#2953 DMX-200 is effective in reducing urine monocyte chemoattractant protein 1 (MCP-1) levels in patients with FSGS without affecting plasma MCP-1 concentration

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a major cause of glomerular disease that affects both adults and children and can rapidly progress to end-stage kidney disease. Lack of safe and effective treatment represents a significant unmet need for patients with FSGS. Activation of the angiotensin II type 1 receptor (AT1R) and the C-C motif chemokine receptor 2 (CCR2) have been independently implicated in the pathogenesis and progression of FSGS. High urine MCP-1 levels (the key endogenous ligand for CCR2) are associated with FSGS disease progression, and AT1R blockade is an existing supportive therapy for glomerular disease including FSGS. In addition, the AT1R and CCR2 receptors form a functional complex so inhibition of both receptors may provide an efficient and novel approach to FSGS treatment. Several CCR2 inhibitors have previously entered clinical development. However, none have yet been approved. Notably, chemokine receptor tolerance has been observed for many CCR2 inhibitors, which may in part be driven by inhibitor mediated increases in plasma MCP-1 that directly counteracts CCR2 blockade. Indeed, studies of other CCR2 antagonists in diabetic kidney disease have observed a negative correlation between the change in urinary albuminuria and plasma MCP-1 levels. DMX-200 (repagermanium) is a CCR2 pathway inhibitor currently in a Phase 3 pivotal trial (ACTION3, NCT05183646) in patients with FSGS concomitantly receiving maximal tolerated angiotensin receptor blocker (ARB). In vivo co-administration of DMX-200 and the ARB irbesartan demonstrated a synergistic reduction in proteinuria, macrophage infiltration, and podocyte loss compared with vehicle or antagonist alone. A subsequent Phase 2a cross-over study (NCT03649152) in n = 8 patients with biopsy-proven primary FSGS showed that the combination of DMX-200 and irbesartan was well tolerated with most patients experiencing a reduction in proteinuria (compared to placebo). However, the effect of DMX-200 on plasma MCP-1 levels has not been established. The aim of this study was therefore to investigate the effect of DMX-200 on urine and plasma MCP-1 levels in a post-hoc analysis. Method Urine from male Sprague-Dawley rats administered vehicle or DMX-200 and irbesartan was collected 12-weeks post subtotal nephrectomy and MCP-1 measured using rat MCP-1 ELISA. As part of ACTION2 (NCT03649152) urine and plasma samples were collected from patients following treatment with placebo or DMX-200 (120 mg BID) for 16-weeks. Samples were analyzed using a V-PLEX human MCP-1 immunoassay. Results In rats, administration of DMX-200 (30 mg/kg/day) and irbesartan (10 mg/kg/day) for 12-weeks reduced the urine MCP-1 concentration following subtotal nephrectomy compared to vehicle (P < 0.01, 2881 ± 162 pg/ml versus 4929 ± 631 pg/ml respectively). In patients with FSGS, the mean change from baseline urine MCP-1 following 16-weeks of treatment with DMX-200 (120 mg BID, and a maximally tolerated dose of irbesartan) was 0.85 (n = 8, 95% CI; 0.62 to 1.07) compared to 1.23 (n = 8, 95% CI; 0.81 to 1.63) for placebo. This corresponded to a between group difference of 37% (geometric mean 0.63 (95% CI; 0.07 to 1.18). In contrast, administration of DMX-200 (120 mg BID) and a maximally tolerated dose of irbesartan had no effect on plasma MCP-1 levels compared to placebo. Conclusion DMX-200 is a CCR2 pathway inhibitor currently in a Phase 3 pivotal trial (ACTION3, NCT05183646) in patients with biopsy-proven FSGS. Data from pre-clinical studies and post-hoc analysis of Phase2 measures suggest DMX-200 can reduce urine MCP-1 levels without increasing plasma MCP-1 (with corresponding reductions in proteinuria). This profile may be beneficial for the treatment effect of DMX-200 and supports its use in patients with FSGS. The effect of long-term administration of DMX-200 on urine and plasma MCP-1 will be analyzed as an exploratory endpoint in the ongoing ACTION3 trial.