Background/Purpose: Efzofitimod, a novel immunomodulator, has shown clinical proof-of-concept in a Phase 1b/2a clinical trial in patients with pulmonary sarcoidosis and is currently enrolling a global Phase 3 clinical trial. By selectively binding to its target neuropilin-2 (NRP2), a membrane protein that is strongly upregulated on myeloid cells during inflammation, efzofitimod reduces inflammation and fibrosis in a range of animal models of interstitial lung disease (ILD). NRP2 appears to also play a role in other inflammatory diseases such as arthritis ¹. In this work, we confirm that connection utilizing a genetic NRP2 knock-out (KO) mouse model. Based on efzofitimod’s anti-inflammatory effects and NRP2’s role in the pathology of arthritis, we tested its therapeutic potential in experimental models of rheumatoid arthritis.

Methods: The collagen-induced arthritis (CIA) model was performed in NRP2 WT and KO animals utilizing the Hooke Kit™ for CIA induction. Efzofitimod was dosed at 1 mg/kg weekly intravenously upon emergence of clinical signs. Study animals were scored every other day until termination. Terminal serum samples were analyzed for pro-inflammatory cytokines. To test the effect of efzofitimod in rheumatoid arthritis-associated ILD (RA-ILD), we utilized the SKG mouse model of RA-ILD. The disease was induced via IP injection of 5 mg of zymosan. Efzofitimod was dosed at 3 mg/kg weekly intravenously starting one day prior to disease induction. At termination, lung single cell suspensions were immunophenotyped and lung sections were analyzed for fibrosis.

Results: NRP2 KO animals exhibited heightened sensitivity to disease induction in the CIA model, resulting in excessive mortality. Analysis of serum samples from these animals demonstrated elevated levels of pro-inflammatory cytokines, indicating a deficiency in the negative regulation of the immune response. Based on the impaired immune regulation observed in NRP2 KO animals, we hypothesized that efzofitimod may produce therapeutic benefit in the CIA model via modulation of NRP2. Encouragingly, we observed improved clinical scores in 37.5% of the study animals treated with efzofitimod, compared to only 12.5% in the control group. Additionally, efzofitimod displayed activity in the SKG model of RA-ILD. Treatment with efzofitimod led to a reduction in the number of immune cell populations in the lungs and exhibited a noteworthy reduction in RA-induced lung fibrosis.

Conclusion: The data presented here indicate a critical role for NRP2 in modulating immune responses in autoimmune diseases, such as rheumatoid arthritis and RA-ILD. By targeting NRP2 with efzofitimod, we observed improved disease outcomes, reduced inflammation, and mitigated lung fibrosis, suggesting the potential of efzofitimod as a therapeutic intervention for rheumatoid arthritis and potentially other immune mediated diseases.

1. Fassold, A. et al. Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis. Arthritis Rheum. 60, 2892–2901 (2009).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efzofitimod-a-first-in-class-nrp2-targeting-immunomodulator-ameliorates-rheumatoid-arthritis-and-associated-lung-fibrosis-in-preclinical-models/