‘Game Changer’ in NASH: Resmetirom Hits Endpoints in Pivotal Study

VIENNA — The investigational agent resmetirom resolved liver biopsy findings in nonalcoholic steatohepatitis (NASH) more often than placebo, according to the phase III MAESTRO-NASH trial.

While 10% of placebo patients achieved resolution of inflammation, ballooning, and disease activity, the rate was 26% among people treated with the 80-mg dose of resmetirom and 30% with the 100-mg dose of resmetirom (P<0.0001), reported Stephen Harrison, MD, of Pinnacle Clinical Research in San Antonio, at the annual meeting of the European Association for the Study of the Liver.

In the co-primary endpoint of the trial, 14% of patients on placebo had liver fibrosis improve by at least one stage without a worsening of non-alcoholic fatty liver disease activity score (NAS) compared with 24% of patients taking 80 mg daily of resmetirom (P=0.0002) and 26% on the 100 mg dose of the agent (P<0.0001).

“This is the first treatment to achieve meaningful effects on both primary liver endpoints and [to be] reasonably likely to produce clinical benefit with these NASH patients,” Harrison said at a press conference.

“When this drug is approved, it will honestly be a game changer,” press conference moderator Aleksander Krag, MD, PhD, of the University of Southern Denmark in Odense, told MedPage Today. “Both the change in NASH and the ability to stabilize or improve fibrosis are really, really important and meaningful. They’ve treated several thousand patients now in the MAESTRO trials. So, I think the signal there is really comforting.”

Harrison noted the “excellent” safety profile. Most common adverse events were gastrointestinal (GI)-related, were mild to moderate, and they tended to occur early in the course of treatment, he said.

He reported that study discontinuations in the 100-mg arm were increased relative to placebo only during the first few weeks of treatment and were similar in all treatment groups for the remaining period of the first 52 weeks of treatment. Most adverse event-related discontinuations in the 100-mg arm were GI-related, with diarrhea occurring in 34% of patients compared with 16% in the placebo group. Episodes were mild or moderate, and the median duration of diarrhea was approximately 2 weeks, he said.

Importantly, there were no adjudicated cases of drug-induced liver injury in the MAESTRO-NASH trial, an issue that has caused concern with other drugs investigated for NASH, a severe form of fatty liver disease for which no approved treatment exists.

To be eligible for the phase III trial, which was presented as a plenary late-breaker, patients were required to have been diagnosed with at least three metabolic risk factors; to have had a biopsy result indicating at least a NAS 4 score; to be in fibrosis stage F1B, F2, or F3; and to have had at least 8% hepatic fat measured by MRI scans.

All baseline and week 52 biopsies were read independently by two central pathologists for the primary analysis. Each pathologist’s scores showed a similar statistically significant magnitude of response at both doses for both primary liver biopsy endpoints.

The primary endpoint of NASH resolution encompassed a ballooning score of 0, inflammation score of 0/1, and at least a 2-point reduction in NAS with no worsening of fibrosis.

The researchers randomly assigned 322 patients to 80-mg resmetirom, 323 patients to 100-mg resmetirom, and 321 patients to placebo. The participants averaged about age 56 years, with 44% men, 90% white, and comorbidities in most (65% with diabetes and 78% with high blood pressure).

The research team reported that patients treated with resmetirom achieved significant reductions relative to placebo in key noninvasive tests, including MRI-proton density fat fraction. At 52 weeks, fat reduction of 42% was observed with the 80-mg dose, 51% among patients treated with 100-mg resmetirom, and 10% among placebo patients.

Harrison said that both 80- and 100-mg doses were effective, giving patients and their doctors options for treatment. He acknowledged that a limitation of the study was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue for 54 months to accrue and evaluate clinical outcomes.