Reduction of Liver Steatosis and Fibrosis with an Ask1 Inhibitor in a Murine Model of Nash is Accompanied by Improvements in Cholesterol, Bile Acid and Lipid Metabolism

Budas, Grant R.; Karnik, Satyajit K.; Jonnson, T.; Shafizadeh, Tracy; Watkins, Simon; Breckenridge, David G.; Tumas, Daniel B.

doi:10.1016/s0168-8278(16)01686-x

Cited by 41 publications

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“…Selonsertib is a selective inhibitor of ASK1, a ubiquitously expressed serine/threonine kinase which is activated by oxidative stress to promote hepatocellular apoptosis, inflammation, and fibrosis . ASK1 is normally bound and repressed by thiol‐containing antioxidant proteins, including thioredoxin 1 .…”

Section: Discussionmentioning

confidence: 99%

“…Ballooned hepatocytes, representing the activation of apoptosis‐related pathways, are a hallmark of NASH and fibrosis progression . In the setting of oxidative stress, activation of apoptosis signal–regulating kinase 1 (ASK1), a serine/threonine signaling kinase, can lead to phosphorylation of p38 mitogen‐activated kinase and c‐Jun N‐terminal kinase (JNK), leading in turn to activation of stress response pathways that worsen hepatic inflammation, apoptosis, and fibrosis . Inhibition of ASK1 has therefore been proposed as a target for the treatment of NASH.…”

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confidence: 99%

“…Inhibition of ASK1 has therefore been proposed as a target for the treatment of NASH. In a murine model of NASH, selonsertib (formerly GS‐4997), a selective inhibitor of ASK1, significantly improved not only metabolic parameters associated with NASH but also reduced hepatic steatosis, inflammation, and fibrosis . Simtuzumab is a humanized monoclonal antibody directed against lysyl oxidase‐like molecule 2, an enzyme that catalyzes the crosslinkage of collagen and elastin, leading to remodeling of the extracellular matrix .…”

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The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial

et al. 2017

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Inhibition of apoptosis signal–regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal–regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open‐label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once‐weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging–estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18‐mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26‐63); in the 6‐mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14‐50); and in the simtuzumab‐alone group, 2 of 10 (20%; 95% confidence interval, 3‐56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusion: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2‐3 fibrosis. (Hepatology 2018;67:549‐559).

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The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial

et al. 2017

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“…In murine models, it has also been shown to contribute to TNFα-mediated insulin resistance and steatosis107 and inhibition of ASK1 ameliorates diet-induced steatosis and fibrosis 108. In an ongoing randomised open-label phase II trial, GS-4997, an oral ASK1 inhibitor, is studied for 24 weeks with or without simtuzumab in patients with NASH and stage 2–3 fibrosis (NCT 02466516).…”

Section: Medications Affecting Oxidative Stress and Inflammationmentioning

confidence: 99%

Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease

Rotman

Sanyal

2016

Gut

369

302

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Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.

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“…Inhibition of ASK1 reduces liver steatosis and fibrosis in a murine model of diet-induced NASH [56]. An open-label phase 2 trial in 72 NASH patients with stage 2/3 fibrosis randomized to an oral ASK1 inhibitor, selonsertib (formerly called GS-4997; 6 mg or 18 mg/day) versus lysyl oxidase-like 2 antibody simtuzumab (25 mg SC weekly) versus selonsertib and simtuzumab was recently completed [57].…”

Section: Oxidative Stress and Inflammationmentioning

confidence: 99%

Current and future pharmacologic treatment of nonalcoholic steatohepatitis

Banini

Sanyal²

2017

Current Opinion in Gastroenterology

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Purpose of review Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD), can progress to cirrhosis and hepatocellular cancer in 5–15% of patients and is rapidly becoming the leading cause for end-stage liver disease. Dietary caloric restriction and exercise, currently the cornerstone of therapy for NAFLD, can be difficult to achieve and maintain, underscoring the dire need for pharmacotherapy. This review presents the agents currently used in managing NAFLD and their pharmacologic targets. It also provides an overview of NAFLD agents currently under development. Recent findings Therapies for NASH can be broadly classified into agents that target the metabolic perturbations driving disease pathogenesis (such as insulin resistance and de novo lipogenesis) and agents that target downstream processes including cell stress, apoptosis, inflammation, and fibrosis. Modulation of peroxisome proliferator-activator receptors, farnesoid-X-receptors, and the glucagon-like peptide 1 pathway have been shown to improve liver histology. The intestinal microbiome and metabolic endotoxemia are novel targets that are currently under review. Antioxidants such as vitamin E, and more recently anti-inflammatory agents such as apoptosis signal-regulating kinase 1 inhibitors show promise as therapy for NASH. Several antifibrotic agents including C-C chemokine receptor type 2 and type 5 antagonists have been shown to inhibit the progression of fibrosis toward cirrhosis. Summary There are currently several agents in the drug pipeline for NASH. Within the next few years, the availability of therapeutic options for NAFLD will hopefully curb the rising trend of NAFLD-related end stage liver disease.

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Reduction of Liver Steatosis and Fibrosis with an Ask1 Inhibitor in a Murine Model of Nash is Accompanied by Improvements in Cholesterol, Bile Acid and Lipid Metabolism

Cited by 41 publications

References 0 publications

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial

The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial

Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease

Current and future pharmacologic treatment of nonalcoholic steatohepatitis

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