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.
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
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
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.