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Presentation Details
| Low Risk for Meningococcal Infections with Systemically Administered Pegcetacoplan, a Complement C3 and C3b Inhibitor Carlos de Castro1, Sheena Patel2, Holly Snyder3, Peter Hillmen3. 1Duke University, Durham, NC, USA.2Swedish Orphan Biovitrum AB, Stockholm, Sweden.3Apellis Pharmaceuticals, Inc, Waltham, MA, USA |
Abstract
Background: Complement inhibitors are effective therapies for complement-mediated conditions, including paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G) and primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN). Clinical benefits of the initially available C5 inhibitors that block terminal complement activation (eculizumab, ravulizumab, crovalimab) paved the way for the development of proximal inhibitors, including the C3/C3b inhibitor pegcetacoplan, the factor B inhibitor iptacopan, and the add-on (to C5 inhibitors) factor D inhibitor danicopan. However, complement inhibition may increase the risk for infections with Neisseria meningitidis and other encapsulated bacteria, including Streptococcus pneumoniae, and Haemophilus influenzae type B. Vaccination for these encapsulated bacteria is recommended or suggested in patients receiving complement inhibitors per the Advisory Committee on Immunization Practices (ACIP) immunization schedule for complement deficiencies; co-administered prophylactic antibiotics can be used in patients who need anticomplement therapies before completing vaccination series. Objectives: Here we report the current, overall infection rates by meningococci and other encapsulated bacteria with systemic pegcetacoplan. Methods: Cumulative exposure was the sum of total treatment duration in all patients who received ≥1 dose of systemic pegcetacoplan in real world or clinical trials and across indications (PNH, C3G, primary IC-MPGN, and other investigative trials). Infection rates were estimated from events of infection by meningococci or other encapsulated bacteria covered by vaccines reported in exposed patients. In the latest phase 3 trial (NCT05067127), patients received the first vaccine dose of each recommended series at least 14 days before randomization and completed the series while on pegcetacoplan. Results: As of August 13, 2025, across 3002 patient-years (py) of total systemic pegcetacoplan exposure, no infections by encapsulated N meningitidis have been reported. Overall, 1 serious unencapsulated meningococcal sepsis that resolved with appropriate treatment and continued pegcetacoplan therapy (rate: 0.03/100 py) and 6 infections by other encapsulated bacterial infections (4 serious, 1 non-serious S. pneumoniae; 1 serious H. influenza type A) that resolved (rate: 0.20/100 py)were reported. The estimated incidence of invasive meningococcal disease in the US general population was 0.2/100,000 population in 2023.[U.S. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report, Emerging Infections Program Network, Neisseria meningitidis, 2023] Meningococcal infection events, sometimes fatal, have occurred across settings and indications in patients receiving C5 inhibitors, yielding cumulative rates of 0.28/100 py with eculizumab and 0.18/100 py with ravulizumab in clinical trials, and 0.25/100 py and 0.10/100 py, respectively, in real world.[Carrillo Infante C, Mujeebuddin A. PLoS One. 2025;20(9):e0332073] Long-term surveillance data remain limited for iptacopan or danicopan, but infections by encapsulated bacteria have been reported in iptacopan clinical trials. Conclusions: Understanding the safety profile of pegcetacoplan and other complement-targeted therapies will help physicians and patients make informed treatment decisions for individuals with complement-mediated conditions. For over 7 years of total systemic pegcetacoplan exposure, no cases of encapsulated N. meningitidis and consistently low rates of infections by other encapsulated bacteria were observed in patients with PNH, C3G, primary IC-MPGN, or other conditions. These findings may reflect effective risk mitigation strategies. Continued follow-up and surveillance for serious infections caused by encapsulated bacteria remain warranted.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.