Phase III data support resmetirom potential for NAFLD/NASH

In individuals with nonalcoholic fatty liver disease (NAFLD) or presumed nonalcoholic steatohepatitis (NASH), resmetirom, an investigational, once-daily, oral selective thyroid hormone receptor beta agonist, significantly improved several hepatic and cardiovascular (CV) parameters, according to the findings of the phase III MAESTRO-NAFLD1 trial presented at ILC 2021.

Following positive phase II trials of resmetirom in NASH, MAESTRO-NAFLD1, a 52-week randomized, placebo-controlled trial initiated in December 2019, evaluated 700 NAFLD/presumed NASH patients with F1–F4 fibrosis identified using noninvasive techniques (eg, biomarkers, imaging) or historical biopsies. Participants were randomized 1:1:1 to receive either resmetirom 80 or 100 mg or placebo. The study also includes an open-label active treatment arm wherein participants were given resmetirom 100 mg. [Lancet 2019;394:2012-2024; www.madrigalpharma.com/wp-content/uploads/2019/11/Final-2019-AASLD-ORAL-Madrigal-HARRISON.pdf, accessed July 14, 2021]

Fibrosis, imaging, biomarker, CV improvements

An exploratory analysis of the open-label arm was conducted (n=169; mean age 55.7 years, 69 percent female, BMI 35.8). The FibroScan kPa (7.7) and mean MRI-PDFF* (18 percent) are consistent with stage F2 NASH. Among the participants, 64 completed 52 weeks. [ILC 2021, abstract GS-2563]

At week 52, MRI-PDFF dropped significantly from baseline, both in the overall cohort (relative percent change, –53 percent; p<0.0001) and in an SHBG** responder group (relative percent change, –62 percent; p<0.0001). There were also improvements in baseline liver stiffness by magnetic resonance elastography (MRE; change, –0.43; and −0.49; p=0.03 for both).

Furthermore, reductions from baseline FibroScan CAP*** score and transient elastography (TE) measurements were similarly observed in the overall (change, –43; p<0.0001 [CAP] and –3.1; p=0.002 [TE]) and SHBG cohorts (change, –48; p<0.0001 and –3.3; p=0.007, respectively).

Week 52 also saw reductions from baseline levels of triglycerides (median, −32 mg/dL), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein-B, and lipoprotein(a) (−23, −22, and −39 percent, respectively), as well as ALT/AST/GGT^# (−22/−12/−25 IU).

“[Our findings show that in] noninvasively identified NASH patients … resmetirom 100 mg daily for up to 52 weeks [led to] rapid and sustained reductions in hepatic fat, fibrosis stage (as assessed by biomarkers, MRE, and FibroScan), LDL, and atherogenic lipids, as well as liver enzymes and inflammatory biomarkers,” said the researchers.

Of note was the inclusion of CV endpoints in the trial. The study also aimed to address the increased CV disease risk among NAFLD/NASH patients, owing to the elevated liver fat and hyperlipidaemia. In MAESTRO-NAFLD1, nearly a third were hypertensive (62 percent), while >70 percent had dyslipidaemia. As this is insufficiently addressed with available therapies, the current findings, along with previous results, underscore the potential of resmetirom to reduce CV risk in this patient setting. [www.madrigalpharma.com/wp-content/uploads/2019/11/Seth-Baum.AASLD-2019_Resmetirom-Managing-Cardiovascular-Risk-in-NAFLD_NASH_20191111.pdf, accessed July 14, 2021]

Taken together, the results support existing literature underpinning the potential of resmetirom to reverse liver disease or prevent its progression into more serious liver complications, and possibly reduce CV morbidity and mortality.

“[Moreover, one of our goals] is to identify noninvasive markers that correlate with patient response to resmetirom treatment … [Our findings also appear to] support the use of noninvasive tests to monitor individual NASH patient response to resmetirom treatment,” said the researchers.