Summary

IPG11406 is a pioneering, first-in-class, orally administered EBI2 antagonist poised to revolutionize the treatment of autoimmune diseases. Unlike current standards of care, such as corticosteroids and TNF-α inhibitors, which are limited to symptomatic management, IPG11406 targets the underlying pathogenesis of the disease. It is designed to eradicate pathological immune cells, leading to a complete resolution of inflammation. 

With its novel mechanism, its position as the only EBI2-targeting therapy in clinical development globally, and the rapid, profound efficacy demonstrated in early clinical studies, IPG11406 is positioned to become a cornerstone disease-modifying therapy for autoimmune conditions.

Mechanism of Action

EBI2 (also known as GPR183) is a receptor that is overexpressed on a range of key pathological immune cells, including B cells, T cells, and macrophages. In multiple autoimmune diseases, EBI2 acts as a "navigation system," directing these immune cells to migrate into target tissues, thereby initiating and exacerbating inflammation and damage.

As a potent small-molecule antagonist, IPG11406 is specifically designed to block the EBI2-mediated signaling pathway. By inhibiting this pathway, IPG11406 effectively prevents the migration and proliferation of pathological immune cells. This action clears inflammatory cells from lesions, reduces the expression of pro-inflammatory cytokines, and ultimately attenuates disease progression by addressing the root cause of immune dysregulation.

Key Differentiation

■ First-in-Class Target: IPG11406 is the only EBI2 antagonist to have entered the clinical trial stage worldwide, giving it a substantial first-mover advantage.

■ Disease-Modifying Potential: By targeting the etiology of autoimmune diseases rather than just symptoms, IPG11406 has the potential to deliver long-term, treatment-free remission and reduce relapse rates.

■ Oral Convenience: As a small-molecule drug, IPG11406 offers the convenience of oral administration, significantly improving patient compliance and accessibility compared to injectable biologics, while also potentially lowering treatment costs.

■ Rapid Onset of Action: Preliminary clinical data in lupus nephritis (LN) patients show substantial improvements as early as two weeks. Notably, after just 28 days of treatment, proteinuria levels declined by up to 73.6% from baseline—a stark contrast to competing therapies that may require months to show a measurable effect.

■ Favorable Safety Profile: Pre-clinical and early clinical data indicate that IPG11406 is well-tolerated, with a therapeutic window exceeding 150-fold the effective dose, distinguishing it from conventional immunosuppressants with narrow safety margins.

Clinical Trials Summary

■ Phase 1 (Completed): A randomized, double-blind, placebo-controlled study in healthy adult participants in China was successfully completed in March 2025. The trial confirmed the safety and tolerability of orally administered IPG11406 and established a favorable pharmacokinetic (PK) profile supporting once or twice-daily dosing.

■ Phase 1b/2a (Ongoing): A multi-center, multiple-dose clinical trial in patients with lupus nephritis was initiated in China in December 2024. Preliminary results to date have been highly encouraging: After just 28 days of treatment, proteinuria levels declined by up to 73.6% from baseline—a stark contrast to competing therapies that may require months to show a measurable effect.

IPG11406 Ph2a: 24-hour proteinuria in lupus nephritis patients showed a significant reduction from baseline after treatment

Current Status

The Phase 1b/2a clinical trial for IPG11406 in lupus nephritis is actively progressing in China. We anticipates completing this trial by the end of 2025 and subsequently advancing to a pivotal Phase 2b study. Furthermore, a Phase 2a clinical trial in ulcerative colitis (UC) is planned to be initiated by the end of 2025, broadening the potential indications for IPG11406.

In vivo Properties

In comprehensive pre-clinical studies, IPG11406 has demonstrated robust, dose-dependent therapeutic efficacy across a range of validated animal models for major autoimmune diseases:

• Systemic Lupus Erythematosus/Lupus Nephritis (SLE/LN): In the MRL/lpr mouse model, IPG11406 treatment resulted in a significant and dose-dependent reduction in proteinuria, a key marker of kidney damage. It also markedly decreased inflammatory cell infiltration in the kidney, leading to a significant amelioration of glomerular and tubulointerstitial damage.

• Inflammatory Bowel Disease (IBD): In the Il10 knockout mouse model, IPG11406 produced a dose-dependent reduction in inflammatory cell infiltration in the colon and a significant improvement in the overall colonic architecture, demonstrating its potential to control gut inflammation.

The changes in histological pathogenesis and inflammatory cell infiltration of the kidney in MRL/lpr mice.              Effects of IPG11406 on histopathological score of colon tissue in mice. (A) Inflammatory cell infiltration; (B) Histopathology score.

• Multiple Sclerosis (MS): In the experimental autoimmune encephalomyelitis (EAE) mouse model, IPG11406 treatment exhibited a delayed onset of disease and a dose-dependent decrease in clinical scores, indicating significant amelioration of MS-like pathologies.

• Rheumatoid Arthritis (RA): In the collagen-induced arthritis (CIA) mouse model, IPG11406-treated mice exhibited a clear, dose-dependent decrease in the clinical arthritis score and paw thickness compared to the vehicle control group.

Clinical score of EAE mice for the treatment of IPG11406.                                                                                                                       collagen-induced arthritis (CIA) mouse model

IPG11406 dose dependently reduced clinical score in the murine EAE model.

Publications

• Xi J, Gong H, Li Z, Li Y, Wu Y, Zhang Y, Wang JF, Fan GH. Discovery of a First-in-Class GPR183 Antagonist for the Potential Treatment of Rheumatoid Arthritis. J Med Chem. 2023 Dec 14;66(23):15926-15943. doi: 10.1021/acs.jmedchem.3c01364. Epub 2023 Dec 4. PMID: 38047891.