>>First Clinical Trial of IDN-6556: First Anti-Apoptotic Caspase Inhibitor Improves Liver Function
Karen Valentino, Maria Gutierrez, Ricardo Sanchez, Paul Pockros, M. J. Winship, David Shapiro, San Diego, CA; Fort Lauderdale, FL
Apoptosis, programmed cell death, is mediated by a cascade of intra-cellular caspase enzymes and is believed important in some hepatic disorders. IDN-6556 is the first broad-spectrum caspase inhibitor to be studied in man. METHODS: IDN-6556 or placebo was administered iv in 3 Groups. Group A, normal volunteers (NV), received 1 of 5 ascending doses of drug (0.1, 0.5, 1, 5 & 10mg/kg over 30 min) N=6/dose (1 Pbo: 5 drug); Group B, NV, 5 doses (0.1, 0.5, 1, 1.5 & 1 (fast) mg/kg qid for 7 days) N=6/dose (1 Pbo: 5 drug); Group C, patients (pats) with mild hepatic failure of mixed etiology, 0.1 & 0.5mg/kg qid for 7 days N=5-6/dose (1 Pbo: 4 drug). RESULTS: Studied N=71. Safety: Dose related, mild-moderate phlebitis occurred in Group A4 (5mg) & A5 (10mg) and with ascending doses in Group B. No subject asked for treatment to be discontinued. No other significant findings were seen. Efficacy: In Group C both ALT, AST were lowered over 7 days of dosing (p<0.0001, 2-way ANOVA). However, the LFTs returned to >40% above pre-treatment levels in 3/8 IDN-6556 & 1/3 Pbo pats after dosing. LFTs returned to baseline by 14 days post therapy; no clinical sequelae were seen. CONCLUSIONS: IDN-6556 appears to be safe when given iv and significantly improved LFTs with 7 days therapy. Further hepatic studies are merited.<<
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