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Clinical Trial
, 55 (2), 419-28

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of GS-9450 in Subjects With Nonalcoholic Steatohepatitis

Affiliations
Clinical Trial

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of GS-9450 in Subjects With Nonalcoholic Steatohepatitis

Vlad Ratziu et al. Hepatology.

Abstract

In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3-cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group.

Conclusion: GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.

Conflict of interest statement

Potential conflict of interest: V.R. has received funding from Gilead Sciences, Astellas Pharma, and Roche and has served as a consultant for Astellas, Axcan, Genentech, Gilead, Roche, and Sanofi.

Figures

Fig. 1
Fig. 1
Subject disposition throughout the study.
Fig. 2
Fig. 2
Percent of subjects with normal ALT. After 4 weeks of treatment, the GS-9450 40-mg group had the highest proportion of subjects achieving ALT normalization, defined as 43 U/L for males and 34 U/L for females. P values versus the placebo arm at 4 weeks of treatment: P = 0.07 for the 40-mg arm; P = 0.41 for the 10-mg arm; P = 0.42 for the 5-mg arm; P = 1 for the 1-mg group.
Fig. 3
Fig. 3
Percent measurable change of ALT at week 4. In a linear regression of percent measurable change in ALT levels (change from baseline/[baseline − 20 U/L]), the percent measurable change at week 4 versus dose was highly significant (P < 0.0001). An outlier value of 600 for percent measurable change of ALT at week 4 was excluded from the assessments.
Fig. 4
Fig. 4
Mean (SD) steady-state GS-9450 concentration-versus-time profiles. GS-9450 was quantifiable over the dosing interval for all treatment groups. Examination of the mean and median GS-9450 trough values and mean predose and 24-hour post-dose concentrations achieved during serial pharmacokinetic assessment for each group indicated that steady state had been reached by 2–4 weeks of daily dosing.

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