Simtuzumab (SIM, GS-6624) in the Treatment of Cirrhosis Due to NASH

Summary

The primary objective of this study is to evaluate the safety and efficacy of SIM (formerly referred to as GS-6624) in adults with compensated cirrhosis due to Non-Alcoholic Steatohepatitis (NASH). It will consist of 2 phases: * Randomized Double-Blind Phase * Open-Label Phase (optional)

Timeline

Start

2012-10-29

Primary completion

2016-09-26

Completion

2017-01-03

Outcome

Missed primary endpoint

paper P = .84 for 200 mg; 95% CI -1.2 to 1.4, P = .88 for 700 mg PMID 29990488 ↗

registry analysis (superiority test); SIM 200 mg vs Placebo; p = 0.41; Stratified log-rank test NCT01672879 ↗

registry analysis (superiority test); SIM 700 mg vs Placebo; p = 0.065; Stratified log-rank test NCT01672879 ↗

Publications

• Results Sanyal A, Harrison S, Ratziu V, Abdelmalek M, Diehl A, Caldwell S, et al. Changes in fibrosis, but not the NAFLD Activity Score (NAS), are associated with disease progression in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis. J Hepatol 2017; 66 (1): S2.
• Results Sanyal A, Abdelmalek M, Diehl A, Caldwell S, Shiffman M, Ghalib R, et al. Efficacy and safety of simtuzumab for the treatment of nonalcoholic steatohepatitis with bridging fibrosis or cirrhosis: results of two phase 2b, dose-ranging, randomized, placebo-controlled trials. J Hepatol 2017; 66 (1): S54.
• Results Bosch J, Harrison S, Ratziu V, Shiffman M, Diehl A, Caldwell S, et al. Impact of modest weight reduction on liver histology, portal pressure, and clinical events in patients with compensated cirrhosis due to nonalcoholic steatohepatitis. J Hepatol 2017; 66 (1): S159-S160.
• Results Sanyal A, Goodman Z, Harrison S, Rockey DC, Diehl AM, Caldwell S, et al. Correlation between the hepatic venous pressure gradient and alpha-smooth muscle actin (SMA) expression in patients with compensated cirrhosis due to nonalcoholic steatohepatitis. J Hepatol 2016; 64 (2): S251.
• Results Shea PR, Sanyal A, Harrison S, Ratziu V, Loomba R, Caldwell S, et al. PNPLA3 variants confer an increased risk of advanced fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2016; 64 (2): S493.
• Results Shea PR, Sanyal A, Rockey DC, Loomba R, Diehl AM, Kleinstein SE, et al. Genome-wide association study of clinically significant portal hypertension in patients with nonalcoholic steatohepatitis and advanced fibrosis. J Hepatol 2016; 64 (2): S280.
• Results Bosch J, Ratziu V, Rockey DC, Ghalib RH, Thuluvath PJ, Shiefke I, et al. Correlation between noninvasive markers of fibrosis and the hepatic venous pressure gradient (HVPG) in patients with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 578A.
• Results Goodman ZD, Alaparthi L, Monge F, Patel K, Loomba R, Caldwell SH, et al. Correlations between hepatic morphometric collagen content, histologic fibrosis staging, and serum markers in patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 906A.
• Results Harrison SA, Goodman ZD, Ratziu V, Loomba R, Diehl AM, Lawitz E, et al. Serum lysyl oxidase-like-2 (sLOXL2) levels correlate with fibrosis stage in patients with nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 910A.
• Results Sanyal AJ, Goodman ZD, Abdelmalek MF, Harrison SA, Rockey DC, Diehl AM, et al. Clinical and histologic correlates of the hepatic venous pressure gradient (HVPG) in patients with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 577A.
• Results Ratziu V, Sanyal AJ, Loomba R, Caldwell SH, Ghalib RH, Torres DM, et al. Characterization of insulin resistance in patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 1298A-1299A.
• Loomba R, Huang DQ, Sanyal AJ, Anstee QM, Trauner M, Lawitz EJ, Ding D, Ma L, Jia C, Billin A, Huss RS, Chung C, Goodman Z, Wong VW, Okanoue T, Romero-Gomez M, Abdelmalek MF, Muir A, Afdhal N, Bosch J, Harrison S, Younossi ZM, Myers RP. Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis. Gut. 2023 Mar;72(3):581-589. doi: 10.1136/gutjnl-2022-327777. Epub 2022 Sep 9.
• Younossi ZM, Anstee QM, Wai-Sun Wong V, Trauner M, Lawitz EJ, Harrison SA, Camargo M, Kersey K, Subramanian GM, Myers RP, Stepanova M. The Association of Histologic and Noninvasive Tests With Adverse Clinical and Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis. Gastroenterology. 2021 Apr;160(5):1608-1619.e13. doi: 10.1053/j.gastro.2020.12.003. Epub 2020 Dec 8.
• 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. doi: 10.1053/j.gastro.2018.07.006. Epub 2018 Jul 7.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Simtuzumab	Monoclonal antibody	200 mg	Intravenous
Subject	Simtuzumab	Monoclonal antibody	700 mg	Intravenous

Indications