PO.1.1 Afimetoran, a potent and selective inhibitor of human toll-like receptor 7 (TLR7) and tlr8, provides robust efficacy in a murine lupus model of advanced disease

Abstract

Purpose TLR7 and TLR8 (TLR7/8) are members of the TollLike Receptor family that recognize single strand RNA. Activation of TLR7/8 within immune cells elevates pro-inflammatory cytokines and type I/III interferons and promotes steroid resistance. TLR7/8 have been implicated in the initiation and progression of lupus, a disease associated with defects in the clearance of apoptotic debris which can activate these receptors. However, the effects of TLR7/8 inhibition in advanced lupus remain unclear. Afimetoran (BMS 986256) is a potent, selective, and orally bioavailable inhibitor of TLR7/8 currently in clinical development for immune mediated diseases. Previously, we observed that afimetoran inhibited the production of both interleukin-6 and interferon alpha in a dose-dependent manner in mice challenged with a TLR7 agonist. In this study, we examined the therapeutic efficacy of afimetoran in a murine model of advanced lupus. Methods NZB/W mice with advanced lupus (proteinuria > 100 mg/dL) were treated orally, once daily, with vehicle or afimetoran and/or prednisolone. The effects of treatment on survival, proteinuria, kidney histology, glomerular IgG deposition, cytokine-secreting cells, and circulating cytokines were measured. Results Afimetoran treatment resulted in near complete (92%) survival in the advanced lupus model, reaching 100% when combined with low-dose prednisolone; survival was 47% in mice treated with vehicle only (Table 1). In the advanced lupus model, afimetoran treatment reversed kidney tissue damage and proteinuria in all surviving animals. In contrast, treatment with low-dose prednisolone alone did not show significant modulation of proteinuria. Treatment with afimetoran reversed both the number of IgG-positive glomeruli and the amount of glomerular IgG deposition, and also reduced cytokine secreting cells and secreted cytokines to a greater extent than low-dose prednisolone alone. Conclusions Afimetoran displayed robust efficacy in a murine model of advanced lupus. Treatment with afimetoran led to improved survival, reversal of proteinuria and glomerular IgG deposition, suppression of kidney injury markers, and reductions in the proportion of cytokine-secreting cells and circulating cytokine levels. These results indicate that afimetoran, now being investigated in a phase 2 clinical trial (NCT04895696), may offer a novel therapeutic approach to the treatment of lupus.