Summary

Epstein-Barr virus （EBV） infection is an important environmental factor for the development of autoimmune diseases. The gene encoding for EBV-induced gene 2 (EBI2), also named as GPR183, is a risk gene for multiple autoimmune diseases. Single nucleotide polymorphisms (SNPs) of this GPCR have shown to be associated with several inflammatory and autoimmune diseases. Both EBV infection for SNP cause aberrant up-regulation of EBI2 on B cells, CD4+ T cells, dendritic cells, and monocytes/macrophages. Together with the increased levels of its oxysterol ligand 7α,25-dihydroxycholesterol in the lesion, EBI2 mediates differentiation and migration of the immune cells to the inflammatory loci, thereby causing long-lasting inflammation and tissue damage. IPG11406, a highly potent small molecule antagonist of the EBI2, effectively suppresses EBI2-mediated activation and chemotaxis of inflammatory cells, resulting in complete inflammation resolution. IND has been approved by both US FDA and China CDE for systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA), and Phase I clinical trial has been successfully completed, showing excellent safety and PK profiles. A Phase IIa trial is ongoing to explore biomarkers and assess preliminary efficacy in patients with SLE/LN. 

Mechanism of Action

■Viral infections or SNPs lead to elevated expression of EBI2 on aberrantly activated immune cells, including dendritic cells, macrophages, T cells, and B cells. 

■The oxysterol ligand of EBI2, 7α,25-dihydroxycholesterol, is overproduced by inflammatory cells in the lesion sites, mediating the chemotaxis of EBI2-expressing immune cells to the inflammatory sites.  

■IPG11406 potently blocks the EBI2-mediated differentiation and chemotaxis of inflammatory cells, including B cells, T cells, monocytes/macrophages, and dendritic cells, resulting in complete inflammation resolution. 

Key Differentiation

■IPG11406 effectively eradicates inflammatory cells in the lesion, leading to complete inflammation resolution, whereas the current mainstream therapies, such antibodies against TNFa, IL-17, and IL-23, relieve symptoms without modifying the disease.

■IPG11406 differentiates itself from the JAK inhibitors by its excellent safety profile. 

In vivo Properties

IPG11406 markedly eradicates inflammatory cells in the lesion of several autoimmune disease models, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease, resulting in complete inflammation resolution and reversal of autoimmunity. 

1. Efficacy of IPG11406 in IBD mouse model

■IPG11406 treatment resulted in dose-dependent reversal of the up-regulated Th1 cells, macrophages and dendritic cells in the colon tissues.  

■IPG11406 treatment resulted in dose-dependent reversal of the up-regulated inflammatory cytokines in the colon tissues.  

■IPG11406 treatment resulted in a reversal of the aberrantly up-regulated genes in the colon tissues.

2. Efficacy of IPG11406 in SLE mouse model

■IPG11406 treatment of spontaneous lupus nephritis mouse model (MRL/Lpr) resulted in a dose-dependent normalization of proteinuria.

■IPG11406 treatment of spontaneous lupus nephritis mouse model (MRL/Lpr) resulted in the eradication of activated macrophages in the kidney.

■IPG11406 treatment of spontaneous lupus nephritis mouse model (MRL/Lpr) resulted in reversal of the aberrant up-regulation of CH25H and CYP7b1, the rate-limiting enzymes for the generation of 7α,25-dihydroxycholesterol，and inflammatory cytokines, in the kidney.

■IPG11406 treatment of spontaneous lupus nephritis mouse model (MRL/Lpr) resulted in reversal of the aberrant up-regulation of gene expression in the kidney.

Clinical trials

■Phase I clinical trial in health volunteers has been completed, and it was demonstrated that IPG11406 is safe, well-tolerated, and exhibits a linear dose-exposure relationship with no evident drug accumulation.

■Phase IIa trial is ongoing to explore biomarkers and assess the preliminary efficacy of IPG11406 in patients with SLE/LN.