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Physiogenex innovates to provide key decisions in preclinical drug development

Science and research biology chemistry and medicine young people couple in bright modern labThe failures of drugs targeting metabolic diseases in late clinical development, highlights the difficulty of predicting the benefit/risk ratio for a given novel drug.Classical biomarkers and genetic models are insufficient to predict drug efficacy and side-effects.

Physiogenex has therefore developed a large panel of predictive diet-induced animal models merging diabetes, dyslipidemia and related complications (e.g. cardiovascular). We are convinced that the nutritional approach remains the best way of obtaining an integrated and clinically relevant pathophysiological picture.

These nutritional animal models are used to perform sensitive radioactive tracer kinetic experiments to better predict clinical efficacy and safety. This unique approach provides kinetic and mechanistic data which are more informative and more sensitive than those obtained with classical plasma biochemistry.

Our current R&D programs are focused on developing new in vivo kinetic methods as well as complementary animal models for selecting, optimizing and prioritizing novel drugs targeting metabolic diseases.

Program 1: Development of predictive animal models and in vivo techniques for the study of NASH, cirrhosis and hepatocarcinoma

Obese/type 2 diabetic patients are prone to liver complications such as non alcoholic steato-hepatitis (NASH) that can lead to severe diseases such as cirrhosis and hepatocarcinoma.

Animal models currently available are based on surgical procedure (bile duct ligation), diet modification (methionine- or choline-deficient diets) or the use of chemical products (e.g. CCl4, DEN) to induce liver fibrosis, cirrhosis and hepatocarcinoma.
However, these animal models are not obese and insulin resistant and are prone to irreversible severe liver lesions. This represents a major limitation for translating preclinical data to the clinical setting.

Therefore, Physiogenex is actively working on the development of diet-induced animal models that develops obesity, insulin resistance and liver complications.
In this way, Physiogenex is taking part of the HEPATOTOX project supported by the Region Midi-Pyrénées.

The project is led by Dr. Hervé Guillou, who has an in-depth expertise in hepatic metabolism and nutrition (INRA). Another research team dedicated to the role of gut microbiota in metabolic diseases is also improved in this project and is represented by Pr Rémy Burcelin (Institute of Metabolic and Cardiovascular Disease, I2MC).

The project not only aims at developing novel models of liver complications (NASH/liver fibrosis) but also at identifying novel biomarkers of liver diseases progression.

Although this research program is still in progress, recent studies have been already presented in scientific meetings and validated models are already provided by Physiogenex.

For on-going models development, please send your request to our experts.

Program 2: Development of a predictive animal model of chronic kidney diseases associated with type 2 diabetes

Type 2 diabetes and hypertension are risk factor for chronic kidney diseases (CKD) and end-stage renal disease (ESRD).
This worldwide health concern requires translatable animal models of diabetic nephropathy to develop novel therapies reducing morbidity/mortality associated with type 2 diabetes-related kidney disease.

In collaboration with experts in chronic kidney diseases, Physiogenex is currently developing a rat model of type 2 diabetes-related kidney complication (e.g. kidney failure and fibrosis).

For more information about this program, please contact our experts.

Program 3: Non invasive imaging of the atherosclerotic plaque in a mouse model with a human-like lipoprotein profile

Although actively used for atherosclerosis studies, mice differ substantially from human regarding lipoprotein cholesterol metabolism.

The use of transgenic mouse models, such as human CETP transgenic mice, represents a valuable strategy to develop therapies targeting atherosclerosis in animal models with a human-like lipoprotein profile.

Physiogenex is currently performing atherosclerosis studies using the human CETP-apoB100 transgenic mouse model, which has been shown to be relevant for evaluating drugs affecting both dyslipidemia and type 2 diabetes (Briand F et al. Diabetes Obes Metab. 2012 Jul;14(7):662-5 and  Briand F et al. Clin Transl Sci. 2011 Dec;4(6): 414-420).

Beside routine histology analysis, Physiogenex is collaborating with the GAIA imaging platform to measure atherosclerotic plaque development with noninvasive in vivo imaging technique, which can be used in both animals and humans, for better translating preclinical data to the clinics.

For more information about this program, please contact our experts.

Program 4: Implication of lipolysis in the development of insulin resistance which leads to metabolic and cardiovascular complications of obesity

Union EuropéennePhysiogenex is taking part in OBELIP R&D project.

This program deals with working on a new therapeutic strategy for complications of obesity: the inhibition of fat cell lipolysis.
The project aims at characterizing the mechanisms linking the inhibition of lipolysis to the improvement of insulin sensitivity and at evaluating antilipolytic drugs.

The project is led by Pr Langin’s team (Institute of Metabolic and Cardiovascular Disease, I2MC). Another research team (INRA) dedicated to hepatic metabolism and nutrition is involved in this project and is represented by Dr Guillou.

Examples of other R&D collaborations:

  • Joseph Fourier University, Grenoble (France): Development of non invasive imaging techniques with GAIA nuclear imaging platform.
  • European FP7 ADAPT, coordinated by Dr. Jürgen Eckel, German Diabetes Center : Adipokines as Drug Targets to Combat Adverse Effects of Excess Adipose Tissue.