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

Clinical results

In the Phase IIA clinical trial, in prediabetic subjects, TOTUM-63 significantly reduced hepatic steatosis and blood triglyceride levels versus placebo. All subjects included in this study had an elevated level of blood triglycerides and an elevated Fatty Liver Index, above the threshold of 60 which predicts steatosis with a high probability. TOTUM-63 reduced, versus placebo:

  • Blood triglyceride level of 32.2%;
  • Fatty Liver Index by 18.7%.

These additional results constitute a proof of concept for the reduction of hepatic steatosis in humans. Details of this Phase IIA study are available in the Company’s corporate presentation.

Safety and tolerance

The safety and perfect tolerance of TOTUM-63 were validated by a Phase I / II clinical study in healthy volunteers and confirmed by the Phase IIA study in prediabetic subjects. The results of the Phase I / II study were selected by the Congress of the American Diabetes Association in June 2017.

A Phase IIB clinical development to come

TOTUM-63 will be the subject of a first phase IIB1 specific clinical study to demonstrate its efficacy in subjects with non-alcoholic hepatic steatosis. The initial steatosis and its evolution will be evaluated by non-invasive methods.

Hepatic 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 Par ß/∂, FXR and Fsp27

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

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