Resmetirom safe, effective in improving NASH fibrosis markers

Treatment with the selective THR-β* agonist resmetirom for 52 weeks was well-tolerated and effective in reducing markers of NASH** fibrosis in a well-compensated Child-Pugh (CP)-A NASH population, a phase III trial has shown.

“There were no differences between cirrhosis severity groups or compared with noncirrhotic NASH patients [in terms of] safety, the primary endpoint of MAESTRO-NAFLD-1,” said Dr Stephen Harrison from the University of Oxford, UK, at AASLD’s The Liver Meeting.

The most common adverse events (AEs) were mild, intermittent loose stools (33 percent) and nausea (33 percent), which were only predominant at treatment initiation. Roughly 15 percent of these events were considered drug-related. [The Liver Meeting, abstract 100]

“Just as importantly, there were no central thyroid axis changes,” Harrison continued. Only small decreases in prohormone FT4 were noted, with no change in active hormone FT3 or TSH.

This analysis comprised the open-label arm of MAESTRO-NAFLD-1 looking at 180 well-compensated NASH cirrhotic patients. Cohort 1 (n=105; mean age 62.4 years, 63 percent female) had completed 52 weeks of treatment, while cohort 2 (n=75; mean age 59.8 years, 60 percent female) is almost complete. Participants received resmetirom 80 g, which could be adjusted to 100 mg based on pharmacokinetic sampling at week 2.

 

Imaging markers

Looking at resmetirom-mediated changes to fibrosis imaging at week 52, 48 percent of participants with low liver fat (ie, baseline PDFF ≤5 percent) showed improvement (25-percent change in liver stiffness measurement) in FibroScan VCTE***. Among those with high liver fat (ie, baseline PDFF >5 percent), the rate was 42 percent. “[For] those who worsened, it was a little bit different, [as] those with low liver fat tended to progress a little bit more than those who had some degree of fat in their liver (22 percent vs 13 percent),” said Harrison.

Magnetic resonance elastography improvement rates were also similar between PDFF groups, both in the subgroups who improved (22 percent vs 26 percent) and worsened (17 percent vs 21 percent). “There was some variability … likely due to the small numbers of patients who had an MRE,” Harrison noted.

There was a 26-percent relative change in MRI-PDFF^# in the low liver fat group. In the high liver fat group, the corresponding rate was 37 percent.

“Interestingly, liver volume was about the same whether you had or did not have fat at week 16 (–13 percent vs –16 percent). But importantly, this continued to drop all the way to week 52, with similar changes between groups (–22 percent vs –21 percent),” noted Harrison.

 

Liver chemistry

The reductions in ALT, AST, and GGT^## were similar in cohort 1 (median, –20, –18, and –32 percent, respectively) and cohort 2 (median, –30, –23, and –37 percent). “[These] were significant reductions in [liver enzymes] in both cohorts of well-compensated cirrhotic patients,” said Harrison.

There were also similar reductions in LDL-C, ApoB^###, and triglycerides (–22, –22, and –23 percent, respectively).

 

Portal hypertension

At baseline, spleen volumes (SV) were higher in the low vs high liver fat group (649 vs 546 cc [cohort 1] and 734 vs 582 cc [cohort 2]). “[This means that] the less fat you have, the higher the SV, [the greater the] evidence of portal hypertension,” Harrison pointed out.

By week 52, almost a third (31 percent) of participants with low liver fat had ≥10 percent change in SV, whereas in the high liver fat group, 45 percent achieved this outcome.

“The potential to monitor SV as a surrogate for portal hypertension was a caveat that further research needs to be done in this area to understand this better,” said Harrison.

 

Summary

“In this well-compensated CP-A NASH population, resmetirom 80 and 100 mg for 52 weeks was well-tolerated. There was some mild gastrointestinal AEs at the beginning typically,” said Harrison. “Reductions in MRI-PDFF, LDL-C, and other atherogenic lipids were seen. [There were] improvements in liver chemistry tests that were significant … and reductions in VCTE and MRE in the responder analysis.”

“Importantly, there was a statistically significant reduction in liver volume by an average of 20 percent,” he continued. While the study was limited by the absence of a placebo group, it provides a rationale for the ongoing MAESTRO-NASH Outcomes trial.