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Focal segmental glomerulosclerosis (FSGS) is a cause of glomerular disease that affects both adults and children. FSGS can rapidly progress to end-stage kidney disease. With no approved treatments there is high unmet need for safe and effective therapies.
DMX-200 (repagermanium) is a CCR2 chemokine receptor inhibitor. Activation of the angiotensin II type 1 receptor (AT1R) and CCR2 have been independently implicated in the pathogenesis and progression of FSGS. Both 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 GFR decline. ACTION3 is one of the few large, randomised, placebo-controlled, double-blind, long-duration studies of FSGS patients and on completion will provide a resource for the wider nephrology community on the natural history of FSGS patients and the effects of a CCR2-inhibitor on the background on an ARB. Here we present the baseline data from the first 79 patients enrolled in ACTION3 at 31st October 2023.
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 >25ml/min/1.73m2. The study plans to enrol ~286 patients.
Primary Objectives: Evaluate 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 (IA) will be conducted by an Independent Data Monitoring Committee, following the first 72 patients have completed ~9 months of treatment. If non-futile, adolescent patients aged 12-17 years will be enrolled.
The study is actively recruiting at 71 sites in 11 countries (Table 1). Demographic data of randomised patients is listed in Table 2. Patients are predominantly male (70%), average age of 44.5 yrs and mean eGFR 58.0 ± 27.3 (ml/min/1.73 m2).
DMX-200 (repagermanium) has shown encouraging signs of safety and efficacy in combination with an ARB for the treatment of FSGS. The baseline characteristics of the patients enrolled in ACTION3 are similar to the populations studied in other recent FSGS trials. No clinically significant safety concerns were observed in FSGS patients during 16 weeks of treatment in Phase 2a, or in patients enrolled to date in the ACTION3 Phase 3 study. We look forward to updating the community on the outcome of the futility analysis in due course.