The original VLX103 compound has been submitted to numerous preclinical evaluations, including the Gold Standard Galactosamine-LPS mouse test, which assesses the LPS binding capacity and subsequent anti-inflammatory properties of the drug. Since this drug’s primary indication was the treatment of liver diseases, well validated models of hepatic disorders have also been used. Positive findings were obtained from the High Fat NAFLD as well as the NIAAA Alcoholic Hepatitis mouse models. Strong anti-steatosis, anti-inflammatory and antifibrotic effects were reported. Moreover, VLX103 was studied in various animal toxicology models, including acute and subchronic toxicology studies in the rat and the dog. A complete pharmacokinetic profile was also established in vivo in these species.

A pre-selection of promising VLX analogs was based on Galactosamine-LPS and CaCo-2 cells permeation studies. Analogs which are less absorbed throughout the GI mucosa are interesting since they can theoretically exert stronger mucosal anti-inflammatory and immunomodulating effects while limiting systemic exposure. Such a profile could provide a better clinical safety profile in patients, while preserving an optimized therapeutic activity. In this context, VLX analogs are proposed in the preclinical development program: ZCS105 and ZCS108. These compounds, despite a higher molecular weight than VLX103, are still small molecules. In order to select the most promising compound, a series of in vivo pharmacological experiments will be carried out, starting with a comparative LPS binding/anti-inflammatory profile in vitro study using CaCo-2 and human colonic epithelial cells. Subsequently, the analogs will be studied in vivo in well-designed pharmacological studies using murine models of ulcerative colitis (oxazolone or DSS induced colitis mouse models), celiac disease (DQ8-DQ2 transgenic mouse/dysbiosis or human colonic dysbiotic flora transplanted in mice) and IBS-D (water avoidance stress induced mouse IBS model). The most effective analog will then be subjected to a comprehensive, IND enabling toxicology program that will include acute and subchronic studies in the rat, as well as a full safety pharmacology panel, in vitro mutagenicity testing and complete ADME profile. The data obtained from all these studies will allow Odan to plan a human Phase I clinical research program. In a parallel fashion, scale-up of the analogs synthesis process as well as oral dosage form development and analytical method development will be undertaken according to cGMP standards.