MGL-3196, a selective thyroid hormone receptor-beta agonist significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy study

Harrison, Stephen A.; Moussa, Sam; Bashir, Mustafa R.; Alkhouri, Naim; Frias, José Aristeu Fachini; Baum, Seth; Tetri, Brent A.; Bansal, Meghana; Taub, Rebecca

doi:10.1016/s0168-8278(18)30292-7

Cited by 28 publications

(25 citation statements)

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“…ACC inhibitors suppress lipogenesis in overweight individuals, and preliminary data suggest they may be effective in reducing hepatic fat and fibrogenesis in patients with NAFLD . Similarly, administration of a pegylated FGF21 analogue or stimulation of thyroid receptor β led a decrease in both hepatic fat and fibrosis markers . Finally, it should not be forgotten that statin therapy may also protect from liver damage, and the mechanism may encompass reduction of hepatic lipid content …”

Section: Therapeutic Trialsmentioning

confidence: 99%

“…ACC: acetyl-CoA carboxylase, FGF: fibroblast growth factor, FFAs: free fatty acids, FXR: farnesoid X receptor, FGFR4: fibroblast growth factor receptor 4, LOXL2: lysyl oxidase like 2, GLP1: glucagonlike peptide 1, PNPLA3: patatin-like phospholipase domain-containing 3, PPAR: peroxisome proliferator-activated receptor led a decrease in both hepatic fat and fibrosis markers. 56,57 Finally, it should not be forgotten that statin therapy may also protect from liver damage, and the mechanism may encompass reduction of hepatic lipid content. 58 All in all, although all the aforementioned compounds have also pleiotropic direct effects on inflammatory and fibrogenic cells, these data suggest that in patients with NAFLD the reduction of hepatic fat content obtained by reducing fatty acids flux, by inhibition of lipogenesis or by stimulation of lipolysis, results in decreased fibrogenesis.…”

Section: Ther Apeuti C Trial Smentioning

confidence: 99%

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Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease

Pelusi

Valenti

2018

Liver International

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Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of advanced liver disease in Western countries. NAFLD is defined in the presence of increased hepatic fat content, which is mainly stored under the form of neutral lipids within intracellular droplets and is not explained by at risk alcohol intake. In order to understand the pathogenesis, monitor the progression and find novel treatments for this condition, previous research efforts mainly addressed the role of inflammation. However, very recent data seem to suggest that hepatic lipid accumulation may be involved in NAFLD pathogenesis by driving secondary inflammation and fibrosis progression. Here, we will briefly review the novel results derived from natural history, genetics, imaging studies and therapeutic trials that support the notion that hepatic fat accumulation may represent a major clinical outcome and therapeutic target for NAFLD. Indeed, prospective and genetic data are consistent with hepatic fat being a driver of NAFLD progression. Furthermore, new technologies will render possible to monitor hepatic fat content without the need of invasive assessment, thereby allowing to identify patients at higher risk, and to monitor the response to drugs that act by decreasing hepatic lipid accumulation.

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Section: Therapeutic Trialsmentioning

confidence: 99%

Section: Ther Apeuti C Trial Smentioning

confidence: 99%

Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease

Pelusi

Valenti

2018

Liver International

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“…Resmetirom (MGL-3196), a thyroid hormone receptor-β (THR-β) agonist, was evaluated in a placebo-controlled, multicenter, phase-II trial in patients with liver-biopsy-confirmed NASH (NCT02912260). 74 MGL-3196-treated patients also saw a reduction in LDL-C (P ˂ .0001), TG (P ˂ .0001), ApoB (P ˂ .0001) and ALT (40% reduction; P = .002) levels. 75 Resmetirom (MGL-3196) is now being investigated in a phase-III clinical trial (NCT03900429).…”

Section: Resmetirommentioning

confidence: 91%

Drug discovery and treatment paradigms in nonalcoholic steatohepatitis

Noureddin

Muthiah

Sanyal

2019

Endocrino Diabet & Metabol

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Nonalcoholic fatty liver disease (NAFLD) affects almost a third of the Western population, and the burden of the disease is set to rise exponentially. 1 Current drug therapies for the resulting nonalcoholic steatohepatitis (NASH) are limited in their efficacy, and there are no FDA-approved drugs for NASH. 2 In this article, we review the potential therapeutic targets for NASH and their biological rationale, the current state of drugs in clinical trials, as well as some practical considerations as to how we manage NASH in the clinic. 2 | TRE ATMENT TARG E TS FOR THER APEUTI C S IN NA S H 2.1 | Targeting homeostasis of lipid and carbohydrate metabolism Excess delivery of fatty acids to the liver or impaired disposal of fatty acids from the liver leads to excess energy supply. Hepatocytes are unable to process this excess energy, forming lipotoxic metabolites with hepatocellular injury. 3 Systemic insulin resistance contributes to this, via increased adipose lipolysis leading to increased delivery

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“…[79] MGL-3196 is a selective THR-β agonist which have been proved to reduce liver steatosis in animal experiments. [210] Other THR-β agonist, such as VK2809 also perform abilities to decrease liver fat and increase FA oxidation and now is in a phase II clinical trial. [210] Other THR-β agonist, such as VK2809 also perform abilities to decrease liver fat and increase FA oxidation and now is in a phase II clinical trial.…”

Section: Metabolismmentioning

confidence: 99%

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

et al. 2018

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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease which affects ≈25% of the adult population worldwide, placing a tremendous burden on human health. The disease spectrum ranges from simple steatosis to steatohepatitis, fibrosis, and ultimately, cirrhosis and carcinoma, which are becoming leading reasons for liver transplantation. NAFLD is a complex multifactorial disease involving myriad genetic, metabolic, and environmental factors; it is closely associated with insulin resistance, metabolic syndrome, obesity, diabetes, and many other diseases. Over the past few decades, countless studies focusing on the investigation of noninvasive diagnosis, pathogenesis, and therapeutics have revealed different aspects of the mechanism and progression of NAFLD. However, effective pharmaceuticals are still in development. Here, the current epidemiology, diagnosis, animal models, pathogenesis, and treatment strategies for NAFLD are comprehensively reviewed, emphasizing the outstanding breakthroughs in the above fields and promising medications in and beyond phase II.

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MGL-3196, a selective thyroid hormone receptor-beta agonist significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy study

Cited by 28 publications

References 0 publications

Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease

Hepatic fat as clinical outcome and therapeutic target for nonalcoholic fatty liver disease

Drug discovery and treatment paradigms in nonalcoholic steatohepatitis

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

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