title: Carcinogenicity assessment of the pan-caspase inhibitor, emricasan, in Tg.rasH2 mice.
abstract: Emricasan, formerly IDN-6556, is a small molecule currently being evaluated in clinical trials to reduce hepatic injury and liver fibrosis. Since emricasan is an irreversible pan-caspase inhibitor that potently inhibits caspase-mediated apoptosis and inflammation, its carcinogenic potential was evaluated in a humanized mouse model. Tg.rasH2 mice received LabDiet formulated with 0, 10, 25, and 75mg/kg/day of emricasan, for 26weeks. At terminal sacrifice, blood was collected for clinical pathology analysis and tissues were collected, processed, and evaluated microscopically. There were no treatment related deaths or overt signs of toxicity for the duration of the study. There was no evidence of a carcinogenic effect in the peripheral blood leukocyte counts. Liver microgranulomas, which are background lesions, were slightly increased, especially in males. Increases in the incidence of the activated germinal centers were seen in the spleens and mesenteric lymph nodes of males and females, and in the mandibular lymph nodes of male mice. Atrophy of ovaries and testicular degeneration were also seen in emricasan treated animals. Although several non-neoplastic lesions were observed, there was no evidence of emricasan-related tumor formation in any tissue. In addition, the non-neoplastic lesions were not considered pre-neoplastic. Thus, emricasan is not considered carcinogenic.
authors.affiliation: BioReliance by SAFC, Rockville, MD, United States. Electronic address: reem.elbekai@bioreliance.com.
authors.forename: R H
authors.initials: RH
authors.lastname: Elbekai
authors.affiliation: BioReliance by SAFC, Rockville, MD, United States.
authors.forename: M G
authors.initials: MG
authors.lastname: Paranjpe
authors.affiliation: Conatus Pharmaceuticals, San Diego, CA, United States.
authors.forename: P C
authors.initials: PC
authors.lastname: Contreras
authors.affiliation: Conatus Pharmaceuticals, San Diego, CA, United States.
authors.forename: A
authors.initials: A
authors.lastname: Spada
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D061945:Caspase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D011905:Genes, ras; D006099:Granuloma / Q000139:chemically induced; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D008822:Mice, Transgenic; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D010421:Pentanoic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D013154:Spleen / Q000033:anatomy & histology / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000473:pathology
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D010421:Pentanoic Acids
keywords: Carcinogenicity; Caspase inhibitor; Emricasan; IDN-6556; Tg.rasH2