title: Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C.
abstract: Increased rates of apoptosis (programmed cell death) have been demonstrated in many hepatic diseases including chronic hepatitis C. IDN-6556 is a potent inhibitor of caspases, the proteases that execute apoptosis. In a prior phase 1 study, IDN-6556 lowered aminotransferase activity in a small number of patients with liver impairment. The purpose of this study was to further explore the effect of IDN-6556 in patients with liver disease in a multicenter, double-blind, placebo-controlled, dose-ranging study with a 14-day dosing period. A total of 105 patients were enrolled in the study; 79 received active drug; 80 patients had chronic hepatitis C and 25 had other liver diseases including nonalcoholic steatohepatitis (NASH), hepatitis B, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). IDN-6556 doses ranged from 5 mg to 400 mg daily, given from 1 to 3 times per day. In the HCV patients, all doses of IDN-6556 significantly lowered ALT and AST (P = 0.0041 to P < 0.0001 for various dosing groups in Wilcoxon tests comparing IDN-6556 to placebo), with the exception of the lowest dose. Declines in aminotransferase activity were also seen in patients with NASH but effects were not apparent in the small number of other liver diseases. Adverse experiences were not different between IDN-6556 and placebo. There were no clinically meaningful changes in other laboratory parameters. In particular, mean HCV RNA levels did not show significant changes.
  
  
  CONCLUSIONS
  Oral IDN-6556, given for 14 days, significantly lowered aminotransferase activity in HCV patients and appeared to be well tolerated. Longer studies to assess potential effects of IDN-6556 on liver inflammation and fibrosis are merited.
authors.affiliation: Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, CA 92037, USA. pockros.paul@scrippshealth.org
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Pockros
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Schiff
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Shiffman
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gish
authors.forename: Nezam H
authors.initials: NH
authors.lastname: Afdhal
authors.forename: Manana
authors.initials: M
authors.lastname: Makhviladze
authors.forename: Mira
authors.initials: M
authors.lastname: Huyghe
authors.forename: David
authors.initials: D
authors.lastname: Hecht
authors.forename: Tilman
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: David A
authors.initials: DA
authors.lastname: Shapiro
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood*; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood*; D061945:Caspase Inhibitors; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010421:Pentanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010421:Pentanoic Acids; D012367:RNA, Viral; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase