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Thyroid receptor agonist for 12 weeks reduces hepatic fat in NASH

PARIS — Twelve weeks of MGL-3196 — an orally active, highly selective thyroid hormone receptor beta-selective agonist — significantly decreased hepatic fat in patients with nonalcoholic steatohepatitis compared with placebo in a phase 2 trial, according to data presented at the International Liver Congress 2018.

“We know in human NASH, the liver is relatively low in thyroid hormone receptor beta activity, potentially exacerbating mitochondrial dysfunction and lipotoxicity,” Stephen A. Harrison, MD, medical director of Pinnacle Clinical Research, San Antonio, said in his presentation. “It’s been shown in humans that thyroid hormone receptor beta-agonist activity lowers LDL cholesterol, lowers triglycerides, lowers liver fat — predominately through the breakdown of free fatty acids — stimulating mitochondrial biogenesis in the NASH liver.”

Harrison referred to topline results from a phase 1 study in which more than 3,000 patients achieved rapid reductions in lipids, LDL cholesterol (30%), triglycerides (40%-60%), and lipoprotein(a) (40%).

The ongoing phase 2 study was designed to evaluate the relative reduction in MRI proton density fat fraction (MRI-PFF) and safety of 12 weeks of MGL-3196 (Madrigal) in 116 patients with NASH. The researchers randomly assigned patients to received 80 mg of MGL-3196 or placebo once daily for 36 weeks.

At 12 weeks, the researchers observed 78 treated patients who demonstrated a 36.3% relative and 7.6% absolute reduction from baseline MRI-PDFF compared with a 9.6% relative and 1.6% absolute reduction in patients who received placebo. Compared with 18.4% of placebo patients, 60.3% of treated patients achieved an MRI-PDFF reduction greater than 30%.

Overall, patients treated with MGL-3196 had a greater relative change (P < .0001) and absolute change in MRI-PDFF (P < .0001), and were more likely to achieve a fat reduction of 30% or higher than placebo (P < .0001).

Relative to fibrosis stage, the relative change in MRI-PDFF was higher in treated patients compared with placebo for fibrosis stage 1 (P = .01), stage 2 to 3 (P = .0007), nonalcoholic fatty liver activity score (NAS) of 4 or less (P = .002), and NAS greater than 4 (P = .005). Similarly, treated patients had greater fat reduction rates at each fibrosis stage compared with placebo (P ≤ .02).

MGL-3196 was well-tolerated and most adverse events were mild (85%) or moderate (15%). The researchers did not consider the three observed severe adverse events related to treatment.

“MGL-3196 significantly reduced blood pressure and multiple atherogenic lipids which provides support for potential cardiobeneficial effects in NASH patients who most frequently die of cardiovascular disease,” Harrison concluded. “Histopathologic assessment by 36-week liver biopsy will allow for correlations with the baseline biopsy in addition to multiple 12-week and 36-week noninvasive imaging and biomarker assessments.” – by Talitha Bennett

For more information:

Harrison S, et al. GS-009. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.

Disclosure: Harrison reports being on the speakers bureau for AbbVie and Alexion; acting as a consultant and participating on advisory boards for Allergan, Axcella, Capulus, Echosens, CiVi Biopharma, Bristol-Myers Squibb, Chronic Liver Disease Foundation, Cirius, Corcept, Cymabay, Galmed, Genfit, Gilead, HistoIndex, Intercept, IQVIA, Madrigal, MedPace, NGM Bio, Novartis, Novo Nordisk, Perspectum, Pfizer, Pharmaceutical Product Development, Prometheus, Second Genome; and he received grant or research support from Allergan, Cirius, Conatus, Galectin, Galmed, Genfit, Gilead, Immuron, Intercept, Madrigal and NGM Bio.

Editor’s note: This item has been updated with clarifications from the presenter.