Development of IMYX-3 for the Treatment of Ulcerative Colitis

About This Grant

Abstract Ulcerative colitis (UC) is a chronic, idiopathic inflammatory disease that affects the colon, most commonly afflicting adults aged 30–40 years and resulting in disability. UC is characterized by relapsing and remitting mucosal inflammation, starting in the rectum and extending to proximal segments of the colon. Existing biological treatments have proved effective for some patients, yet up to one third of moderate-severe colitis patients are refractory to these therapies and may require colectomy. Novel biological targets are needed to modulate the dysregulation of the intestinal epithelial cells (IECs) as well as the activated intestinal immune population causing excessive host damage. RAB27A belongs to the RAS superfamily of monomeric G proteins and has been shown to localize to specific cellular compartments to regulate membrane trafficking in numerous cell types. Recent reports have shown its upregulation in UC patient colon samples, both in the intestinal epithelial cells and the surrounding immune population. In mouse models of UC, knock-down of RAB27A has been shown to improve the disease phenotype. RAB27A activity has also been shown critical to the toxic function of certain refractory immune cells including the neutrophil, NK-cells and dendritic cells . Notably, studies have suggested a potential role for neutrophil modulation in improving disease outcome. Both results from UC rodent models and descriptive clinical studies have shown that activated neutrophil toxicity is present and damaging to the colon, indicating that lowering its effect could substantially alleviate disease burden particularly in refractory patients. Nonetheless, currently there are no RAB27A or neutrophil targeting therapeutics in the clinic. To this end, Immunyx Pharma has developed a soluble small molecule RAB27A inhibitor to block the deleterious activities of the protein in ulcerative colitis. Our lead compound, IMYX-3 has already shown efficacy in rodent inflammatory models and has demonstrated positive PK and toxicity results. In this Phase II application, we will define, optimize and validate a treatment regimen and dosing for IMYX-3 in advanced models of mouse ulcerative colitis. Based on these murine validation and dosing studies, we will evaluate specific pharmacokinetic data for the therapeutic window. Next, we will prepare our drug formulation for GMP manufacturing and use this validated batch for our GLP toxicity studies in rodents. These key milestones will form the basis of FDA regulatory filings and prepare IMYX-3 for first in human studies.