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BOSTON -- Treatment with an investigational thyroid hormone receptor-beta (THR-β) agonist significantly reduced liver fat content in patients with metabolic dysfunction-associated steatohepatitis (MASH), a placebo-controlled phase IIa trial showed.

Significant reductions from baseline were seen as early as 6 weeks with the novel oral compound (TERN-501). By 12 weeks, mean relative reductions ranged from 27% to 45% with 3-mg and 6-mg doses of the THR-β agonist, as compared with a 4% reduction with placebo (P=0.0036 and P<0.0001 for the two comparisons), reported Mazen Noureddin, MD, of Houston Methodist Hospital.

As detailed here at the annual Liver Meeting sponsored by the American Association for the Study of Liver Diseases, a significantly higher percentage of patients in the investigational arms achieved a ≥30% MRI proton density fat fraction (MRI-PDFF) reduction at week 12 as well, with even greater reductions at the 6-mg dose level:

• ≥30% reduction on MRI-PDFF: 64% with the 6-mg dose vs 4% with placebo
• ≥50% reduction on MRI-PDFF: 41% vs 0%
• Normalization of liver fat (<5%) on MRI-PDFF: 23% vs 0%

This higher dose-level also improved liver fibroinflammation, increased sex hormone binding globulin (SHBG, a predictor of histologic response), while being associated with low rates of gastrointestinal side effects and no cardiovascular adverse events (AEs).

Investigators also found that results were similar when the THR-β agonist was combined with a liver-directed nonsteroidal FXR agonist in development (TERN-101). Noureddin called it one of the most important findings of the study since it suggests the THR-β agonist can be combined with multiple drugs.

"Collectively, these data warrant further investigation of TERN-501 as a monotherapy or in combination with other mechanisms of action in MASH," he said during a late-breaking session.

No approved drug currently exists for the treatment of MASH (formerly nonalcoholic steatohepatitis [NASH]), though not for a lack of trying. Patients with the often symptom-less disease are at increased risk of progressive fibrosis and cirrhosis, and the condition represents the second leading cause of liver transplant.

THR-β has emerged as an effective target, Noureddin explained, and TERN-501 is a potent, highly selective THR-β agonist that in a phase I study "was safe, well-tolerated, and showed robust target engagement."

In the , 162 patients with phenotypic or prior histologic MASH were randomized to one of seven once-daily treatments: monotherapy with TERN-501 (1 mg, 3 mg, or 6 mg), with TERN-101 (10 mg); combination therapy with TERN-501 (3 mg or 6 mg) plus TERN-101 (10 mg); or placebo.

Patients were required to have a body mass index (BMI) of 25 or above and pre-cirrhotic MASH identified on prior liver biopsy and/or imaging and clinical criteria. All participants had liver fat content of at least 10% on MRI-PDFF and an MRI-corrected T1 relaxation time of ≥800 msec.

Mean age of the study participants was in the 50s, and most were female and Hispanic. Between 27% and 57% of the different cohorts had type 2 diabetes, and mean BMI was in the high 30s, representing a harder-to-treat population, Noureddin said.

In addition to the results regarding liver fat content, treatment with the 6-mg dose of the THR-β agonist led to a significant reduction (mean change of -72 msec) in corrected T1 -- a marker of liver fibroinflammation -- and a 127% increase in SHBG. Noureddin pointed out that an increase of at least 120% has been associated with histological MASH improvement and liver fat reduction in other studies.

Finally, Noureddin reported that TERN-501 also demonstrated dose-dependent decreases in atherogenic lipids, including apolipoprotein B.

Regarding safety, investigators observed no grade ≥3 drug-related AEs or serious AEs with the THR-β agonist, as well as minimal diarrhea and no nausea. "We have seen multiple MASH drugs have gastrointestinal problems, including nausea, vomiting, and diarrhea," Noureddin observed. "If you look at the safety profile [of TERN-501], this drug is very clean in general."

Moreover, he noted that there were no clinically significant changes in thyroid axis hormones or serum bone markers.

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