Novel enzyme inhibitor improves hepatic steatosis in NASH

WASHINGTON — Treatment with a novel acetyl-CoA carboxylase inhibitor significantly improved hepatic steatosis and selected fibrosis markers in patients with nonalcoholic steatohepatitis, according to a presentation at The Liver Meeting 2017.

Rohit Loomba

“Previous studies have shown that [de novo lipogenesis] is associated with NASH pathogenesis and may be linked to steatohepatitis and lipotoxicity,” Rohit Loomba, MD, MHSc, director of the NAFLD Research Center, UC San Diego Health, and professor of medicine at UC San Diego School of Medicine, said in his presentation. “In pre-clinical model, [acetyl-CoA carboxylase] inhibition has been shown to improve steatosis inflammation as well as fibrosis.”

The researchers enrolled 126 patients with NASH without cirrhosis in the study of GS-0796, an oral acetyl-CoA carboxylase inhibitor that previously demonstrated reduction of de novo lipogenesis and liver fat. They randomly assigned patients to receive 20 mg once daily, 5 mg once daily or placebo. Most patients were women (65%) and had diabetes (60%).

The researchers also obtained proton density fat fraction – estimated by MRI – transient elastography measurements and serum markers of fibrosis at baseline and after 12 weeks of therapy.

At 12 weeks, 48% of patients who received 20 mg of GS-0976 had a 30% or more reduction in PDFF compared with 15% in the placebo group (P = .004). Patients who received 5 mg had a 23% reduction in PDFF, though this was not significant compared with placebo.

While changes in liver stiffness did not change significantly, those treated with 20 mg of GS-0976 had significant reductions in serum levels of TIMP metallopeptidase inhibitor 1, which correlated with changes in N-terminal propeptide of type III collagen (r = 0.47; P = .001) and hyaluronic acid (r = 0.62; P < .001).

Triglyceride levels increased by 11% for those treated with 20 mg of GS-0976 and 13% in the 5-mg group, but decreased by 4% in the placebo group. Seven patients treated with 20 mg and 9 patients treated with 5 mg had triglyceride elevations above 500 mg/dL at 12 weeks. Four of those patients responded to fibrate or fish oil therapy and the other seven resolved triglyceride elevations without treatment or discontinuation of GS-0976. Those with elevations above 500 mg/dL were more likely to have a baseline triglyceride level over 250 mg/dL (P < .001).

Severe adverse events occurred in two patients who received 20 mg of GS-0976 and two patients who received 5 mg, though the researchers report no deaths or cases of discontinuation. Compared with placebo, those who received GS-0976 were more likely to have nausea, diarrhea, vomiting and headaches.

“GS-0796 appeared to be safe and well-tolerated over 12 weeks of therapy,” Loomba concluded. “Triglyceride elevations and its effect requires long-term follow-up. Future studies of GS-0796 monotherapy and combination approaches are planned.” – by Talitha Bennett

Reference:

Loomba R, et al. Abstract LB-9. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.

Disclosure: Loomba reports he is a consultant to Alnylam, Celgene, Corgenix, Deutrx, Gilead, Inanta, Janssen and Zafgen; received grants or research support from Adheron, AGA, Daiichi Sankyo, Immuron, Kinemead, Merck and Promedior; is an advisory committee member or review panel member of Arrowhead, Galmed and Tobira; and is a member of AASLD.