#2961 DMX-200 does not induce a haemodynamic effect or an acute change in GFR and has a strong cardiovascular safety profile

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. Change in estimated glomerular filtration rate (eGFR slope) has been used as a key measure of treatment efficacy in clinical studies. However, when using eGFR as surrogate endpoint for kidney failure, treatments that exert haemodynamic effects or have an acute eGFR reductions complicate the estimation of long-term benefit. Therefore, it is important to establish if new interventions influence blood pressure and exert acute reductions in eGFR. DMX-200 (repagermanium) is a CCR2 pathway inhibitor that is currently in a Phase 3 pivotal trial (ACTION3, NCT05183646) in patients with biopsy-proven FSGS concomitantly receiving maximal tolerated angiotensin receptor blocker (ARB). Mechanistically, the inhibition of CCR2 is not anticipated to reduce blood pressure nor have an acute effect on GFR. The aim of this investigation was to establish whether DMX-200 has an acute effect on haemodynamics or eGFR. Method A post-hoc review of haemodynamic, eGFR and cardiovascular safety parameters was performed using data from two double blind cross over clinical studies NCT03627715 and NCT03649152 (ACTION2). In these studies, patients with FSGS (n = 8) or DKD (n = 45) that were receiving a stable dose of irbesartan 300mg were administrated DMX-200 (120 mg BID) or placebo for up to 12- or 16-weeks respectively. Results Administration of DMX-200 (120 mg BID) for up to 16-weeks had no noticeable effect on systolic blood pressure compared to placebo (mean change from baseline; Δ0.1 ± 12.4 mmHg versus Δ3.7 ± 10.8 mmHg respectively, n = 8). Similarly, no acute effect on eGFR has observed following administration of DMX-200 (120 mg BID) with a mean change from baseline eGFR; Δ3.9 ± 10.0 mL/min/1.73 m2, Δ2.1 ± 8.0 mL/min/1.73 m2 and Δ0.6 ± 6.2 mL/min/1.73 m2 at 1, 8 and 16-weeks respectively, n = 8). Creatine levels were also comparable following administration of DMX-200 or placebo for up to 16-weeks (mean change from baseline; Δ2.1 ± 16.3 µmol/L versus Δ−1.9 ± 19.2 µmol/L respectively, n = 8). Comparable results for blood pressure, eGFR and creatinine were observed in patients with DKD administered DMX-200 (120 mg BID) for up to 12-weeks. Confirming the cardiac safety of DMX-200, there were no significant effects on QT/QTc following administration of DMX-200 or placebo and adverse events reflected of the underlying disease and associated comorbidities. Conclusion DMX-200 is a CCR2 pathway inhibitor currently in a Phase 3 pivotal trial (ACTION3, NCT05183646) in adult patients with biopsy-proven FSGS. As anticipated, data from post-hoc analysis of Phase 2 studies indicate that DMX-200 does not induce a haemodynamic effect or acute change in eGFR. Notably, DMX-200 has a strong cardiovascular safety profile. These data support the design of ACTION3 where patients receive a stable maximally tolerated dose of an angiotensin receptor blocker prior to randomization.