14 February 2020 - - French biopharmaceutical company Poxel SA (Euronext: POXEL FR0012432516) has presented new preclinical proof-of-concept results for PXL770 for the treatment of NASH were reported in an oral presentation during the 3rd Annual Global NASH Congress held in London, the company said.

The results highlight PXL770 as a potentially novel therapeutic approach for the treatment of NASH, improving core aspects of disease pathophysiology.

Inflammation is known as a core component of the pathophysiology of NASH and as a major contributing factor leading to fibrogenesis.

In addition to known effects to suppress hepatic steatosis, published literature suggests the involvement of adenosine monophosphate-activated protein kinase in the modulation of inflammatory responses. In a preclinical diet-induced obese -NASH model, treatment with PXL770, a direct AMPK activator clinical candidate, improved inflammation score assessed by histology.

More specific observations included a decrease in multiple subtypes of inflammatory cells in the liver, including macrophages and B-lymphocytes in addition to suppression of elevated chemokine (MCP-1) levels, which correlated with the decrease in liver monocyte-derived macrophages.

These effects may contribute to the concomitant improvement of fibrogenesis measured in this study. PXL770 is currently being assessed in a pharmacokinetic and pharmacodynamic (PK/PD) trial and a Phase 2a efficacy and safety study for the treatment of NASH.

PXL770 may also be differentiated from other compounds in development for liver diseases since AMPK activation has the potential to also treat NASH comorbidities by specifically targeting cardiovascular risk factors, such as hyperglycemia, insulin resistance, dyslipidemia and obesity.

In this study, Poxel assessed the effect of PXL770 in a diet-induced (high fat, fructose and cholesterol for 34 weeks) obese NASH (DIO-NASH) mouse model. DIO-NASH mice with biopsy-confirmed steatosis (score ≥2) and fibrosis (stage ≥F1) received 75 mg/kg of PXL770 orally twice daily for 8 weeks versus vehicle treatment in the control group.

As described in the literature, both liver monocytes-macrophages and B-cells promote fibrogenesis. The reduction in inflammatory cells observed with PXL770 may contribute to the benefits of PXL770 reported on fibrogenesis.

In this study, PXL770 reduced total inflammatory liver cells, which may contribute to observed improvements in fibrogenesis. Poxel believes these benefits induced by PXL770 appear promising for the treatment of NASH.

Non-alcoholic steatohepatitis is a metabolic disease with no clear disease origin that is quickly becoming a worldwide epidemic.

It is characterised by the accumulation of fat in the liver causing inflammation and fibrosis.

The disease can be silent for a long period of time, but once it accelerates, severe damage and liver cirrhosis can occur, which can significantly impact liver function or can even result in liver failure or liver cancer.

Typical risk factors for NASH include obesity, elevated levels of blood lipids (such as cholesterol and triglycerides) and type 2 diabetes.

Currently no curative or specific therapies are available.

PXL770 is a first-in-class direct adenosine monophosphate-activated protein kinase activator. AMPK is a central regulator of multiple metabolic pathways leading to the control of lipid metabolism, glucose homeostasis and inflammation.

Based on its central metabolic role, targeting AMPK offers the opportunity to pursue a wide range of indications to treat chronic metabolic diseases, including diseases that affect the liver, such as non-alcoholic steatohepatitis 1.

Poxel is a  biopharmaceutical company that uses its expertise in developing innovative drugs for metabolic diseases, with a focus on type 2 diabetes and non-alcoholic steatohepatitis.

In its mid-to-late stage pipeline, the company is currently advancing three drug candidates as well as earlier-stage opportunities. Imeglimin, Poxel's first-in-class lead product, targets mitochondrial dysfunction.

Together, with its partner Sumitomo Dainippon Pharma, Poxel successfully completed the Phase 3 Trials of IMeglimin for Efficacy and Safety (TIMES) program for the treatment of type 2 diabetes in Japan.

Poxel also established a partnership with Roivant Sciences for Imeglimin's development and commercialization in countries outside of the partnership with Sumitomo Dainippon Pharma, including the US and Europe.