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Abstract: PO1654

BCX9930, an Oral Factor D Inhibitor in Development for Treatment of Complement-Mediated Diseases, Inhibits Complement Alternative Pathway (AP) Activity in Healthy Subjects

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Chen, Xilin, BioCryst Pharmaceuticals Inc, Birmingham, Alabama, United States
  • Zhu, Fugang, BioCryst Pharmaceuticals Inc, Birmingham, Alabama, United States
  • Parker, Cynthia D., BioCryst Pharmaceuticals Inc, Birmingham, Alabama, United States
  • Cornpropst, Melanie, Biocryst Pharmaceuticals Inc, Durham, North Carolina, United States
  • Sheridan, William P., Biocryst Pharmaceuticals Inc, Durham, North Carolina, United States
  • Davidson, Matthew, Biocryst Pharmaceuticals Inc, Durham, North Carolina, United States
  • Babu, Yarlagadda S., BioCryst Pharmaceuticals Inc, Birmingham, Alabama, United States
Background

Factor D, the rate-limiting enzyme of the AP, is required for the formation of C3 convertase as well as amplification of complement activities initiated by the lectin pathway (LP) and classical pathway (CP). AP amplification is responsible for up to 80% of the LP and CP complement responses (Harboe et al, Clin Exp Immunol 2004). BCX9930 is an orally administered, potent and selective inhibitor of factor D, and has potential for the treatment of complement mediated glomerular diseases including, C3 glomerulopathy, IgA nephropathy, primary membranous nephropathy, and lupus nephritis. This study assessed the effects of oral dosing of BCX9930 on the AP activities in ex vivo activated serum in healthy subjects.

Methods

Serum samples from the BCX9930-101 study (NCT04330534) of multiple ascending doses ranging from 50 to 500mg every 12hrs (Q12h) were used to evaluate complement activities with AP-specific Wieslab C5b-9 (AP Wieslab) assay. Levels of complement split products Bb, C3a, C5a and soluble C5b-9 (sC5b-9) in the supernatants from the AP Wieslab assay were further analyzed by multiplex assays.

Results

Oral dosing of BCX9930 resulted in rapid (within ≤1hr) and maximal suppression (median >98% relative to pre-dose levels) of AP Wieslab at all dose levels. The duration of suppression was dose-dependent. At steady state for doses ≥200mg Q12h, maximal suppression persisted for at least 2 dosing intervals (24hrs) following the last dose.
Doses of 200, 400 and 500mg Q12h reduced Bb, C5a and C5b-9 levels by >95% through 12hrs post-dose at steady state in the supernatants from AP Wieslab assays. At the highest dose level analyzed, 500mg Q12h, mean inhibition of Bb, C5a, and C5b-9 increased to >98%, and mean inhibition of C3a was 95%.

Conclusion

Oral BCX9930 potently suppressed AP activity in healthy subjects. Suppression ≥95% was achieved through at least 12hrs post-dose across all described assays for the selected clinical dose of 500mg twice daily. As the AP amplification loop also enhances the signal of the CP and LP, BCX9930 has potential to treat diseases mediated by any of the 3 complement pathways. These results support further development of oral BCX9930 for the treatment of complement mediated glomerular diseases.