Ongoing Trials Put Focus Back on Fatty Liver Disease

The Liver Meeting 2017: American Association for the Study of Liver Diseases (AASLD)

William F. Balistreri, MD


December 11, 2017

In This Article

Novel Therapeutic Approaches to NASH

Acetyl-CoA Carboxylase (ACC) Inhibition

ACC catalyzes the rate-limiting step in de novo lipogenesis, which is increased in patients with NASH; therefore, ACC inhibition should reduce steatosis and hepatic injury.

Loomba and colleagues[2] described the safety and efficacy of GS-0976, an orally administered, liver-targeted inhibitor of ACC, in a phase 2, double-blind, placebo-controlled trial. Noncirrhotic subjects with NASH, diagnosed by liver biopsy or noninvasively by an MRI-PDFF ≥8% and liver stiffness ≥2.5 kPa by MRE, were randomly assigned to receive GS-0976 at 5 or 20 mg, or placebo, orally for 12 weeks. Median MRI-PDFF and MRE stiffness at baseline were 14% and 3.43 kPa, respectively; 40% of subjects had an MRE >3.64 kPa, consistent with advanced (≥F3) fibrosis.

After 12 weeks of treatment, GS-0976 (20 mg) recipients had a statistically and clinically significant decrease in MRI-PDFF compared with placebo recipients. The differences between GS-0976 (5 mg) and placebo were not statistically significant. In addition, a ≥30% decline in MRI-PDFF was observed in 48% of subjects treated with GS-0976 (20 mg), 23% with GS-0976 (5 mg), and 15% with placebo. While changes in liver stiffness by MRE did not differ between groups, subjects treated with GS-0976 (20 mg) had significant reductions in serum levels of TIMP-1, which correlated with changes in serum levels of other markers of fibrosis (PIII-NP and hyaluronic acid). Dose-dependent but not statistically significant reductions in serum alanine aminotransferase (ALT), liver stiffness by FibroScan® (Echosens, Waltham, MA), and PIII-NP were also observed.

GS-0976 was generally well tolerated; however, asymptomatic elevations in triglyceride levels were observed, which responded to fibrate or fish oil therapy or resolved without treatment or cessation of GS-0976.

Pegylated Fibroblast Growth Factor 21 (FGF21)

FGF21, a nonmitogenic hormone with a short half-life, is a key regulator of metabolism. It has been shown to be capable of increasing insulin sensitivity, decreasing lipogenesis, improving serum lipid levels, and exerting antifibrotic properties. These effects could be of therapeutic benefit in patients with NASH.

BMS-986036, a pegylated analog of human FGF21, was shown to improve steatosis, inflammation, hepatocyte ballooning, and fibrosis in preclinical models of NASH. In a phase 2 study[3] of obese patients with type 2 diabetes, BMS-986036 improved insulin sensitivity and serum levels of lipids, adiponectin, and biomarkers of fibrosis. Sanyal and colleagues[3] reported the results of a multicenter, randomized, double-blind, placebo-controlled study of the safety, tolerability, and efficacy of BMS-986036 in adults with biopsy-confirmed NASH and a hepatic fat fraction ≥10%, as assessed by MRI-PDFF. Patients received subcutaneous injections of BMS-986036 at 10 mg daily or 20 mg weekly or placebo. After 16 weeks of treatment, both BMS-986036 regimens significantly reduced MRI-PDFF hepatic fat fraction compared with placebo and improved the biomarkers of fibrosis, MRE findings, serum adiponectin levels, and markers of liver injury (ALT and aspartate aminotransferase [AST] levels).

The most frequent adverse events in BMS-986036-treated patients were diarrhea (17% vs 8% in placebo recipients) and nausea (15% vs 8%, respectively), most of which were considered mild.


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