7 nM EC50 in GT 1b replicon)
- In-vitro selectivity index of >13,000 (CC50>50 uM in all cell lines tested)
- Low metabolic turnover for all CYP450 isoforms examined. Significant drug interactions unlikely
- majority of drug excreted in bile, non-metabolized (pre-clinical tox)
- minimal metabolism by CYP1A2 (very slow turnover, high Km)
- CYP inhibition: IC50 vs 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 >30uM
- CYP induction: no activation of AhR (CYP1A) or PXR (CYP3A)
- No interaction with major drug transport proteins (Pgp, MRP2)
NS5B RNA Polymerase is the target of inhibition
Fold shift in EC50 in subgenomic replicons


S-9190: study S-US-196-0101
Randomized, double-blind, placebo controlled trial
- HCV GT1 infected, treatment na´ve patients
PART A: SINGLE DOSE (completed)
5 successive cohorts, escalating doses of GS9190
- 40mg, 120mg, 240mg, 240mg + food, 480mg
4 successive cohorts, escalating doses of GS-9190 for 8 days - 40mg bid, 120mg bid, 240mg qd, 240mg bid
-Antiviral activity


PART A single dose mean change from pre-dose in log HCV RNA. At 24 hours after dose the mean viral load decline was -1.2 log in the 480 mg dose group, and -1.2 log in the 240mg dose group (cohort 3), and -1.00 log in the 240mg group w/food).


Single dose safety data
Single doses of GS-9190 were well tolerated
- No serious or treatment limiting AEs
- All AEs mild, except one moderate headache
No grade 3-4 treatment emergent lab abnormalities
Only grade 1-2 lab abnormalities in about 1/3rd of patients
- Grade 1 ALT or AST elevation, n=3
- Cholesterol elevation, n=3
- Hyperglycemia, n=4
- Hypoglycemia, n=1