#1166 ACTION3 pivotal Phase 3 & open-label extension study assessing DMX-200 in adult & paediatric patients with focal segmental glomerulosclerosis (FSGS)

Abstract

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a major cause of glomerular disease that affects both adults and children. FSGS can rapidly progress to end-stage kidney disease. Lack of safe and effective treatment represents a significant unmet need for patients with FSGS. Development of treatments has been hampered by complexities including the rare nature of the disease, varying drivers of pathogenesis, and the evolving diagnostic and clinical trial designs, necessitating innovative research approaches. DMX-200 (repagermanium) is a C-C motif chemokine receptor 2 (CCR2) pathway inhibitor. Activation of the angiotensin II type 1 receptor (AT1R) and CCR2 have been independently implicated in the pathogenesis and progression of FSGS. These receptors form a functional complex so inhibition of both receptors may provide an efficient approach to FSGS treatment. In vivo data shows co-administration of DMX-200 and the angiotensin receptor blocker (ARB) irbesartan demonstrated a synergistic reduction in proteinuria, macrophage infiltration, and podocyte loss compared with vehicle or either 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 (compared to placebo) was well tolerated with most patients experiencing a reduction in proteinuria. Based on these data, the global Phase 3 study (ACTION3) was initiated to confirm the proteinuria lowering effects of DMX-200 and assess effects on eGFR decline. ACTION3 is a randomised, placebo-controlled, double-blind, long-duration study of FSGS patients and on completion will provide a resource for the wider nephrology community and advocacy groups on the natural history of FSGS patients and the effects of a CCR2-inhibitor on the background of an ARB. Here we present the baseline data from the first 90 patients enrolled in ACTION3 at 12th January 2024. Method The ACTION3 (NCT05183646) study is a pivotal Phase 3, multicentre study of the efficacy and safety of DMX-200, 120 mg twice daily compared with placebo in adult patients with biopsy-proven FSGS receiving maximal tolerated ARB, with persistent proteinuria >1.5g/ day and eGFR >25 ml/min/1.73 m2. The study plans to enroll approximately 286 patients with primary FSGS, genetic FSGS and FSGS of undetermined cause with the primary objective of evaluating the efficacy of DMX-200 in percent change in 24-hour urine PCR and eGFR slope. The initial 104-week randomized period will be extended in a 2-year open label extension study. A futility analysis by an Independent Data Monitoring Committee following the first 72 patients completing 35 weeks of treatment confirm that continuation of the study is non-futile. Results The study is actively recruiting at 71 sites in 11 countries listed in Table 1. Demographic data of randomised patients is listed in Table 2. Patients are predominantly male (65%), with an average age of 46.6 yrs. and mean eGFR 56.3 ± 27.6 (ml/min/1.73 m2). The study is expanding recruitment into additional countries in the Asia Pacific, Europe, and Latin American regions. Further, the study protocol has sought and received regulatory approval to enroll adolescent patients aged 12-18 in Argentina, Mexico, UK and the US. Conclusion DMX-200 (repagermanium) has shown encouraging signs of safety and efficacy in combination with an ARB for the treatment of FSGS. The contributing countries and baseline characteristics of the patients enrolled in ACTION3 are similar to the populations studied in other recent FSGS trials. No clinically significant safety concerns have been observed in patients enrolled to date in the ACTION3 Phase 3 study.