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Abstract: SA-PO708

The ACTION (AT1R and CCR2 Targets for Inflammatory Nephrosis) Program in Focal Segmental Glomerulosclerosis

Session Information

Category: Glomerular Diseases

  • 1303 Glomerular Diseases: Clinical‚ Outcomes‚ and Trials

Authors

  • Roger, Simon D., Gosford Hospital, Gosford, New South Wales, Australia
  • Mudge, David William, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
  • Nelson, Craig L., Western Health, Footscray, Victoria, Australia
  • Wong, Muh Geot, Concord Repatriation General Hospital, Concord, New South Wales, Australia
  • Shepherd, Robert, Dimerix Bioscience, Melbourne, Victoria, Australia
  • Smith, Alisha J., Dimerix Bioscience, Melbourne, Victoria, Australia
  • Packham, David K., Melbourne Renal Research Group, Melbourne, Victoria, Australia

Group or Team Name

  • ACTION-FSGS
Background

Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. Complications include nephrotic syndrome and progressive kidney failure. There is no approved treatment. The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2) are G protein coupled receptors that form functional heteromers. Simultaneous antagonism of these receptors demonstrated synergistic renoprotective effects in preclinical models. In a Phase 2a study of 27 patients with proteinuric chronic kidney disease, 25% of patients achieved > 50% reduction in proteinuria with combination of DMX-200 (propagermanium, a CCR2 antagonist) and irbesartan, an angiotensin receptor blocker (ARB). Proteinuria reduction is a positive prognostic sign for preserving kidney function.

Methods

ACTION is a Phase 2a randomised, placebo-controlled, 2-way crossover study in primary FSGS patients receiving ARB, exploring the safety and efficacy of DMX-200 in reducing proteinuria. Patients were randomised to receive DMX-200 240mg daily or placebo for 16 weeks, followed by 6-week washout, then crossed over to the alternate treatment for a further 16 weeks. Eligible patients were aged 18-80 with biopsy-proven primary FSGS. Patients received stable dose of irbesartan 300 mg/day throughout the study. Screening urine protein/creatinine ratio (UPCR) was ≥ 150 mg/mmol and eGFR ≥ 25 ml/min/1.73m2. Exclusion criteria included secondary FSGS and diabetes mellitus.

Results

8 patients were enrolled and completed the study. DMX-200 for 16 weeks demonstrated a safety profile similar to placebo, with no safety concerns associated with combined DMX-200 and irbesartan. The study was not powered for efficacy but greater reduction in UPCR (-84.3 mg/mmol vs -5.1mg/mmol) from baseline was observed with DMX-200 compared with placebo. Mixed model for repeated measures (MMRM) analysis showed placebo-corrected ratio was < 1, indicating a greater reduction in UPCR with DMX-200 vs placebo.

Conclusion

These encouraging data suggest that DMX-200 may result in clinically meaningful reduction in proteinuria when added to ARB in patients with primary FSGS. This has led to the initiation of an international Phase 2/3 randomised double-blind, placebo-controlled study (ACTION3) to further evaluate the efficacy of DMX-200 in patients with FSGS receiving an ARB.

Funding

  • Commercial Support