Author information
1
Pinnacle Clinical Research, San Antonio, Texas, USA. Electronic address: sharrison@pinnacleresearch.com.
2
Duke Clinical Research Institute, Durham, NC, USA.
3
University of Virginia, Charlottesville, VA, USA.
4
Liver Institute of Virginia, Richmond, VA, USA.
5
Texas Clinical Research Institute, Arlington, TX, USA.
6
Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA.
7
Medical University of South Carolina, Charleston, SC, USA.
8
Gilead Sciences, Inc., Foster City, CA, USA.
9
Inova Fairfax Hospital, Falls Church, VA, USA.
10
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
11
Hôpital Pitié-Salpêtrière, Paris, France.
12
Inselspital, Bern University, Switzerland, and IDIBAPS, University of Barcelona, Barcelona, Spain.
13
Virginia Commonwealth University, Richmond, VA, USA.
Abstract
BACKGROUND & AIMS:
Lysyl oxidase like 2 (LOXL2) contributes to fibrogenesis by catalyzing cross linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against LOXL2, in a phase 2b trial of patients with advanced fibrosis caused by nonalcoholic steatohepatitis (NASH).
METHODS:
We performed a double-blind study of 219 patients with bridging fibrosis, caused by NASH, randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsies were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary endpoint was change between baseline and week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis the primary endpoint was change in hepatic venous pressure gradient (HVPG) between baseline and week 96.
RESULTS:
Both studies were stopped after week 96 due to lack of efficacy. All 3 groups of patients with bridging fibrosis-including those given placebo-had significant reductions in hepatic collagen content, but there was no statistically significant difference in reduction between patients receiving simtuzumab (75 mg) and placebo (-0.2%; 95% CI, -1.3 to 1.0; P=.77), or between patients receiving simtuzumab (125 mg) and placebo (-0.4%; 95% CI, -1.5 to 0.8; P=.52]). In patients with cirrhosis, the mean difference in HVPG between both simtuzumab groups and the placebo group was 0.1 mmHg (95% CI, -1.2 to 1.5; P=.84 for 200 mg and 95% CI, -1.2 to 1.4; P=.88 for 700 mg). Simtuzumab did not significantly reduce fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups.
CONCLUSION:
In a phase 2b trial of patients with bridging fibrosis or cirrhosis associated with NASH, simtuzumab was ineffective in reducing fibrosis or HVPG. Clinicaltrials.gov no: NCT01672866 and NCT01672879.