Comparative Evaluation of Complement Factor D, C3, and C5 Inhibitors on Serum Bactericidal Activity Against Neisseria Meningitidis Isolates

Abstract

Introduction: Treatment of complement-associated disorders with the terminal complement inhibitor eculizumab brings a thousand-fold elevated risk of meningococcal disease due to blockage of serum bactericidal activity (SBA) and opsonophagocytosis against Neisseria meningitidis (Nm). Vaccination against Nm is recommended for eculizumab recipients yet infection remains a risk in immunized individuals. Eculizumab was reported to inhibit killing of Nm serogroups B and C in an in vitro study with whole blood from vaccinated donors; in contrast, the investigational complement factor D (FD) inhibitor danicopan (ACH-4471), currently in phase 2 trials for treatment of disorders including paroxysmal nocturnal hemoglobinuria (PNH), had much less effect in the same study. Danicopan also showed limited effect in a separate study of SBA against unencapsulated (non-groupable) Nm strains recovered from eculizumab recipients who developed invasive meningococcal disease, whereas eculizumab blocked all observed SBA. The present study undertakes a comparative evaluation of danicopan, eculizumab, and the complement C3 inhibitor compstatin against SBA with donor sera against Nm strains comprising multiple serogroups. Methods: Serum from three donors (1-3) was obtained before and after vaccination with MenB-4C against serogroup B and conjugate vaccine against serogroups A, C, W, and Y. Five Nm isolates were tested comprising serogroups B, C, W, and Y. SBA was considered positive when bacterial viability was half or less of that observed with inactive control serum following incubation in 20% serum for one hour. Results: Partial SBA was observed in pre-vaccination sera (positive in eight of 15 serum-strain pairings) whereas post-vaccination sera were positive in nearly all cases (13 of 15). Serum donor 3 was selected for comparative inhibitor studies; pre-vaccination serum was SBA-positive against three of five Nm isolates (serogroups C, W, and Y), whereas post-vaccination serum was SBA-positive against all five. Danicopan in pre-vaccination serum inhibited SBA against two of three serogroups (W and Y), likely indicating a requirement of AP activity for amplification when anti-Nm antibody titer is low. However, danicopan in post-vaccination serum had no effect on SBA against all five Nm isolates, indicating no AP requirement when anti-Nm antibody titer is sufficient. In contrast to danicopan, compstatin and eculizumab inhibited SBA of pre-vaccination and post-vaccination serum against all Nm isolates. Conclusions: We conclude that selective FD inhibition, such as by danicopan or the second-generation FD inhibitor ACH-5228, presents a reduced risk of meningococcal disease compared with treatment with C3 or C5 inhibitors. Disclosures Zhao: Achillion Pharmaceuticals, Inc.: Employment. Patel:Achillion Pharmaceuticals, Inc.: Employment. Thanassi:Achillion Pharmaceuticals, Inc: Employment. Huang:Achillion: Employment, Equity Ownership. Podos:Achillion Pharmaceuticals, Inc: Employment.