title: Fibrogenesis assessed by serological type III collagen formation identifies patients with progressive liver fibrosis and responders to a potential antifibrotic therapy.
abstract: There are no approved treatments for liver fibrosis. To aid development of antifibrotic therapies, noninvasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to antifibrotic therapy are much needed. Samples from a phase II antifibrotic trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow-up liver biopsies, and from a phase III study of balaglitazone in patients with late-stage Type 2 diabetes (BALLET study) were analyzed for serological Pro-C3 levels in conjunction with other disease parameters. In the farglitazar study, a predefined cutoff value for Pro-C3 as a selection criterion led to the identification of subjects who 1) progressed by histological scores and 2) responded to therapy, as documented by attenuated fibrosis in liver biopsies. In the BALLET trial, subjects with the highest tertile of Pro-C3 levels responded to balaglitazone with reductions in levels of alanine aminotransferase and Pro-C3, as well as improved insulin sensitivity and lipid profile. Elevated Pro-C3 levels are indicative of active fibrogenesis and structural progression of fibrosis, and it can potentially identify patients most likely to benefit from antimetabolic and antifibrotic treatments. Serum Pro-C3 may facilitate patient selection and could help to speed up antifibrotic drug development and validation.
authors.affiliation: Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark; mk@nordicbioscience.com.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
authors.affiliation: Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
authors.affiliation: Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark.
authors.forename: Mette Juul
authors.initials: MJ
authors.lastname: Nielsen
authors.affiliation: Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark.
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.affiliation: Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Leeming
authors.affiliation: Infectious Diseases Therapeutic Area Unit, GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gardner
authors.affiliation: Hepatic Pathology Consultation and Research, INOVA Fairfax Hospital, Falls Church, Virginia.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Goodman
authors.affiliation: Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.affiliation: University of Southern Denmark, Odense, Denmark; and.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Krag
authors.affiliation: Nordic Bioscience Biomarkers & Research A/S, Herlev, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.affiliation: Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; and.|Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachussetts.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D018579:Patient Selection; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D024061:Collagen Type III; D010080:Oxazoles; D011799:Quinazolines; D045162:Thiazolidinediones; C422415:farglitazar; D014443:Tyrosine; C497232:balaglitazone
keywords: Type 2 diabetes; fibrosis; liver; nonalcoholic steatohepatitis; peroxisome proliferator-activated receptor γ; procollagen III