Damian McNamara

October 25, 2017

WASHINGTON, DC — An acetyl-CoA carboxylase inhibitor reduced the fat content of the liver in patients with nonalcoholic steatohepatitis (NASH) in a placebo-controlled phase 2 trial.

GS-0976, the oral inhibitor under development by Gilead, led to "significant improvement in hepatic steatosis," said Rohit Loomba, MBBS, from the UC San Diego School of Medicine.

Some patients experienced a clinically significant 29% reduction in liver fat after 12 weeks of therapy, he reported.

For secondary measures, such as changes in fibrosis and liver blood chemistries, the results were mixed, he said during a late-breaking abstract session here at The Liver Meeting 2017.

In their study, Dr Loomba and his colleagues evaluated 126 people with a clinical diagnosis of NASH at 41 centers in the United States. Study participants were randomly assigned to one of three once-daily treatment regimens for 12 weeks: 49 to GS-0976 20 mg, 51 to GS-0976 5 mg, and 26 to placebo.

Patients were stratified by the presence or absence of diabetes, and those with cirrhosis were excluded from the study. MRI-estimated proton density fat fraction was used to measure changes in liver fat.

At baseline, fat content ranged from 13.6% to 15.9% in the three groups. All patients had stage 1 to 3 liver fibrosis detected in the previous year, and a diagnosis of NASH confirmed by a fat fraction of at least 8%, a magnetic resonance elastography measurement of at least 2.5 kPa, or biopsy.

Increase in Triglycerides

The most notable blood chemistry changes were in triglyceride levels in patients taking GS-0976. Seven patients in the 20 mg group and nine in the 5 mg group experienced grade 3 or 4 triglyceride elevations, which are above 500 mg/dL, yet all were asymptomatic. At 12 weeks, triglyceride levels had dropped below 500 mg/dL in the four patients treated with fibrates or fish oil and in seven of the 12 patients not treated.

These 16 patients with grade 3 or 4 triglyceride levels were significantly more likely than the other patients at baseline to have triglyceride levels above 250 mg/dL (P < .001) and to have more liver stiffness (P = .007).

After the presentation, a member of the audience asked how liver fat content could decrease while fat in the blood (triglycerides) increased.

We think that when fat is released, people are not able to get rid of it because of a decrease in lipoprotein lipase activity.

The exact mechanism is not yet known, Dr Loomba explained, but he cited a recent report that offers some potential explanations (Cell Metab. 2017;26:394-406.e6). "We think that when fat is released, people are not able to get rid of it because of a decrease in lipoprotein lipase activity," he said.

Other grade 3 or 4 lab abnormalities included elevations in aspartate transaminase (AST), experienced by two patients in the 20 mg group; elevations in alanine aminotransferase (ALT) and AST, experienced by two patients in the 5 mg group; and elevations in glucose, experienced by seven patients in the 20 mg group and three patients in the 5 mg group.

"When we looked into these, many patients had these abnormalities at baseline and had poorly controlled diabetes," Dr Loomba reported.

Acetyl-CoA carboxylase catalyzes the rate-limiting step in de novo lipogenesis. "Previous studies have shown that de novo lipogenesis is associated with NASH pathogenesis, and may be linked to steatosis and hepatotoxicity. In preclinical models, acetyl-CoA carboxylase inhibition has been shown to improve steatosis, inflammation, and fibrosis," he said.

The primary end point — a reduction in estimated liver fat at 12 weeks — was achieved by 48% of patients in the 20 mg group, 33% in the 5 mg group, and 15% in the placebo group, all of which were statistically significant.

For the secondary end point of change in liver stiffness from baseline to 12 weeks, median stiffness decreased 11.0% in the 20 mg group, 8.4% in the 5 mg group, and 3.0% in the placebo group, but none of these decreases were significant.

Improvements in TIMP1 were significant, but dose-related reductions in ALT and PIIINP assays were not. Enhanced liver fibrosis score remained unchanged.

This looks "promising," said Alex Befeler, MD, from Saint Louis University Hospital.

"They had a nice reduction in fat. I guess with the mechanism of action of the drug, you would expect that. There was no real change in fibrosis, but you wouldn't expect that in the short term," he told Medscape Medical News.

"It would have been nice to see pathology. It's not clear for sure all these people had NASH; some had biopsies, but it's not clear how many," Dr Befeler said.

Safety Data

"GS-0976 appears to be safe and well-tolerated over 12 weeks of therapy," Dr Loomba said.

There were no deaths in the study, but some serious adverse events did occur in the 20 mg group. One patient experienced a transient ischemic attack and sepsis, and another experienced abdominal pain and encephalopathy. "Both occurred after 12 weeks of treatment," he reported.

In addition, one patient in the 20 mg group experienced febrile illness and another developed diverticulitis. And rates of gastrointestinal adverse effects and headache were slightly higher in the 20 mg and the 5 mg groups than in the placebo group.

The elevation in triglyceride levels associated with treatment requires long-term follow-up, Dr Loomba acknowledged.

Studies that assess GS-0976 as monotherapy and as combination therapy are being planned, he added.

The study was funded by Gilead Sciences. Dr Loomba is a consultant for Gilead. Dr Befeler has disclosed no relevant financial relationships.

The Liver Meeting 2017: American Association for the Study of Liver Diseases (AASLD): Abstract LB-9. Presented October 24, 2017.

Follow Medscape Gastroenterology on Twitter @MedscapeGastro and Damian McNamara @MedReporter


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