Resmetirom, a β-selective thyromimetic, has emerged as a promising therapeutic agent for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Recent studies and clinical trials highlight its potential in addressing both hepatic steatosis and related metabolic complications.
Resmetirom's Mechanism of Action
Resmetirom selectively targets liver thyroid hormone receptors (THRs), specifically THRβ, which are crucial in regulating hepatic metabolic functions. Thyroid hormones, such as thyroxine (T4) and triiodothyronine (T3), influence carbohydrate metabolism and fatty acid β-oxidation. Resmetirom's selectivity for THRβ avoids THRα-mediated cardiac effects, enhancing its safety profile. This targeted approach allows the liver to leverage the metabolic benefits of thyroid hormone, potentially offering therapeutic benefits in hepatic disorders while minimizing adverse effects elsewhere in the body.
MAESTRO-NAFLD-1 Trial: Safety and Biomarker Improvements
The MAESTRO-NAFLD-1 trial, a multicentric RCT, investigated resmetirom's safety and efficacy in MASLD/MASH treatment. The study demonstrated an adequate safety profile for both resmetirom dosages (80 mg and 100 mg) over a 52-week period. Treatment-emergent adverse events (TEAEs) included mild or moderate diarrhea and nausea, particularly within the first 12 weeks, with nausea being more common in females.
At 16 weeks post-treatment, significant reductions in hepatic fat content were observed compared to placebo. At 52 weeks, the resmetirom arms showed an average mean reduction of 36.7–51.8% in hepatic fat from baseline, with the effect more pronounced in the 100-mg dosage groups. Weight loss ≥5% in combination with resmetirom treatment, or high resmetirom exposure (reflected in a high sex hormone-binding globulin (SHBG) response), was associated with a greater reduction in hepatic fat.
Impact on Atherogenic Biomarkers
Resmetirom significantly reduced atherogenic biomarkers such as LDL-C, apolipoprotein B (apoB), and triglycerides (TG) compared to placebo. This effect was sustained from 24 to 48 weeks after treatment initiation. Further cardiovascular improvements included reductions in remnant-like particle (RLP) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and small LDL particles. The study found no significant impact on blood sugar control and body weight.
Phase 2 Clinical Trials: Early Efficacy and Safety
Phase 2 trials provided early evidence of resmetirom's efficacy and safety. A double-blind, randomized controlled trial (NCT02912260) by Harrison et al. demonstrated that resmetirom 80 mg once daily significantly reduced hepatic fat fraction compared to placebo (-32.9% vs -10.4% at 12 weeks, p<0.0001). Histopathological improvements were also noted, with a higher proportion of patients in the resmetirom group experiencing at least a two-point reduction in NAS (non-alcoholic fatty liver disease activity score) and at least a one-point reduction in ballooning or inflammation.
Common adverse effects in these trials included gastrointestinal symptoms such as diarrhea and nausea, which were generally self-limited and did not lead to study withdrawals. An open-label extension (OLE) study of NCT02912260 further assessed the response to 80 mg and 100 mg doses, emphasizing the drug's safety profile. Results showed continued reductions in fibrosis markers, LDL cholesterol, apolipoprotein B, and triglycerides from baseline.
MAESTRO-NASH Trial: Pivotal Phase 3 Results
The MAESTRO-NASH trial, a Phase 3 double-blind placebo-controlled study, evaluated the efficacy of 80 or 100 mg of resmetirom in resolving NASH and/or reducing liver fibrosis. Results showed that 25.9% of patients in the 80 mg resmetirom arm and 29.9% in the 100 mg arm achieved NASH resolution with no worsening of fibrosis, compared to only 8.7% in the placebo group. Additionally, 24.2% and 29.3% of patients in the 80 mg and 100 mg resmetirom groups, respectively, achieved fibrosis improvement (by at least one stage), compared to 14.2% in the placebo group.
Ongoing Research and Future Directions
Recognizing MASLD as a chronic, dynamic disease, ongoing research is exploring resmetirom's long-term effects. The MAESTRO-NASH-OUTCOMES trial is investigating resmetirom in patients with MASH-cirrhosis, evaluating disease progression and hepatic decompensation events. These trials will provide further evidence on the sustainability of the encouraging responses observed in earlier publications.
