Investigational Liver Drug Also Effective in Patients With Hypothyroidism

SAN DIEGO -- Treatment with resmetirom effectively reduced liver fat among patients with hypothyroidism and nonalcoholic fatty liver disease (NAFLD), according to a phase III trial.

In an open-label part of the MAESTRO-NAFLD-1 study, treatment with 100 mg of the investigational agent resulted in a 20% reduction in liver volume by week 52 among patients with hypothyroidism taking thyroxine, reported Kathryn Jean Lucas, MD, of Lucas Research in Morehead, North Carolina.

This was similar to the roughly 23% liver volume reduction seen in euthyroid noncirrhotic, nonalcoholic steatohepatitis (NASH) patients, she said in a presentation at the American Association of Clinical Endocrinology (AACE) annual meeting.

Hypothyroid patients on the agent also saw around a 50% reduction in MRI-measured proton density fat fraction (MRI-PDFF) from baseline to week 52, similar to the 53% reduction seen in euthyroid patients. While both males and females saw this significantly reduced MRI-PDFF with treatment, females on thyroxine saw a little less than a 40% change from baseline versus a near 70% reduction seen in males.

The majority of the treatment effects were seen by week 16 of treatment, Lucas and colleagues reported.

This analysis is part of the ongoing MAESTRO phase III clinical program, including trials focused on patients with NASH plus fibrosis previously presented at the 2021 European Association for the Study of the Liver virtual meeting. The first-in-class study drug acts as a selective thyroid hormone receptor beta agonist to reduce liver fat, triglycerides, and LDL cholesterol. Participants were treated with 100 mg of the oral, once-daily agent.

All patients, regardless of hypothyroid status, saw similar improvements in several liver enzymes, including ALT, AST, and GGT with treatment. The majority of treated patients achieved a normalizing of liver enzymes with resmetirom.

Hypothyroid patients also achieved a similar reduction in atherogenic lipids compared with euthyroid NASH patients, as well as reductions in CK18, a marker of apoptosis, plus an increase in adiponectin, which acts as a potential marker of reduced fibrosis in NASH.

"This is yet another reason endocrinologists should get involved in fatty liver disease," Lucas said. "Because we know all about these drugs; we know all about thyroid hormones. This should be our field."

Patients on thyroxine were able to tolerate resmetirom, as did euthyroid patients, with no significant differences in adverse events (AEs) between the two groups. The most common AEs in both resmetirom-treated groups were gastrointestinal related, including diarrhea and nausea. Few participants dropped out because of side effects, Lucas noted. No AEs indicated increased hyperthyroid or hypothyroidism.

"It appeared that [resmetirom] was only working in the liver to correct that blockage from T4 to T3," she explained.

All treatment groups also saw a slight reduction in blood pressure, which Lucas said was "interesting."

This open-label analysis included 171 participants with confirmed NAFLD-1: 95 of whom were euthyroid and 76 were hypothyroid treated with thyroxine. Thyroxine-treated patients tended to be female, older, and have greater risk for atherosclerotic cardiovascular disease. Compared with euthyroid individuals, thyroxine-treated patients also tended to have more advanced NASH fibrosis measures, including Fibrosis-4 score (0.9 for euthyroid vs 1.2), NAFLD score (-1.2 vs -0.8), and Enhanced Liver Fibrosis scores (8.9 vs 9.4).

At baseline, hypothyroid patients were on an average thyroxine dose of 109 μg. Half were taking a stain, and 15.8% and 17.1% were taking a GLP-1 receptor agonist and SGLT2 inhibitor, respectively.

"I think this is an exciting trial because it uses noninvasive biomarkers and imaging to assess treatment effects," said AACE session moderator Maria Papaleontiou, MD, of the University of Michigan in Ann Arbor.

Lucas added that her group plans to do liver biopsies after 1 year of treatment in the ongoing study, and again at the very end of the 5-year study, to confirm if there are lasting histological changes that correlates with the reduced liver volume and fat seen here.

Developer Madrigal Pharmaceuticals has not yet filed for FDA approval of resmetirom, although in a January 2022 press release, the company stated that "Data from the 52-week portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1 and other data...will form the basis for a potential subpart H submission to FDA for accelerated approval for the treatment of NASH."

Comment