Kidney Week

Abstract: FR-PO905

Mechanistic and Potency Evaluation of Complement Factor D and Factor B Inhibitors

Session Information

• Glomerular Diseases: Membranous Nephropathy, SLE, Complement
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

• Thanassi, Jane A., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States

Jane A. Thanassi,

• Patel, Dharaben, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States

Dharaben Patel,

• Zhao, Yongsen, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States

Yongsen Zhao,

• Gadhachanda, Venkat R., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States

Venkat R. Gadhachanda,

• Wiles, Jason, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States

Jason Wiles,

• Huang, Mingjun, Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States

Mingjun Huang,

• Podos, Steven D., Achillion Pharmaceuticals, Inc., New Haven, Connecticut, United States

Steven D. Podos,

Background

Complement factor D (FD) and complement factor B (FB) are serine proteases essential for complement alternative pathway (AP) activity. FD and FB are present in normal human serum (NHS) at approximately 0.07 µM and 2 µM, respectively. Small molecule inhibitors of FD and FB have been discovered and a few, including ACH-4471 (FD inhibitor) and LPN023 (FB inhibitor), are in clinical development for multiple indications of AP dysregulation including the rare renal disease C3 glomerulopathy (C3G). In this study, we evaluated FD and FB inhibitors for potency and mechanism of action. We also examined their effect on ex vivo C3 consumption in serum from C3G patients.

Methods

FD and FB inhibitor potencies were profiled by AP hemolysis with rabbit erythrocytes and NHS. Mechanism of action (MOA) and potency of inhibitors were assessed in soluble and bound C3 convertase studies with purified components, including FB titrations and order-of-addition tests; convertase activity was assessed from C3 cleavage product generation measured by ELISA. Compound inhibition in C3G patient sera mixed equally with NHS was assessed in fluid phase, with convertase activity assessed by monitoring C3 cleavage products.

Results

ACH-4471 and next generation FD inhibitors were more potent than LNP023 in AP hemolysis with 4.0-fold to 32-fold lower IC₅₀ values. A reference FD inhibitor (Schubart et al, PNAS 2019) was less potent, with a 1.2-fold lower IC₅₀ than LNP023. LNP023 potency was comparable to input serum FB concentration, suggesting a stoichiometric limit for FB inhibition and a relative advantage for FD inhibitors. MOA studies with C3 convertase revealed that LNP023 binds free intact FB, and that it inhibits AP convertase activity but not proconvertase assembly or its activation to convertase. Inhibitor assessments in C3G patient sera also showed a potency advantage for FD inhibitors over LNP023; ACH-4471 and next-generation inhibitors showed comparable inhibition to LNP023 at 1 μM but all FD inhibitors were more inhibitory than LNP023 at 0.1 μM.

Conclusion

ACH-4471 and next generation FD inhibitors demonstrated greater achievable potencies than the FB inhibitor LNP023 in serum from healthy donors and C3G patients, likely due to the molar difference in systemic FD and FB concentrations.

Funding

• Commercial Support –