#4321 ACTION3 PHASE 3 STUDY: EVALUATING A NOVEL THERAPEUTIC STRATEGY OF A CCR2 INHIBITOR (DMX-200) WITH ANGIOTENSIN RECEPTOR BLOCKADE IN FSGS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. Complications include nephrotic syndrome progressive kidney failure. FSGS condition with high unmet need there no approved treatment. The angiotensin II receptor type 1 (AT1R) chemokine 2 (CCR2) are G protein coupled receptors that form functional heteromers. Simultaneous antagonism these suggested synergistic renoprotective effects in preclinical early phase clinical studies proteinuric disease. DMX-200 (repagermanium) C-C inhibitor that, when administered concurrently an blocker (ARB), designed to inhibit recruitment monocytes implicated the inflammatory environment chronic In Phase 2a open-label study 27 patients disease, 25% achieved > 50% reduction uPCR combined use irbesartan. A placebo-controlled cross-over 8 primary receiving stable dose irbesartan demonstrated evidence promising efficacy clinically relevant 17% compared placebo. These encouraging data suggest treatment may result meaningful proteinuria added ARB glomerular diseases such as FSGS. Proteinuria positive prognostic sign for preserving function. observations from earlier trials have led initiation international randomised double-blind, 3 trial (ACTION3) further evaluate ARB. Method Eligible adults (18-80 years) biopsy-proven FSGS, genetic or undetermined cause (FSGS-UC), >1.5g/g based on 24hr urine collection eGFR ≥25 ml/min/1.73 m2. Blood pressure ≤160/100 mmHg BMI ≤40kg/m2. Patients secondary those treated strong immunomodulatory agents (other than corticosteroids) excluded. All required receive concomitant at least maximum according product label. ACE-inhibitors switch Other background therapies SGLT-2 inhibitors mineralocorticoid antagonists permitted if months prior screening. randomized 1:1 ratio (120 mg twice daily) objective PCR after 35 weeks slope 104 Secondary objectives safety tolerability effect response criteria composite endpoint worsening Exploratory assessment changes biomarkers MCP-1 pharmacokinetic profile DMX-200. Two interim analyses (IA) planned, first planned IA futility will be performed by Independent Data Monitoring Committee ​72 (36 per group) complete ​of second once approximately​ 144 enrolled treatment.​ final analysis approximately 286 currently open 11 countries 75 investigational sites expanded more subject successful analysis. Results ACTION3 progress expected completed 2026. Conclusion randomized, which evaluates novel approach combining CCR2 inhibitor, DMX-200, blockade