Thyromimetics as emerging therapeutic agents for nonalcoholic steatohepatitis: rationale for the development of resmetirom (MGL-3196)

Alkhouri, Naim

doi:10.1080/13543784.2020.1708899

Cited by 12 publications

(10 citation statements)

References 15 publications

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“…[33] Res, the most advanced THRβ agonist currently in a Phase 3 NASH trial, demonstrated NASH resolution (27.4% vs. 6.5% placebo) in subjects with NASH. [19] ACCi, Ela, Saro, and Res increased FAO in vitro as monotherapies, in line with expected biology. However, while ACCi was very potent (EC 50 = 8-33 nM) at inducing FAO, the other agents were not (Figure 2).…”

Section: Discussionsupporting

confidence: 64%

“…[ 33 ] Res, the most advanced THRβ agonist currently in a Phase 3 NASH trial, demonstrated NASH resolution (27.4% vs. 6.5% placebo) in subjects with NASH. [ 19 ]…”

Section: Discussionmentioning

confidence: 99%

“…THRβ agonism represents an orthogonal mechanism to PPAR agonism to increase hepatic FAO and Resmetirom (Res), a liver‐targeted THRβ agonist, has been shown to improve plasma lipid profiles and promote hepatic TG reduction and NASH resolution clinically. [ 19 ] Therefore, we also compared the effect of ACCi/Res combinations on circulating and liver TG, and NASH and fibrosis efficacy in our preclinical models.…”

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confidence: 99%

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Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis

et al. 2022

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Dysregulated hepatocyte lipid metabolism is a hallmark of hepatic lipotoxicity and contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl CoA carboxylase (ACC) inhibitors decrease hepatocyte lipotoxicity by inhibiting de novo lipogenesis and concomitantly increasing fatty acid oxidation (FAO), and firsocostat, a liver‐targeted inhibitor of ACC1/2, is under evaluation clinically in patients with NASH. ACC inhibition is associated with improvements in indices of NASH and reduced liver triglyceride (TG) content, but also increased circulating TG in subjects with NASH and preclinical rodent models. Here we evaluated whether enhancing hepatocyte FAO by combining ACC inhibitors with peroxisomal proliferator‐activated receptor (PPAR) or thyroid hormone receptor beta (THRβ) agonists could drive greater liver TG reduction and NASH/antifibrotic efficacy, while ameliorating ACC inhibitor–induced hypertriglyceridemia. In high‐fat diet–fed dyslipidemic rats, the addition of PPAR agonists fenofibrate (Feno), elafibranor (Ela), lanifibranor (Lani), seladelpar (Sela) or saroglitazar (Saro), or the THRb agonist resmetirom (Res), to an analogue of firsocostat (ACCi) prevented ACCi‐induced hypertriglyceridemia. However, only PPARα agonists (Feno and Ela) and Res provided additional liver TG reduction. In the choline‐deficient high‐fat diet rat model of advanced liver fibrosis, neither PPARα (Feno) nor THRβ (Res) agonism augmented the antifibrotic efficacy of ACCi. Conclusion : These data suggest that combination therapies targeting hepatocyte lipid metabolism may have beneficial effects on liver TG reduction; however, they may not be sufficient to drive fibrosis regression.

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Section: Discussionsupporting

confidence: 64%

“…[ 33 ] Res, the most advanced THRβ agonist currently in a Phase 3 NASH trial, demonstrated NASH resolution (27.4% vs. 6.5% placebo) in subjects with NASH. [ 19 ]…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis

et al. 2022

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“… 68 Nonetheless, efforts were taken to investigate a new generation of THR-β agonist in NAFLD treatment, irrespective of thyroid function. 69 , 70 In a phase 2 clinical trial investigating such, the drug resmetirom (MGL-3196) was applied to patients with biopsy-confirmed NASH and a significant decrease in liver fat after 12 and after 36 weeks of the treatment was achieved. 71 In March 2019, initiation of a phase 3 trial testing the use of resmetirom in patients with fibrotic NASH was announced by Madrigal Pharmaceuticals.…”

Section: Treatment Implicationsmentioning

confidence: 99%

Hypothyroidism and Nonalcoholic Fatty Liver Disease: Pathophysiological Associations and Therapeutic Implications

Kizivat

Marić

Mudri

et al. 2020

Journal of Clinical and Translational Hepatology

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Nonalcoholic fatty liver disease (NAFLD) is a complex clinical entity which can be secondary to many other diseases including hypothyroidism, characterized by lowering of thyroid hormones and increased thyroid stimulating hormone (TSH). A lot of emerging data published recently advocates the hypothesis that hypothyroid induced NAFLD could be a separate clinical entity, even suggesting possible treatment options for NAFLD involving substitution therapy for hypothyroidism along with lifestyle modifications. In addition, a whole new field of research is focused on thyromimetics in NAFLD/NASH treatment, currently in phase 3 clinical trials. In this critical review we summarized epidemiological and pathophysiological evidence linking these two clinical entities and described specific treatment options with the accent on promising new agents in NAFLD treatment, specifically thyroid hormone receptor (THR) agonist and its metabolites.

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“…The signaling pathways downstream of thyroid hormone receptors (THRs) play fundamental roles in regulating organogenesis, growth, and differentiation and significantly influence energy metabolism, lipid utilization, and glucose homeostasis, implying the potential value of liver disease treatment by targeting THRs [ 28 ]. Although little benefit was obtained from thyromimetics in improving NASH due to unwanted side effects, significant therapeutic effects on NASH were observed with resmetirom (MGL-3196), a new oral, liver-directed, highly selective thyroid receptor β agonist [ 19 , 29 , 30 ]. However, there has been little attention paid to the need to evaluate the underlying mechanism by which resmetirom exerts its intervention effect on NASH until now.…”

Section: Discussionmentioning

confidence: 99%

Resmetirom Ameliorates NASH-Model Mice by Suppressing STAT3 and NF-κB Signaling Pathways in an RGS5-Dependent Manner

Wang

et al. 2023

IJMS

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Resmetirom, a liver-directed, orally active agonist of THR-β, could play a favorable role in treating NASH, but little is known about the underlying mechanism. A NASH cell model was established to test the preventive effect of resmetirom on this disease in vitro. RNA-seq was used for screening, and rescue experiments were performed to validate the target gene of the drug. A NASH mouse model was used to further elucidate the role and the underlying mechanism of resmetirom. Resmetirom effectively eliminated lipid accumulation and decreased triglyceride (TG) levels. In addition, repressed RGS5 in the NASH model could be recovered by resmetirom treatment. The silencing of RGS5 effectively impaired the role of resmetirom. In the NASH mouse model, obvious gray hepatization, liver fibrosis and inflammation, and increased macrophage infiltration were observed in liver tissues, while resmetirom almost returned them to normal conditions as observed in the control group. Pathological experimental data also confirmed that resmetirom has great potential in NASH treatment. Finally, RGS5 expression was suppressed in the NASH mouse model, but it was upregulated by resmetirom treatment, while the STAT3 and NF-κB signaling pathways were activated in NASH but inhibited by the agent. Resmetirom could improve NASH by recovering RGS5 expression and subsequently inactivating the STAT3 and NF-κB signaling pathways.

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Thyromimetics as emerging therapeutic agents for nonalcoholic steatohepatitis: rationale for the development of resmetirom (MGL-3196)

Cited by 12 publications

References 15 publications

Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis

Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis

Hypothyroidism and Nonalcoholic Fatty Liver Disease: Pathophysiological Associations and Therapeutic Implications

Resmetirom Ameliorates NASH-Model Mice by Suppressing STAT3 and NF-κB Signaling Pathways in an RGS5-Dependent Manner

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