15 November 2018 - - French research and development company Valbiotis has expanded the application for Valedia to NASH2prevention, the company said.

This new field of application is based on new results that demonstrate the clinical potential for the reversion of non-alcoholic fatty liver, for NASH prevention.

Studies conducted by the Leiden University (Netherlands), one of Valbiotis' scientific partners, have demonstrated a complete reversion of fatty liver by the active ingredient of Valedia, TOTUM-63, in NAFLD3 in vivomodel, confirmed by histological data.

In parallel, in vivo studies have highlighted a mechanism of action of TOTUM-63 on three key cellular targets of the physiopathology of NAFLDs: the transcription factors Ppar ß/∂ and FXR as well as the Fsp27 protein.

These data suggesting a mechanism of action focused on NAFLDs prevention will be presented at the American Association for the Study of Liver Diseases (AASLD) Conference, being held from November 9-13, 2018 in San Francisco, California.

Based on these results,the company plans to launch Phase II clinical studies in addition to ongoing studies for the risk reduction of type 2 diabetes.

This expanded field of application strengthens Valedia as a precursor product for new prevention strategies in the field of severe metabolic diseases, focused on managing the risk factors for this diseases.

In addition to prediabetes, Valedia could be the first product for subjects with NAFL, the first stage of liver metabolic diseases prior to severe stages such as NASH. It is now estimated that these metabolic disorders affect 25% of the world's population and are expanding rapidly.

New additional results from the Phase I/II clinical study conducted in 2017 on Valedia have also confirmed significant improvement in lipid profile, including a significant reduction in blood triglycerides and total cholesterol levels.

Lipid profile and insulin sensitivity, which improvement by Valedia had already been demonstrated in this first clinical study, are two metabolic components known to have a strong link with the development of fatty liver disease.

Once clinical development is complete in prediabetic subjects, Valedia will be marketed with a health claim related to the risk reduction of type 2 diabetes by 2021.

Beyond this initial label, Valedia may also be recommended by healthcare professionals for subjects with NAFL without prediabetes.

This recommendation could be made based on the first clinical data issued by Valedia studies in steatotic patients.

Obtaining a specific health claim for the reduction of NAFL and the risk reduction of NASH will be targeted in 2023.

This claim will allow to meet the needs of this entire NAFL population, without prediabetes, estimated by the company to be 13.3% of the general population in the USA and 4.5% in Europe.

Phase II clinical development of Valedia for NASH risk reduction will start with a Phase IIA randomized, placebo-controlled study, with planned launch in 2019 in a target population with NAFL. The primary endpoint will be the reduction of hepatic steatosis. The initial steatosis and its evolution will be evaluated by a non-invasive method.

Detailed data for TOTUM-63, the active ingredient of VALEDIA, on non-alcoholic fatty liver

A complete reversion of fatty liver demonstrated in a steatosis model
Within a scientific partnership with Leiden University, a study evaluated the efficacy of TOTUM-63 in an in vivopreclinical model with severe steatotic liver.

During this "reversion" study, the addition of the active ingredient of Valedia restored the liver to a non-steatotic state, within 4 weeks.

The elimination of steatosis was demonstrated by histological analyses and associated with a drastic improvement in insulin sensitivity (HOMA-IR index), back to control level.

A mechanism of action on 3 essential cellular targets for the prevention of hepatic steatosis
In an in vivo model of NAFLD, supplementation with TOTUM-63, the active ingredient of VALEDIA, simultaneously with a high-fat diet for 16 weeks prevented the development of severe hepatic steatosis, observed in non-supplemented models.

Mechanism of action studies revealed a significant increase in gene expression of Ppar ß/∂ (increased by a factor 3) and FXR, both key transcription factors of the hepatic energy metabolism.

Simultaneously, the active ingredient of VALEDIA 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 control of the hepatic metabolism, represents a major asset in reducing the risk of NASH in the early stages of the disease.

In human trials, a significant improvement in two metabolic components strongly linked to the development of NAFLDs.

The Phase I/II clinical study conducted in 2017 on TOTUM-63, the active ingredient of VALEDIA, had already demonstrated improvement in insulin sensitivity.

New results from this initial study show an improvement in the lipid profile, including the significant reduction in blood levels of total cholesterol (-5.5%) and triglycerides (-18.5%) with the first tested dosage (2.5 g/day).

No elevation of blood LDL-cholesterol was observed (-7,3% with 2,5 g/day, p=0,07; -7,4% with 5 g/day, p=0,08), whereas it is an adverse event already encountered for an active ingredient acting on the FXR pathway. Insulin resistance and dyslipidemia are recognized to be strongly associated with the development of NAFL and then NASH.

Worldwide, the prevalence of NAFLD is estimated to be more than 25%4. It affects 50 to 70% of diabetic patients5, 60 to 75% of obese subjects and 50% of dyslipidemic patients6. Correlated to the diabetes and obesity pandemic, the number of subjects with NAFL or NASH is constantly increasing in high-income countries: the projections anticipate a growth of + 21% for NAFL and of + 63% for NASH by 20307.

Valbiotis is a French Research and Development company committed to scientific innovation for preventing and combating metabolic diseases. Its products are made for manufacturers in the agri-food and pharmaceutical industries.

The company particularly focuses on solutions to prevent type 2 diabetes, NASH (nonalcoholic steatohepatitis), obesity and cardiovascular diseases.

Valbiotis was founded in La Rochelle in early 2014 and has formed numerous partnerships with top academic centers in France and abroad, including La Rochelle University, the CNRS and Clermont Auvergne University located in Clermont-Ferrand.

These partnerships have enabled Valbiotis to benefit from strong financial leverage, particularly thanks to experts and technical partners who support its projects. The company has established three sites in France Périgny, La Rochelle and Riom and an American office in Boston.