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Abstract: SA-PO424

Evaluation of Urine Complement Biomarker in C3G Following Complement Alternative Pathway Inhibition with ACH-4471

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Galvan, Manuel D., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Thanassi, Jane A., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Patel, Dharaben, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Podos, Steven D., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Luu, Amanda, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Yang, Guangwei, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Zhao, Yongsen, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Kocinsky, Hetal S., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Kelleher, Catherine L., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Geffner, Michael, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Barbour, Thomas D., Royal Melbourne Hospital, Parkville, Victoria, Australia
  • Yang, Wengang, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
  • Huang, Mingjun, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States
Background

C3 glomerulopathy (C3G) is a rare disease of complement alternative pathway (AP) dysregulation that is characterized by glomerular C3 fragment accumulation, progressive kidney damage, and proteinuria. Preliminary data from an ongoing 14-day proof-of mechanism clinical trial provided evidence that ACH-4471, an oral AP-specific inhibitor that blocks complement factor D (CFD) function, can reverse the systemic AP hyperactivation and reduce the proteinuria in C3G patients. Although complement biomarkers in blood are valuable for assessing systemic AP activation, their levels in urine may provide additional information about AP activation in the kidney. Here, we report a comparative evaluation of systemic and urinary AP biomarkers in C3G patients enrolled in the aforementioned clinical study of ACH-4471.

Methods

Urine and blood samples were collected from patients at protocol-specified timepoints prior to, during, and after dosing with ACH-4471. Complement biomarkers including the proximal and terminal complement activation products, Ba and sC5b-9, were measured in serum or plasma and in urine samples. Serum, plasma, and urine from non-study healthy volunteers served as control samples. Urinary levels of complement products were normalized to urinary creatinine levels and are denoted as “/Cr”.

Results

Urinary Ba/Cr and/or sC5b-9/Cr levels at baseline were significantly higher in patients than in healthy controls, even though plasma Ba and sC5b-9 levels were not always above normal. Following dosing with ACH-4471, urinary Ba/Cr and/or sC5b-9/Cr levels were significantly decreased, often to a greater extent than the levels of plasma Ba and sC5b-9. Lastly, the reductions in urinary Ba/Cr and sC5b-9/Cr levels during treatment were independent of the accompanying reduction in proteinuria, as indicated by the comparable reductions observed when urinary Ba and sC5b-9 levels were normalized to urinary albumin.

Conclusion

Our findings suggest that complement proteins in urine may serve as additional biomarkers for understanding C3G pathology and predicting responsiveness to ACH-4471.

Funding

  • Commercial Support