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: of the first nine patients enrolled, seven showed substantial reductions in 24-hour proteinuria, with one patient achieving a complete renal remission.

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 across 17 clinical sites in China, with plans to expand to over 40 sites. The company 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.