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Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis.

Publication ,  Journal Article
Harrison, SA; Abdelmalek, MF; Caldwell, S; Shiffman, ML; Diehl, AM; Ghalib, R; Lawitz, EJ; Rockey, DC; Schall, RA; Jia, C; McColgan, BJ ...
Published in: Gastroenterology
October 2018

BACKGROUND & AIMS: Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis. METHODS: We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were 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. Biopsy specimens 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 end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96. RESULTS: The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis-including those given placebo-had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (-0.2%, 95% confidence interval [CI] -1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (-0.4%, 95% CI -1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI -1.2 to 1.5, P = .84 for 200 mg; 95% CI -1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease 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 two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.govNCT01672866 and NCT01672879.

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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

October 2018

Volume

155

Issue

4

Start / End Page

1140 / 1153

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Time Factors
  • Portal Pressure
  • North America
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Male
  • Liver Cirrhosis
  • Liver
  • Injections, Subcutaneous
 

Citation

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Chicago
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Harrison, S. A., Abdelmalek, M. F., Caldwell, S., Shiffman, M. L., Diehl, A. M., Ghalib, R., … GS-US-321-0105 and GS-US-321-0106 Investigators, . (2018). Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology, 155(4), 1140–1153. https://doi.org/10.1053/j.gastro.2018.07.006
Harrison, Stephen A., Manal F. Abdelmalek, Stephen Caldwell, Mitchell L. Shiffman, Anna Mae Diehl, Reem Ghalib, Eric J. Lawitz, et al. “Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis.Gastroenterology 155, no. 4 (October 2018): 1140–53. https://doi.org/10.1053/j.gastro.2018.07.006.
Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, et al. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology. 2018 Oct;155(4):1140–53.
Harrison, Stephen A., et al. “Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis.Gastroenterology, vol. 155, no. 4, Oct. 2018, pp. 1140–53. Pubmed, doi:10.1053/j.gastro.2018.07.006.
Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, Lawitz EJ, Rockey DC, Schall RA, Jia C, McColgan BJ, McHutchison JG, Subramanian GM, Myers RP, Younossi Z, Ratziu V, Muir AJ, Afdhal NH, Goodman Z, Bosch J, Sanyal AJ, GS-US-321-0105 and GS-US-321-0106 Investigators. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology. 2018 Oct;155(4):1140–1153.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

October 2018

Volume

155

Issue

4

Start / End Page

1140 / 1153

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Time Factors
  • Portal Pressure
  • North America
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Male
  • Liver Cirrhosis
  • Liver
  • Injections, Subcutaneous