Introduction: Complement inhibitors are promising 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 blocked 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 encapsulated bacteria is recommended in patients treated with complement inhibitors; co-administered prophylactic antibiotics can be used in patients who need anticomplement therapies before completing vaccination series. This study aimed to report rates of meningococcal and other encapsulated bacteria infections in patients treated with pegcetacoplan, and to review published evidence with other complement inhibitors.

Methods: In this descriptive analysis, the current (May 13, 2025) pegcetacoplan cumulative exposure was estimated as the sum of total treatment duration in patients receiving systemic pegcetacoplan, either in trials or post-marketing setting (central pharmacy data). Cases of encapsulated bacteria infections in these patients were used to estimate the infection rate. In the recent VALIANT trial (NCT05067127), patients received the first vaccine dose of each recommended series at least 14 days before randomization and continued to receive the remaining vaccine doses while on pegcetacoplan per the Advisory Committee on Immunization Practices (ACIP) immunization schedule for complement deficiencies.

Findings from reports of other complement inhibitors used in clinical trials and extensions, real-world and observational studies, and case reports were also reviewed and summarized, as well as estimated rates of encapsulated bacteria infection in the general population.

Results: As of May 13, 2025, 1724 patients had 2558 years of systemic pegcetacoplan exposure across clinical trials and post-marketing setting (for PNH); 1 case of serious unencapsulated meningococcal sepsis that resolved with appropriate treatment and continued pegcetacoplan therapy (rate of 0.04/100 patient-years [py]), 6 cases of encapsulated bacterial infections (0.23/100 py), and no cases of encapsulated N meningitis infection have been reported.

The estimated incidence of N meningitidis infection 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]

Cases of meningococcal infection, sometimes fatal, occurred in registries of patients treated with C5 inhibitors, including patients with PNH receiving eculizumab in Japan (0.12/100 py),[Ikezoe T, et al. Int J Hematol 2022;115:470] and patients with PNH on eculizumab or ravulizumab in the United Kingdom (0.35/100 py).[Kelly RJ, et al. Blood 2024;143:1157]

Long-term surveillance data are not yet available for iptacopan or danicopan, but adverse events of meningococcal and encapsulated bacteria infection have been reported in iptacopan trials, including 1 serious P. aeruginosa infection (APPLY-PNH) and 1 serious bacterial pneumonia (APPOINT-PNH),[Peffault de Latour R, et al. New Engl J Med 2024;390:994] and 3 likely encapsulated bacteria infections (APPULSE-PNH).[Kulasekararaj A, et al. European Hematology Association Congress; 12–15 June 2025; Milan, Italy]

Conclusions: Understanding the safety profile of pegcetacoplan and other complement-targeted therapies, especially the risk for meningococcal and other encapsulated bacteria infections, will help physicians and patients make informed treatment decisions for individuals with complement-mediated conditions. For nearly over 7 years, systemically administered pegcetacoplan has had a consistently low rate of encapsulated bacteria infections in patients with PNH, C3G, or primary IC-MPGN. 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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2025
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