title: A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis.
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.
  
  
  CONCLUSIONS
  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.
authors: Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France. vratziu@teaser.fr
authors: Vlad
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authors: Ratziu
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authors: Sheikh
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authors: Bhandari
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authors: Cornpropst
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authors: Benjamin
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authors: King
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authors: Mondou
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authors: Rousseau
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authors: McHutchison
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authors: Chojkier
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D061945:Caspase Inhibitors; D004311:Double-Blind Method; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects
chemical_list: D015415:Biomarkers; D061945:Caspase Inhibitors; D053538:Keratin-18; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase