Thyroid hormone receptor agonists reduce liver fat in people with NAFLD

Thyroid hormone activation appears to be a promising approach for treating fatty liver disease, according to a pair of studies presented at the AASLD Liver Meeting this month in San Francisco.

Two thyroid hormone receptor beta agonists – MGL-3196 and VK2809 – reduced liver fat and blood lipid levels in people with non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH).

NAFLD and NASH are often associated with obesity and the metabolic syndrome. The build-up of fat in the liver triggers inflammation and development of scar tissue (fibrosis), which over time can lead to cirrhosis, liver cancer and the need for a liver transplant. Now that direct-acting antivirals can cure most people with hepatitis C, fatty liver disease accounts for a growing share of advanced liver disease. But to date there are no good therapies and management relies on lifestyle changes such as weight loss.

Thyroid hormones play an important role in metabolism, and agents that promote thyroid hormone receptor-beta activity can reduce blood lipid levels and reduce liver fat by breaking down fatty acids. Selective agonists aim to stimulate the beta receptor without increasing thyroid hormone receptor alfa activity, which can have detrimental effects such as increased heart rate and bone loss.

Stephen Harrison of Oxford University presented the latest findings from a study of MGL-3196, a liver-directed thyroid hormone receptor beta agonist.

This phase II trial included 125 people with NASH confirmed by liver biopsy. Just over half were men, most were white, about half were Latino and the mean age was about 50 years. They had mild (stage 1) to advanced (stage 3) fibrosis. MRI-PDFF (magnetic resonance imaging estimation of proton density fat fraction) indicated at least 10% liver fat. Reflecting the population with NASH, about 35% had diabetes, the mean body mass index was in the obese range and many were taking statins.

Participants were randomly assigned to received MGL-3196 or a placebo. The MGL-3196 group started at a dose of 80mg per day, which could be adjusted up to 100mg at week 4. Treatment lasted for 12 weeks with follow-up to week 36.

As Harrison reported at the EASL International Liver Congress in April, after 12 week of treatment, liver fat content according to MRI-PDFF declined by 10% in the placebo group, by 36% in the MGL-3196 group overall and by 42% in high-dose MGL-3196 recipients. At The Liver Meeting he reported 36-week results showing that liver fat reductions were sustained after stopping treatment, with a 37% reduction for MGL-3196 recipients overall and a 49% drop in the high-dose group.

At 12 weeks, 18% of placebo recipients, 60% of MGL-3196 recipients overall and 75% of high-dose recipients had at least a 30% reduction in liver fat. These proportions continued to rise in all groups, with 30%, 68% and 77%, respectively, having a 30% or greater reduction at week 36. Harrison noted that fat loss in placebo recipients was generally related to weight loss.

Looking at lipid levels at week 36 among MGL-3196 recipients, LDL cholesterol fell by 22%, apolipoprotein B by 22%, triglycerides by 36%, and lipoprotein(a) and apolipoprotein C-III by 37% each.

Liver enzyme levels also fell, suggesting decreased inflammation. At week 36, ALT levels fell by 40% in MGL-3196 recipients with elevated levels at baseline; at that point 60% of MGL-3196 recipients had ALT below 30 IU/ml, compared with 37% of placebo recipients. AST and GGT levels also decreased more in the MGL-3196 group than in the placebo group. Finally, MGL-3196 recipients showed a greater reduction in an inflammation biomarker known as reverse T3.

Comparing baseline and week 36 liver biopsies, 51% of MGL-3196 recipients overall, 61% in the high-dose group and 65% of those with MRI-PDFF response showed at least a 2-point reduction in NAFLD activity score, versus 32% of placebo recipients. NASH resolution occurred in 27% of MGL-3196 recipients overall and 39% of MRI-PDFF responders, most of whom had no worsening of fibrosis. A third showed at least a 1-point improvement in fibrosis, rising to 47% among those who started with stage F3.

MGL-3196 was generally safe and well tolerated. Adverse events were mostly mild and similar in the MGL-3196 and placebo groups, although the MGL-3196 group was more likely to have transient loose stools.

Based on these phase II findings, the researchers concluded that MGL-3196 led to significant resolution of NASH that is correlated with reduction in liver fat on MRI-PDFF, warranting ongoing phase III development.

Rohit Loomba of the University of California at San Diego presented late-breaking findings from a study of another liver-directed thyroid receptor beta agonist, VK2809.

This phase IIa study included 47 people with NAFLD and elevated blood lipids. About 60% were men and the mean age was about 50 years. They had at least 8% liver fat according to MRI-PDFF, LDL cholesterol >110 mg/dl and triglycerides >120 mg/dl.

Participants were randomised to receive VK2809 daily (QD) or every other day (QOD), or else a placebo for 12 weeks.

People who received VK2809 had significantly greater reductions in liver fat, falling by 60% in the daily group and by 57% in the QOD group, compared with just 9% in the placebo group. At 12 weeks, 91% of those in the daily group and 77% in the QOD group had at least a 30% liver fat reduction; 72.7% and 61.5%, respectively, were 'super responders' with a decrease of 50% or more.

LDL cholesterol levels decreased as well, falling by 25.2 mg/dl in the daily group and by 32.2 mg/dl in the QOD group. Lipoprotein(a) and apolipoprotein B levels also declined in VK2809 recipients while remaining stable in the placebo group. This suggests the treatment may also have cardiovascular benefits, Loomba said.

At week 12, ALT levels rose in the placebo group with little change in the VK2809 groups, but by week 16 the levels had declined in VK2809 recipients only.

VK2809 was also safe and well tolerated. About a third of participants in all study arms reported adverse events, but none of these were considered serious or deemed to be drug-related. Loomba reported that gastrointestinal tolerability was 'excellent'. There were no notable changes in vital signs.

The researchers concluded that VK2809 produced a "robust reduction" in liver fat on MRI-PDFF in NAFLD patients after 12 weeks. A study in people with NASH is being planned.

This represents "one of most significant reductions we've seen at 12 weeks with an oral agent," Loomba said.