Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection.
OBJECTIVE
Farglitazar (GI262570), an insulin-sensitizing agent, selectively binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibits stellate cell activation. We evaluated its antifibrotic effect in patients with chronic hepatitis C that did not respond to standard-of-care therapy.


METHODS
Patients with fibrosis of Ishak stages 2-4 (n = 265), based on analysis of liver biopsy samples, were randomly assigned to groups given once-daily doses of 0.5 mg farglitazar, 1.0 mg farglitazar, or placebo for 52 weeks; repeat liver biopsy samples were then obtained. The primary end points were changes in levels of alpha-smooth muscle actin (SMA) expression and collagen, based on morphometry and ranked histologic assessments.


RESULTS
Two hundred nine patients had paired biopsy specimens adequate for analysis (81.5% with pretreatment Ishak scores of stage 2 or 3). There was no overall difference in SMA (P = .58) or collagen (P = .99) levels at week 52. SMA levels increased by a median of 49% in samples from patients given placebo, 58% in patients given 0.5 mg farglitizar and 52% in patients given 1.0 mg farglitizar, respectively. Collagen increased by 27% in placebo samples and 31% in samples from patients given either dose of farglitizar. There were no significant differences between treatment groups in the ranked assessment of paired biopsy specimens or in the proportion of patients with a change in fibrosis score > or = Ishak stage.


CONCLUSIONS
In patients with chronic hepatitis C and moderate fibrosis, 52 weeks of treatment with farglitazar does not affect stellate cell activation or fibrosis (measured by morphometry or comparison of paired biopsy specimens).
McHutchison
John
J
Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina 27715, USA. mchut001@mc.duke.edu
Goodman
Zachary
Z
Patel
Keyur
K
Makhlouf
Hala
H
Rodriguez-Torres
Maribel
M
Shiffman
Mitchell
M
Rockey
Don
D
Husa
Petr
P
Chuang
Wan-Long
WL
Levine
Robert
R
Jonas
Mark
M
Theodore
Dickens
D
Brigandi
Richard
R
Webster
Alison
A
Schultz
Margaret
M
Watson
Helen
H
Stancil
Britt
B
Gardner
Stephen
S
D000328:Adult; D000368:Aged; D001706:Biopsy; D004311:Double-Blind Method; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000009:adverse effects / Q000627:therapeutic use*; D047495:PPAR gamma / Q000819:agonists*; D014443:Tyrosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
D010080:Oxazoles; D047495:PPAR gamma; C422415:farglitazar; D014443:Tyrosine