VK2809 Treatment Leads to Rapid Reduction in Steatosis, Inflammation and Liver Size in Mouse Model of Glycogen Storage Disease Type Ia (GSD Ia)
Viking Therapeutics, Inc. (“Viking”) (NASDAQ: VKTX), a clinical-stage biopharmaceutical company focused on the development of novel therapies for metabolic and endocrine disorders, today announced the presentation of positive data from a study of VK2809 in an in vivo model of glycogen storage disease type Ia (GSD Ia) at the 88thAnnual Meeting of the American Thyroid Association (ATA) in Washington, D.C. The results demonstrated that treatment with VK2809 led to an overall improvement in liver health highlighted by restoration of autophagy, reduction in steatosis, and improvements in inflammation and liver size. The study investigators concluded that these histological improvements are potentially relevant to non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), due to certain similarities between those conditions and GSD Ia.
Study results were summarized in an oral presentation titled, “Liver-selective Thyromimetic, VK2809, Reduces Hepatosteatosis in Mouse Model of the Glycogen Storage Disease GSD Ia,” by professor Paul Yen, M.D., head of the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore. GSD Ia is a rare genetic disease that results in excess accumulation of glycogen and lipids in liver tissue. This study utilized the glucose-6-phosphatase (G6PC) knockout mouse model, which is intended to replicate the impairment of this enzyme’s activity in patients with GSD Ia. G6PC knockouts develop enlarged livers due to elevated fat content.
The results demonstrated decreases in steatosis, liver mass, and triglyceride concentration in VK2809-treated cohorts compared with vehicle controls. Significant improvements in LC3B-II protein density, an important mediator of fat disposal, as well as reduced levels of p62 protein, were also observed. These data suggest that, in addition to stimulation of beta-oxidation via increased PGC1-alpha and CPT1-alpha expression, restoration of autophagy may be contributing to the reduction of fat content in this setting.
Importantly, this study also demonstrated indications of reduced inflammatory signalling following treatment with VK2809. The expression of inflammatory markers such as tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6) were normalized or reduced in the livers of VK2809-treated cohorts compared with vehicle controls, suggesting an overall reduction in inflammation. These data may be of interest for other indications in which inflammation plays a role in disease progression and severity.
“These results are exciting not only in the context of GSD Ia but also, as Dr. Yen highlighted, due to their relevance to settings like NAFLD and NASH. The impressive reduction in steatosis observed in this model is supported by improved expression of genes important for autophagy and fat metabolism. The normalization of inflammatory gene expression is of particular interest due to role of inflammation in the onset of hepatocyte damage, and ultimately fibrosis, in various liver diseases,” said Brian Lian, Ph.D., chief executive officer of Viking. “We believe the GSD I data presented at ATA, combined with our recently reported Phase 2 results in NAFLD, provide compelling support for VK2809 as a best-in-class thyroid beta receptor agonist with significant therapeutic potential in NAFLD and NASH.”
The proof-of-concept study was conducted under a sponsored research agreement between Duke University and Viking Therapeutics and designed to evaluate the effects of VK2809 in Duke University’s G6PC knockout mouse model. The G6PC knockout model is intended to replicate many of the same biochemical and physiological characteristics present in GSD Ia patients.
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