Abstract: TH-PO501

A Phase 2a Trial of DMX-200: Synergistic Blockade of AT1R and CCR2 in Patients with CKD

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 305 CKD: Clinical Trials and Tubulointerstitial Disorders

Authors

  • Power, David A., Austin Health, Heidelberg, Victoria, Australia
  • Holt, Stephen G., Royal Melbourne Hospital, Melbourne, New South Wales, Australia
  • Champion de Crespigny, Paul J., The Royal Melbourne Hospital, Parkville, New South Wales, Australia
  • Roberts, Matthew A., Eastern Health, Blackburn, Victoria, Australia
  • Williams, James H., Dimerix Bioscience Pty Ltd, Nedlands, Western Australia, Australia
  • Harrison, Kathryn M., Dimerix Bioscience Limited, Melbourne, New South Wales, Australia
  • Packham, David K., Melbourne Renal Research Group, Melbourne, Victoria, Australia
Background

The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2), both G protein-coupled receptors, form functional heteromers. Simultaneous antagonism of these receptors had a beneficial effect on proteinuria, podocyte viability and recruitment of inflammatory monocytes to the kidney in the sub-total nephrectomy rat model of nephrotic syndrome.

Methods

Patients (n=27) were enrolled in an open label, Phase 2a, dose escalation study at 4 sites in Australia. The primary objective was to determine the safety and tolerability of the CCR2 antagonist organic germanium added to stable treatment of the AT1R antagonist irbesartan in patients with proteinuria. The secondary objective was to evaluate the effects of organic germanium on various biomarkers including proteinuria. All patients were on a stable dose of irbesartan for ≥ 3-months prior to enrolment and throughout the study. Patients received escalating doses of organic germanium (10, 20, 30, 50, 80mg TID) at 4-week intervals unless proteinuria was within normal limits. Participants remained on their maximum dose for a further 2 intervals

Results

No serious safety concerns were observed in patients on irbesartan when treated with 10-80 mg TID organic germanium. The average age of patients was 61±13 (SD) years. Primary diagnoses were diabetic nephropathy (n=7), IgA nephropathy (n=5), and other proteinuric diseases (n=15). The baseline eGFR was 32±12 (range 15-59), PCR 255±174 mg/mmol (range 70-700), and irbesartan dose 75-300 mg (81% on 300 mg). Three patients withdrew from the study for reasons unlikely to be related to the study drug. There were no clinically relevant changes in blood pressure, eGFR and serum potassium. Of the 24 patients that completed dosing, 6 achieved ≥ 50% reduction in proteinuria during at least one dose level of organic germanium.

Conclusion

No safety concerns were observed in patients on irbesartan when treated with 10-80 mg TID organic germanium. The additive reduction in proteinuria over and above AT1R blockade in some patients warrants additional clinical investigation of DMX-200 for proteinuric CKD.

Funding

  • Commercial Support