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) regulates the positioning and migration of B cells, CD4+ T cells, and Dendritic cells in the lymphoid organs, thereby Influencing antibody responses and immune homeostasis. In multiple autoimmune diseases, EBI2 acts as a "navigation system," Elevated levels of the ligand 7α,25-OHC are produced in affected tissues such as the glomeruli of LN patients and the intestinal mucosa of IBD patients. This activates GPR183, leading to the recruitment of B cells, T cells, and dendritic cells to inflammatory sites, thereby exacerbating the inflammatory response. IPG11406 blocks the recruitment and activation of inflammatory cells, alleviates inflammation, reduces tissue damage, and reverses abnormal gene expression. IPG11406 demonstrates potential for achieving functional cure in autoimmune diseases.

Key Differentiation

1. IPG11406 is a first-in-class GPR183 antagonist: Instead of radical B cell depleting, it targets immune-cell trafficking and inflammatory amplification, selectively modulating pathogenic immune populations (including B cells, T cells, dendritic cells, and monocyte/macrophages) to achieve deep inflammatory remission with better safety, supporting early-line positioning in SLE/LN.

2. Globally ready clinical package: China Phase 1b/2a (2a ongoing) in SLE with LN, with 15 patients’ data available, topline expected in July 2026; China Phase 2 initiated in IBD; FDA INDs in place for LN and Crohn's disease to support U.S. development.

3. Rapid onset with strong early efficacy: Proteinuria reduction was observed as early as 2 weeks. By Day 15, 40% (6/15, 3 CRR + 3 PRR) achieved renal remission. Within 2 months, responses deepened to 53.3% (8/15) overall renal remission, including 40% (6/15) CRR.

4. Convenience of use and better safety than existing therapies: Easy for long-term oral administration, without CRS, severe infections or hematologic toxicity observed in TCE/CAR-T therapies

5. Strong Potential for Indication Expansion: IPG11406 has demonstrated across multiple in vivo disease models, and established robust evidence among the indications: MS, RA, IBD, SLE et, al.

6. Favorable Safety Profile: Pre-clinical and clinical results indicate IPG11406 is safe and well-tolerated (a therapeutic window exceeding 150-fold the effective dose).

Clinical Trials Summary

■ Phase 1b/2a (2a Ongoing): 

1. Strong Response Rate: In the Ph2a study, 80% patients showed substantial reductions in 24-hour proteinuria (12 out of 15), while renal response could be as quick as two weeks. In contrast, 3-6 months are required to show measurable effects in current mAbs (anti-CD20 and anti-BAFF mAbs).

2. Remarkable Proteinuria Decline: In the Ph2a study, 40% of patients attained a complete renal response (CRR) within the 2-month period. The overall renal remission rate was 53.3%. Additionally, 66.7% of patients demonstrated a greater than 30% reduction in proteinuria in the same timeframe.

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

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

Current Status

1. Phase 2 PoC Study: Both Phase 2a study in Lupus Nephritis and Phase 2 study in IBD are ongoing.

2. The Phase 1 clinical trial in healthy subjects has been completed, showed the safe and well-tolerated profile in all SAD and MAD cohorts (no above grade 2 AE), with a relatively linear relationship between dose and exposure observed.

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.