The Liver Meeting
The Liver Meeting
November 14, 2018
4 min read

Thyroid receptor agonist shows sustained response in NASH

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SAN FRANCISCO — A novel thyroid receptor agonist — MGL-3196 — showed a sustained reduction in liver fat and other markers of nonalcoholic steatohepatitis in a 36-week study, according to data presented at The Liver Meeting 2018.

“Ultimately, we saw sustained statistically significant reduction in liver fat on MRI-PDFF compared with placebo, sustained statistically significant lowering of multiple atherogenic lipids including as well as statistically significant lowering and normalization of serum liver transferases and, overall, well tolerated and safe,” Stephen A. Harrison, MD, of the University of Oxford, said during his presentation. “There was statistically significant resolution of NASH that is correlated with reduction in liver fat on MRI-PDFF and we believe this provides evidence to move forward to a registrational phase 3 trial.”

In this phase 2, 36-week, double-blind, serial liver biopsy study in patients with NASH at F1 to F3, patients were treated with MGL-3196 (Madrigal) or placebo and underwent liver biopsies prior to and after 36 weeks of treatment. At week 2, pharmacokinetics were drawn and patients were titrated up or down as deemed appropriate. Patients were also offered extension after the trial.

Primary endpoint was relative reduction of liver fat at 12 weeks, as measured by MRI-PDFF, with the 36-week measurements as a secondary endpoint. Other secondary endpoints were reduction or resolution of NASH without worsening of fibrosis but with a 2-point reduction in NAFLD activity score (NAS); reduction of fibrosis on biopsy; 30% or greater liver fat reduction; absolute liver fat reduction; and liver enzyme measurements.

Noninvasive measurements

“You see a significant reduction in MRI-PDFF compared to placebo,” Harrison said.

At 36 weeks, Harrison showed 37% relative fat reduction with MGL-3196 compared to just 8% reduction in the placebo group (P < .0001) using MRI-PDFF as the measurement tool. In the high exposure MGL-3196 group, there was a 49% relative fat reduction at 36 weeks (P < .0001).

“When we look at absolute liver fat, we see the same trend,” he said.

In looking at absolute fat reduction, Harrison showed 2.3% reduction in placebo compared with 8.5% reduction in the overall MGL-3196 group (P < .0001) and 9.4% reduction in the high exposure group (P < .0001).

A response of 30% or more relative fat reduction was seen in 30% of placebo participants at week 36, which Harrison noted that generally related to weight loss of 5% or more. In contrast, 68% of the overall MGL-3196 group saw the same results (P < .0001) and 77% of the high exposure group (P < .0001). In those participants who had F2 or F3 fibrosis at baseline, 68% reached the 30% fat reduction threshold at 36 weeks (P = .009). Similar results were seen in the extension trial, Harrison showed.


Liver enzymes showed similar improvement with treatment, Harrison said.

“At week 36, there was a 40% reduction in ALT in patients with an elevated baseline ALT [P = .01]. If you look at all comers in patients, there is still significant reduction in ALT comparing the drug to placebo [P = .002],” Harrison said. There was also a reduction in AST in MGL-3196 groups vs. placebo (P = .002). Lastly, Harrison showed a reduction in GGT for those treated with MGL-3196 vs. placebo (P = .02), “suggesting this drug may also improve oxidative stress as well.”

Biopsy results

Week 36 biopsy was used to determine NAS reduction and NASH resolution, Harrison explained. Both placebo (32%) and the overall MGL-3196 group (51%) showed 2-point reductions in NAS, but in those that responded on MRI-PDFF in the MGL-3196 group, 65% showed that 2-point reduction on biopsy (P = .06). In the MGL-3196 high exposure group, 61% had the same response (P = .006).

“If you cross out those that had less than 5% weight loss – essentially taking weight loss out of the equation – you see significant results as well [P = .02],” Harrison said.

NASH resolution as measured by biopsy and defined as no ballooning or inflammation with at least a 2-point reduction in NAS occurred in just 6% of the placebo group. In the overall MGL-3196 group, 27% showed resolution (P = .02) and in the MGL-3196 group that also responded on MRI-PDFF, 39% had resolution (P = .001). In those same treatment groups, 25% overall (P = .03) and 37% of MRI-PDFF responders (P = .003) had no worsening of fibrosis.

“You actually see a nice correlation between improvement in ballooning and inflammation and MRI-PDFF,” Harrison said.

Biomarkers of fibrosis

“ELF, CK-18 and pro-C3 scores – biomarkers correlated with liver fibrosis stage – were statistically significantly reduced in MGL-3196 treated, especially in patients with advanced fibrosis at baseline,” Harrison said.

He showed that in patients with ELF at 9 or greater at week 36, patients in the high exposure MGL-3196 group dropped by 0.62 (P = .007) and those with F2 or F3 dropped by 0.62 (P = .05), both at 36 weeks. Similarly, the high exposure group dropped CK-18 by 33% (P = .004) and those in the higher fibrosis groups dropped by 38% (P = .02). Pro-C3 levels in the high exposure group also dropped by 68% (P = .003) and by 119% in the F2/F3 group.


At week 36, Harrison showed a fibrosis reduction of a point or more by Second Harmonic Generation (SHG) microscopy in the MGL-3196-treated group. Based on pathology score, fibrosis lessened by more than one point in 29% of the MGL-3196 group and 23% of the placebo group. When looking solely at those patients with F3 fibrosis, Harrison showed that 47% of the MGL-3196 group had one point or more reduction in fibrosis while none of the placebo group showed the same change.

“We’re getting to see some of that difference [in fibrosis]. It’s very exploratory,” Harrison said. – by Katrina Altersitz


Harrison SA, et al. Abstract 14. Presented at: The Liver Meeting 2018; Nov. 9-13, 2018; San Francisco.

Disclosure: Harrison reports consulting relationships with Allergan, Axcella, Chronic Liver Disease Foundation, Cirius, CiVi, Corcept, Cymabay, Echosens, Galmed, Genfit, Hightide, HistoIndex, Innovate, Intercept, IQVIA, Madrigal, Medpace, Metacrine, Novartis, Perspectum, Pfizer, Pippin, PPD, Prometheus, NGM Bio, Novo Nordisk and Terns; receiving grant or research support from Allergan, Cirius, Conatus, Cymabay, Galectin, Genfit, Gilead, Immuron, Madrigal, Pfizer, NGM Bio, Novartis and Novo Nordisk; speaking and teaching relationships with AbbVie and Alexion; is a stock shareholder with Cirius, Genfit, Madrigal and Metacrine; and acts on the advisory or review panel for Gilead.