Resmetirom Delivers Promising Outcomes in NASH Without Invasive Follow-Up

Patients with nonalcoholic steatohepatitis (NASH) who were treated with the investigational agent resmetirom (MGL-3196) saw “rapid and sustained responses,” and were successfully monitored with noninvasive testing, a researcher reported.

In an analysis of an open-label portion of the MAESTRO trials, there was a statistically significant 53% reduction in MRI-measured proton density fat fraction (MRI-PDFF) from baseline (P<0.0001) after 52 weeks of treatment with a daily 100-mg dose of resmetirom, according to Stephen Harrison, MD, of Pinnacle Clinical Research in San Antonio.

There also was a 62% reduction in sex hormone binding globulin, and reductions in ultrasound measurements (FibroScan), he said during a press conference at the European Association for the Study of the Liver (EASL) virtual meeting.

Harrison reported a 23% reduction in LDL cholesterol, a 22% reduction in apolipoprotein-B, a 39% reduction in triglycerides, and a 39% reduction in lipoprotein(a), and all reductions were statistically significant versus baseline measurements.

In addition, various liver enzyme levels were significantly reduced, along with inflammatory markers, such as C-reactive protein, and “no safety flags were identified,” he said.

Resmetirom is an oral, liver-directed thyroid hormone receptor beta agonist. Harrison noted that treatment in a phase II trial, reported at the 2020 EASL virtual meeting, showed that it had an impact on NASH resolution.

The open-label part of the MAESTRO trials enrolled 150 patients, and Harrison reported on the first 115 who completed 52 weeks of treatment with the agent. The on-going phase III study MAESTRO-NASH is evaluating the efficacy and safety of resmetirom in patients with NASH and fibrosis, while MAESTRO-NAFLD1 looks at the safety and biomarkers of resmetirom in non-alcoholic fatty liver disease.

Patients were eligible for the current study if they had at least three metabolic risk factors, FibroScan kilopascals consistent with ≥F1 fibrosis stage, and MRI-PDFF ≥8%.

Harrison said the agent appears to be pleiotropic in nature in that resmetirom “really helps burn fatty acids within the mitochondria,” he told MedPage Today. “In NASH patients, mitochondria are often dysfunctional and sick, and so we see upregulation of reactive oxygen species that triggers all the downstream inflammatory effects. And so another benefit of resmetirom is that it tends to increase mitochondrial biogenesis.”

He added that there were other effects on the inflammatory molecular cascade, and treatment with the drug may improve fibrosis.

In the current study, patients were 56 years old on average, and about 71% were women, with a mean BMI of 36. About 41% of the patients had been diagnosed with diabetes, 64% with hypertension, and 70% with dyslipidemia. Harrison noted that the group represented a “real-world” cohort with metabolic syndrome.

“What we found is that the 100-mg dose is very well tolerated,” he said. “There are some early mild gastrointestinal issues with loose stools that tend to abate after about 2 weeks. And that was seen in roughly 10% over the placebo. We also know that 95% of patients completed the study; none discontinued due to an adverse event.”

David Bernstein, MD, of the Sandra Atlas Bass Center for Liver Diseases at Northwell Health in Manhasset, New York, stressed to MedPage Today that these “are interim findings.” Bernstein, who was not involved in the study, called them “encouraging,” but pointed out that “the patient population appears to have more mild fibrosis, as stages F1-F3 were lumped together into a single group.”

“This investigational product will need to be studied further in a much larger cohort of patients, differentiated by fibrosis stage, and until we have approved noninvasive endpoints, future studies will need histological endpoints,” he stated.