TOTUM-63 – Non-alcoholic hepatic steatosis

NAFL, NASH: new epidemics requiring new preventive measures

Metabolic liver diseases are becoming a major public health issue worldwide. They are closely linked to the development of type 2 diabetes and obesity in the population.
NAFL (non-alcoholic fatty liver), is characterized by the accumulation of triglycerides in the liver. It is a risk condition that can develop into NASH (non-alcoholic steatohepatitis). This disease strongly increases the risk of cirrhosis and hepatocellular carcinoma and has very low survival rates.

According to the World Gastroenterology Organization, the prevalence of NAFL and NASH has doubled in the last 20 years. Today, NAFL affects 20 to 26% of the population in Europe and 20 to 46% of the population in the United States.
There is currently no therapeutic or preventive treatment with proven efficacy available for these hepatic disorders.

 

Sources: World Gastroenterology Organization Global Guidelines,
Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis, 2012;
Younossi et al. Hepatology, 2016;
Williams et al., Gastroenterology, 2011.

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Key figures

Prognosis

38%

chance of surviving 10 years: this is the current prognosis for patients with NASH.

Source: WGO Guidelines, 2012.

A risk condition

Up to 40%

of subjects with non alcoholic fatty liver (NAFL) will at least develop NASH within 8 to 13 years.

Source: EASL-EASD-EASO 2016 Clinical Guidelines on the management of non-alcoholic fatty liver disease. J Hepatol 2016.

TOTUM-63: a strong candidate to reduce the risk of NASH

The active substance TOTUM-63 is also developed in the field of non alcoholic fatty liver diseases (NAFLDs), for the reduction of hepatic steatosis (fatty liver), a risk factor for NASH. This program is backed by promising preclinical and clinical results on hepatic steatosis and lipid metabolism.

Key results

Preclinical data

The studies conducted on NAFLDs preclinical models repeatedly demonstrated the efficacy of TOTUM-63 on hepatic steatosis:

  • A 68% reduction in hepatic triglyceride levels in diabetic models (db/db);
  • Prevention of hepatic steatosis in high-fat diet models (steatosis was 40% lower than control);
  • Complete reversion of hepatic steatosis in models with prior massive fatty liver.

Reversion of fatty liver by TOTUM-63, in NAFLD models

Clinical results

TOTUM-63 was the subject of a Phase I/II study completed in June 2017. This study validated the safety and tolerance of this active substance from a clinical perspective.

Furthermore, this Phase I/II study  also confirmed significant improvement in insulin sensitivity and significant reduction in blood triglycerides and total cholesterol levels. Insulin resistance and dyslipidemia are known to have a strong link with the development of fatty liver disease.

Mechanism of action

Mechanism of action studies revealed a significant increase in gene expression of Ppar ß/∂ and FXR by TOTUM-63, both key transcription factors of the hepatic energy metabolism. Simultaneously, the active substance TOTUM-63 almost completely inhibited the expression of the protein Fsp27, which regulates lipid storage and is specifically expressed in steatotic livers.

This mechanism of action, which targets the control of the hepatic metabolism, represents a major asset in reducing the risk of NASH.

TOTUM-63 effects on the expression of PPARß/∂, FXR and Fsp27

Phase II clinical development pending

TOTUM-63 will be tested in a Phase II clinical study on the target population, to demonstrate its efficacy in reducing hepatic steatosis (“fatty liver”) in patients at risk of developing NASH. Steatosis and its evolution will be measured by a non-invasive method.

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