The concept of neutralizing LPS for therapeutic purposes in gastrointestinal diseases has previously been proposed by Verlyx Pharma, a biotech acquired by Odan Laboratories in 2018. Verlyx had previously developed VLX103, the very first oral formulation of pentamidine. Pentamidine is an old drug originally approved as an antiparasitic drug and subsequently used to treat HIV related P. Carinii opportunistic lung infection. This compound has been shown to efficiently neutralize LPS and prevent its deleterious effects both in vitro and in vivo. VLX103 binds strongly to LPS, even more than Polymyxin B – the reference in LPS sequestration. Preventing LPS to induce TLR4 mediated pro-inflammatory signaling pathways represents a logical therapeutic goal, and an upstream intervention compared to using anticytokines therapies. Moreover, this approach is expected to be safer that inhibiting directly the TLRs, since these cellular surface receptors play a key role in immunological defense, and their complete blockade may lead to significant adverse effects.
As a Proof of Principle, several in vivo animal studies confirmed that pentamidine can prevent the hepatoxic effects of LPS, including improved survival in a sepsis rodent model. VLX103 binds to the LPS molecule through a strong ionic interaction between the negatively charged phosphoryl moieties of the Lipid A portion of LPS and the positively charged diamidine functional groups of pentamidine. These ionic bonds prevent the binding of LPS to the Lipopolysaccharide Binding protein (LBP), which carries endotoxin to the TLR4-CD14 complex.
The unique pharmacokinetic properties and distribution profile of VLX103 have led the company to believe that better and more potent molecules could be synthesized with improved efficacy and safety than VLX103, or different pharmacokinetic properties such as reduced oral bioavailability. In this context, the synthesis of VLX analogs featuring a decreased GI absorption is interesting since higher luminal drug concentrations are therapeutically desirable to treat mucosal conditions such as IBD, CD and celiac disease. Development of modified molecules (analogs) often results in the development of new pharmaceuticals. Research and experimentation to develop new analogs succeeded in elucidating the structure/biological activity interrelationship leading to theoretically improve the LPS binding capacity of the compounds. These analogs have been submitted to in vivo screening, using the gold standard Galactosamine-LPS mouse model. This model is efficient, relevant to human endotoxemia and sepsis, and is more reliable than in vitro LPS binding assessment. So far, several analogs have also been submitted to pharmacological testing, and a few have shown promising results. In light of this scientific evidence, VLX analogs appear to be potentially active in modulating the pathogenic pathways involving LPS in IBD (UC, CD), celiac disease and IBS-D, in particular post-infectious IBS. Consequently, these disease states have been selected for the pharmacological exploration of the VLX compounds.