Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials

Connolly, James J.; Ooka, Kohtaro; Lim, Joseph K.

doi:10.14218/jcth.2017.00056

Cited by 54 publications

(69 citation statements)

References 65 publications

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“…This reduces liver fat, including triglycerides and free fatty acids, resulting in an improvement in insulin resistance. ( 44 )…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

“…Activation of these receptors induces migration of macrophages into the liver. ( 44 ) It was initially developed as an HIV drug, ( 46 ) but it was shown to reduce the rates of hepatic fibrosis.…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

“…In animal models, PPAR‐delta activation leads to fatty acid consumption in skeletal muscle and adipose tissue. ( 44 )…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

“…Farnesoid X nuclear receptor is a bile acid receptor that regulates lipid and glucose metabolism, and its activation leads to reduction in serum and hepatic triglyceride levels. ( 44 )…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

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New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

et al. 2020

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on behalf of the SHIVER Network In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug-drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug-drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies. (Hepatology 2020;71:1831-1844).

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“…This reduces liver fat, including triglycerides and free fatty acids, resulting in an improvement in insulin resistance. ( 44 )…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

“…In animal models, PPAR‐delta activation leads to fatty acid consumption in skeletal muscle and adipose tissue. ( 44 )…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

“…Farnesoid X nuclear receptor is a bile acid receptor that regulates lipid and glucose metabolism, and its activation leads to reduction in serum and hepatic triglyceride levels. ( 44 )…”

Section: Investigational Agents For Nash and Potential Ddis In The Comentioning

confidence: 99%

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New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

et al. 2020

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“…Regarding VCAM-1, it has also been recently validated as an accurate biomarker of fibrosis in NASH patients (Lefere et al, 2017). Furthermore, apoptosis signaling kinase 1 (ASK1/MAP3K5) has been largely described in the literature as a pharmacological target for NASH disease treatment (Povsic et al, 2019, Connolly et al, 2018, Drescher et al, 2019 and, interestingly, its upregulation is observed in our human 3D NASH model (Table S2).…”

Section: Discussionmentioning

confidence: 67%

A 3D human liver model of nonalcoholic steatohepatitis

Duriez

Jacquet

Hoet

et al. 2020

Preprint

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We developed a 3D human liver model which exhibits many features of nonalcoholic steatohepatitis and that could become a platform for medium throughput drug screening. ABSTRACTWe have developed an in vitro preclinical 3D Non-Alcoholic SteatoHepatitis (NASH) model by co-culturing four human primary liver cell types: hepatocytes, stellate, endothelial and Kupffer cells. Cells were embedded in a hydrogel of rat collagen in 96-well plate and a NASH-like environment was induced with a medium containing free fatty acids (FFAs) and tumor necrosis factor  (TNF). This model was characterized by biochemical, imaging and transcriptomics analysis. On the one hand, we succeed in defining suitable culture conditions to maintain the 3D co-culture up to 10 days in vitro with the lowest level of steatosis, and reproducible low levels of inflammation and fibrosis. On the other hand, we induced NASH disease with a custom medium mimicking NASH features (hepatocyte injury, steatosis, inflammation and fibrosis). The 10-day cell viability and cost effectiveness of the model make it suitable for medium throughput drug screening and provide attractive avenues to better understand disease physiology and to identify and characterize new drug targets.

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Dietary carbohydrates: Pathogenesis and potential therapeutic targets to obesity‐associated metabolic syndrome

Akter

Akhter

Chaudhury³

et al. 2022

BioFactors

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Metabolic syndrome (MetS) is a common feature in obesity, comprising a cluster of abnormalities including abdominal fat accumulation, hyperglycemia, hyperinsulinemia, dyslipidemia, and hypertension, leading to diabetes and cardiovascular diseases (CVD). Intake of carbohydrates (CHO), particularly a sugary diet that rapidly increases blood glucose, triglycerides, and blood pressure levels is the predominant determining factor of MetS. Complex CHO, on the other hand, are a stable source of energy taking a longer time to digest. In particular, resistant starch (RS) or soluble fiber is an excellent source of prebiotics, which alter the gut microbial composition, which in turn improves metabolic control. Altering maternal CHO intake during pregnancy may result in the child developing MetS. Furthermore, lifestyle factors such as physical inactivity in combination with dietary habits may synergistically influence gene expression by modulating genetic and epigenetic regulators transforming childhood obesity into adolescent metabolic disorders. This review summarizes the common pathophysiology of MetS in connection with the nature of CHO, intrauterine nutrition, genetic predisposition, lifestyle factors, and advanced treatment approaches; it also emphasizes how dietary CHO may act as a key element in the pathogenesis and future therapeutic targets of obesity and MetS.

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Future Pharmacotherapy for Non-alcoholic Steatohepatitis (NASH): Review of Phase 2 and 3 Trials

Cited by 54 publications

References 65 publications

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

A 3D human liver model of nonalcoholic steatohepatitis

Dietary carbohydrates: Pathogenesis and potential therapeutic targets to obesity‐associated metabolic syndrome

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