Resmetirom (MGL-3196) is a first-in-class, orally administered, small-molecule, liver-directed, thyroid hormone receptor (THR) β-selective agonist. Preclinical, toxicology, Phase 1, and Phase 2 clinical data suggest resmetirom has an attractive, differentiated profile as a potential treatment for non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and associated dyslipidemias.
THR-β selectivity also enhances the safety profile of resmetirom, compared to non-selective agents. Resmetirom has shown neither suppression of the central thyroid axis nor THR-α effects on heart rate or bone, and it reduces elevated liver enzymes in NASH patients. We believe these characteristics make resmetirom among the most promising molecules in development in this therapeutic area and have supported its advancement into Phase 3 clinical development.
About the Phase 3 Registration Program for the Treatment of NASH
Based on positive Phase 2 clinical trial results in patients with NASH (see The Lancet Publication – Madrigal Phase 2 Study and AASLD 36-Week Extension study presentation), Madrigal announced the initiation of a Phase 3 multinational, double-blind, randomized, placebo-controlled clinical trial of resmetirom in patients with NASH and liver fibrosis, called MAESTRO-NASH (Phase 3 Initiation Press Release and ClinicalTrials.gov NCT03900429).
The Phase 3 MAESTRO-NASH trial is expected to enroll 2000 patients with biopsy-proven NASH (fibrosis stage 2 or 3), randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. After 52 weeks of treatment a second biopsy is performed. The primary surrogate endpoint on biopsy will be NASH resolution, with at least a 2-point reduction in NASH Activity Score (NAS) and no worsening of fibrosis. Two key secondary endpoints will be fibrosis improvement of at least one stage with no worsening of NASH and lowering of LDL-cholesterol.
In the NASH Phase 2 study and a second positive Phase 2 clinical study in patients with heterozygous familial hypercholesterolemia (HeFH; Madrigal Pharmaceuticals Phase 2 HeFH Results), significant reductions in multiple atherogenic lipids were observed.
A second 52-week, Phase 3, multi-center, double-blind, randomized, placebo-controlled study of resmetirom, MAESTRO-NAFLD-1, in 700 patients with NAFLD, presumed NASH, randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo was initiated in December 2019. MAESTRO-NAFLD-1 also includes a 100 mg resmetirom open-label arm in up to 100 patients. Unlike MAESTRO-NASH, MAESTRO-NAFLD-1 is a non-biopsy study. NASH or presumed NASH is documented using non-invasive techniques or historical liver biopsy. MAESTRO-NAFLD-1 is designed to provide incremental safety information to support the NASH indication, as well as additional data regarding clinically relevant key secondary efficacy endpoints to better characterize the potential clinical benefits of resmetirom on cardiovascular and liver related endpoints using noninvasive measures. These key secondary endpoints include reductions in LDL-cholesterol; apolipoprotein B, an atherogenic lipoprotein particle; triglycerides; liver fat as determined by magnetic resonance imaging, proton density fat fraction (MRI-PDFF); and fibrosis biomarker, PRO-C3. (ClinicalTrials.gov NCT04197479) Additional secondary and exploratory endpoints will be assessed including reduction in liver enzymes, fibroscan scores and other fibrosis and inflammatory biomarkers.
These and other data, including safety parameters, form the basis for potential subpart H submission to the Food & Drug Administration (FDA) for accelerated approval for the treatment of NASH. The original 900 patients in the MAESTRO-NASH study will continue on therapy after the initial 52-week treatment period. Up to another 1,100 patients are to be added using the same randomization plan, and the study is expected to continue for up to 54 months to accrue and measure clinical events – most relevantly progression to cirrhosis.
Patients in MAESTRO-NAFLD-1 and MAESTRO-NASH are at elevated risk of cardiovascular disease because of their metabolic risk factors, hyperlipidemia, and elevated liver fat. Cardiovascular risk is not adequately treated with the current standard of care for these patients, and resmetirom has the potential to reduce the elevated cardiovascular risk in this patient population. Seth Baum, M.D. AASLD 2019 Presentation
The long term goal of the resmetirom development is to demonstrate benefit to NASH patients by:
- Reversing their liver disease and/or preventing progression to more serious liver disease (such as cirrhosis)
- Reducing their cardiovascular morbidity and mortality through the reduction of heart attacks and strokes.
With respect to this, it should be noted that many more NASH patients die of cardiovascular disease than progressive liver disease.