Resmetirom: An Orally Administered, Small-molecule, Liver-directed, β-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty liver disease, including non-alcoholic fatty liver (NAFL) and its more progressive form, non-alcoholic steatohepatitis (NASH). The prevalence of NAFLD/NASH along with type 2 diabetes and obesity is rising worldwide. In those who develop NASH, unlike those with bland steatosis (NAFL), lipotoxic lipids drive hepatocyte injury, inflammation and stellate cell activation leading to progressive accumulation of collagen or fibrosis, ultimately leading to cirrhosis and increased risk of hepatocellular carcinoma. Hypothyroidism is associated with NAFLD/NASH; specifically, intrahepatic hypothyroidism drives lipotoxicty in preclinical models. Agonists of thyroid hormone receptor (THR)-β, which is primarily found in the liver, can promote lipophagy, mitochondrial biogenesis and mitophagy, stimulating increased hepatic fatty acid β-oxidation, and thereby decreasing the burden of lipotoxic lipids, while promoting low-density lipoprotein (LDL) uptake and favourable effects on lipid profiles. A number of THR-β agonists are currently being investigated for NASH. This review focuses on resmetirom, an orally administered, once-daily, small-molecule, liver-directed, ß-selective THR agonist, as it is furthest along in development. Data from completed clincal studies outlined in this review demonstrate that resmetirom is effective in reducing hepatic fat content as measured by magnetic resonance imaging-derived proton density fat fraction, reduces liver enzymes, improves non-invasive markers of liver fibrogenesis and decreases liver stiffness, while eliciting a favourable cardiovascular profile with a reduction in serum lipids, including LDL cholesterol. Topline phase III biopsy data showed resolution of NASH and/or fibrosis improvement after 52 weeks of treatment, with more detailed peer-reviewed findings anticipated in order to certify these findings. Longer term clinical outcomes from both MAESTRO-NASH and MAESTRO-NASH OUTCOMES will be a pivotal juncture in the drug’s road towards being approved as a NASH therapeutic.

Comparison of Wild-Type and High-risk PNPLA3 variants in a Human Biomimetic Liver Microphysiology System for Metabolic Dysfunction-associated Steatotic Liver Disease Precision Therapy

“…We evaluated the on-target pharmacodynamic activity of resmetirom by quantifying the secretion of SHBG in PNPLA3 GG variant and CC wild type LAMPS treated with 1µM resmetirom as the sex hormone binding globulin (SHBG) is a downstream target of THR-β activity in the liver (86, 87). On day 8, resmetirom treatment resulted in significantly increased SHBG secretion in both GG variant and CC wild type LAMPS (Fig S8A) , supporting the on-target pharmacodynamic activity of resmetirom.…”

Emerging therapies for MASLD and their impact on plasma lipids

“…Resmetirom (MGL-3196) is a selective THR-β agonist which avoids unwanted effects on the central thyroid axis (i.e., causing hyperthyroidism and thyrotoxicosis) and targets the liver specifically. Patients treated with resmetirom 80 mg daily had a greater reduction in hepatic fat measured by MRI-PDFF compared to placebo at weeks 12 and 36 [65] . Patients treated with resmetirom also had 30 % reduction in LDL-C, 25 % reduction in apolipoprotein-B, and 60 % reduction in triglycerides [66] .…”

“…Pruritus resolved after drug discontinued. Total cholesterol 189 placebo 179 aramchol 400 mg 188 aramchol 600 mg At 52 weeks: Total cholesterol 193 placebo 183 aramchol 400 mg 192 aramchol 600 mg Placebo 27.5 % Aramchol 400 mg 27.3 % Aramchol 600 mg 30.2 % (Magnetic resonance spectroscopy) Placebo 27 % Aramchol 400 mg 23.8 % Aramchol 600 mg 27 % HDL-C 45 placebo 45 aramchol 400 mg 46 aramchol 600 mg HDL-C 44 placebo 43 aramchol 400 mg 46 aramchol 600 mg LDL-C 119 placebo 110 aramchol 400 mg 117 aramchol 600 mg LDL-C 125 placebo 120 aramchol 400 mg 124 aramchol 600 mg TG 170 placebo 175 aramchol 400 mg 170 aramchol 600 mg TG 178 placebo 178 aramchol 400 mg 184 aramchol 600 mg Aramchol Ongoing, will be completed in 2024 In process In process In process In process In process Resmetirom (MGL-3196) [65] Resmetirom led to reduction in hepatic fat and lipid parameters. Adverse events included diarrhea and nausea, which were limited to duration of therapy.…”

Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD

“…Furthermore, to minimize side effects related to the remaining affinity with THRα, the MGL-3196 compound has recently been optimized, and it seems that its newer form, compound 15, has higher potency and affinity for THRβ, with a liver-to-serum ratio of 93:1 compared to the 6:1 ratio of MGL-3196 [ 168 ]. Karim et al nicely reviewed the ongoing studies on resmetirom in NAFLD including ASC-41 and TERN-501, two compounds recently developed that can be orally administered, and are currently in phase 2 studies (NCT05462353, NCT05415722) after having shown promising results in rodents [ 169 , 170 ].…”