Introduction

Rare chronic diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) are caused by uncontrolled complement activation [1–4]. Without proper treatment, patients are at risk for significant complications such as intravascular hemolysis and thrombosis in PNH, end-stage renal disease in aHUS, muscle weakness in gMG, and irreversible neurological disability in NMOSD [1–4]. One treatment strategy has been the inhibition of the terminal effector of the complement pathway, complement component 5 (C5), which prevents the formation of the terminal complement complex while preserving critical functions of upstream components that mediate pathogen opsonization and immune complex clearance [5–7]. Eculizumab and ravulizumab are humanized monoclonal antibodies that bind to C5 [5,6] with established safety and efficacy in patients with PNH, aHUS, gMG, and AQP4-Ab+ NMOSD in several clinical trials [8–12]. From their initial approvals in March 2007 and December 2018, respectively, eculizumab and ravulizumab have been approved in 46–64 and 61–70 countries for the treatment of these diseases.

The complement system is critical for innate immunity and responsible for eliminating pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria species including Neisseria meningitidis (Nm) through cell lysis and/or phagocytosis [13,14]. Patients with proximal complement deficiencies have an increased risk of infection by nonmeningococcal encapsulated bacteria, whereas terminal complement deficiencies and complement inhibitor therapies are associated with an increased risk of being infected by Nm [13–15]. Historically, patients with a terminal complement deficiency who had invasive meningococcal disease were less likely to succumb to the infection compared with the general population [16]. Given the known increased risk of infection, an enhanced postmarketing pharmacovigilance surveillance was established for eculizumab and ravulizumab to collect data across a larger patient population to ascertain the safety profile of both treatments. To minimize the risk of meningococcal disease when starting complement-inhibiting therapies, several mitigation strategies are in place, including meningococcal vaccination, drug safety programs, safety cards and educational materials for patients and physicians, and the use of antibiotic prophylaxis in patients who are not yet fully vaccinated until 2 weeks after vaccination or per local guidelines. As availability of vaccines against specific meningococcal serogroups (e.g., A, C, W, Y, MenB), guidance for boosters, and protocols for antibiotic prophylaxis vary by country/region, local guidelines and local/regional product information for eculizumab and ravulizumab should be consulted for specific guidance on the mitigation of meningococcal infection.

The objective of this analysis is to summarize the exposure-adjusted meningococcal infection and mortality rates in patients treated with eculizumab and ravulizumab based on clinical trial and real-world pharmacovigilance data.

Methods

Global clinical trial and real-world safety data regarding eculizumab and ravulizumab use in the treatment of PNH, aHUS, gMG, and NMOSD were collected and recorded in the Alexion pharmacovigilance database. Eculizumab data were analyzed from March 16, 2007, (the date of first marketing authorization) through October 1, 2024. Ravulizumab data were analyzed from December 21, 2018, (the date of first marketing authorization) through December 31, 2024. Both solicited and spontaneous adverse events were included and may have been identified through review of individual case safety reports (ICSRs), published articles and conference abstracts, results from Alexion-sponsored trials and externally sponsored scientific research, reports from the product complaints management systems, regular analysis of aggregated ICSR data, or safety-related inquiries from health authorities, healthcare providers, and consumers. The pharmacological database was searched based on the Medical Dictionary for Regulatory Activities versions 26.1, 27.0 and 27.1 High-Level Term “Neisseria infection.” Only cases associated with Nm were included.

Data were analyzed using summary tables of cumulative Nm cases generated from the Alexion pharmacovigilance database. Cumulative postmarketing exposure was calculated by adding the exposure in patient-months of new, continuing, and discontinued patients for all indications during the analysis period. Patient-months were converted to patient-years (PY) by dividing by 12; the cumulative PY exposure was calculated by adding the exposure from the given month to that of each previous month. Cumulative clinical trial exposure is based on exposure data from completed clinical trials and the enrollment/randomization schemes of ongoing trials. Rates of meningococcal infections and mortality were calculated as number of events per 100 PY. Other quantitative data were reported using descriptive statistics.

Results

Exposure to eculizumab from March 16, 2007, through October 1, 2024, was 2457 PY in the clinical trial setting and 91,052 PY in the real-world setting. Cumulatively, 239 cases of meningococcal infections in patients treated with eculizumab were recorded, with seven (2.9%) cases from clinical trials and 232 (97.1%) cases from the real-world setting. Exposure to ravulizumab from December 21, 2018, through December 31, 2024, was 3287 PY in the clinical trial setting and 34,582 PY in the real-world setting. In patients treated with ravulizumab, there were 42 cases of meningococcal infections, with six (14.3%) cases from clinical trials and 36 (85.7%) cases from the real-world setting. The individual clinical trials with ≥1 meningococcal infection are listed in S1 Table.

The cumulative rate of meningococcal infections in clinical trials was 0.28 and 0.18 per 100 PY in patients treated with eculizumab and ravulizumab, respectively. In the real-world setting, cumulative rates were 0.25 and 0.10 per 100 PY, respectively. The rates of meningococcal-associated mortality were ≤0.03 in both eculizumab- and ravulizumab-treated patients in clinical trials (0.00 and 0.03) and real-world settings (0.03 and 0.01) (Fig 1). Demographics and characteristics of patients with meningococcal infection are summarized in Table 1. Frequencies of meningococcal-related events are summarized in Table 2.

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Table 1. Demographics, vaccination status, and identified serogroup among patients with meningococcal infection.

https://doi.org/10.1371/journal.pone.0332073.t001

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Table 2. Type and frequency of meningococcal-related events by MedDRA preferred term.

https://doi.org/10.1371/journal.pone.0332073.t002

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Fig 1. Cumulative rates of meningococcal infections and associated mortality per 100 PY among patients treated with eculizumab and ravulizumab in clinical trial and real-world settings.

PY patient-years.

https://doi.org/10.1371/journal.pone.0332073.g001

In a real-world setting, cumulative meningococcal infection rates in patients treated with eculizumab decreased from ≈0.57 per 100 PY in 2007 to 0.25 per 100 PY in 2024. Associated mortality rates have been stable in the same time frame from ≈0.00 to 0.03 per 100 PY (Fig 2). In patients treated with ravulizumab, the cumulative meningococcal infection rates have remained stable from 0 per 100 PY in 2019 to 0.10 per 100 PY in 2024, and associated mortality rates remained stable in the same time frame from 0 to 0.01 per 100 PY, respectively (Fig 2). The number of meningococcal infections and associated deaths among eculizumab- and ravulizumab-treated patients in both clinical trials and real-world settings per indication are shown in S2 and S3 Tables.

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Fig 2. Rate of meningococcal infection and associated mortality per 100 PY among patients treated with eculizumab and ravulizumab in the real-world setting from 2007 to 2024.

Grey vertical lines indicate EMA approval years. Data are inclusive of patients with PNH, aHUS, gMG, and AQP4-Ab+ NMOSD. The cutoff dates for these data were October 2024 (eculizumab) and December 2024 (ravulizumab). aHUS atypical hemolytic uremic syndrome, AQP4-Ab+ anti-aquaporin-4 antibody-positive, EMA European Medicines Agency, gMG generalized myasthenia gravis, NMOSD neuromyelitis optica spectrum disorder, PNH paroxysmal nocturnal hemoglobinuria, PY patient-years.

https://doi.org/10.1371/journal.pone.0332073.g002

Discussion

In patients with complement deficiencies or patients who are treated with complement inhibitors, there is a risk of infection with the Neisseria species [15]. The global incidence of meningococcal infections is difficult to determine as the incidence rate varies geographically, temporally, and by age [17–20]. Although the true global burden of meningococcal infections is not known, the incidence of invasive meningococcal disease caused by Nm is approximately 433,000 to 1.2 million cases a year, including the most common clinical manifestations of meningitis and septicemia [17,19–21]. The incidence rate for meningococcal infections is estimated to be 1000- to 2000-fold higher in patients receiving a complement inhibitor compared with the general population [22]. Meningococcal infections are serious in nature and can be life-threatening or fatal if not recognized early and treated with appropriate antibiotics [23].

This report is the largest compilation of pharmacovigilance data on eculizumab and ravulizumab exposure to date, reflecting over 91,000 PY of eculizumab exposure and 34,500 PY of ravulizumab exposure in the real world. Long-term trends of meningococcal infections in patients receiving eculizumab or ravulizumab show that cumulative rates of meningococcal infections have decreased or remained stable over time with increasing exposure. There were a total of 25 and three meningococcal-associated deaths among patients treated with eculizumab and ravulizumab, respectively, reported across clinical trial and real-world experience. The case fatality rate of meningococcal infections in real-world settings for this analysis (≈5%−10%) is similar to the reported case fatality rate in the general population (≈6%−18%) [17,24,25]. The majority of events with fatal outcomes in this analysis were a consequence of delays in diagnosis and/or treatment of meningococcal infection, which is also likely the case in the general population [26].

Risk mitigation strategies are critical to reduce the morbidity and mortality related to meningococcal infections in patients when taking complement-inhibiting therapies. The findings from this analysis of pharmacovigilance surveillance data for eculizumab and ravulizumab suggest that the current mitigation measures, including meningococcal vaccination in accordance with local guidelines and use of antibiotic prophylaxis treatment when starting complement-inhibiting therapies, are generally effective, with only a small number of meningococcal infections reported in these data compared with the estimated number of meningococcal infections occurring each year. Although other complement inhibitors are approved for different indications, we are only able to speak to our experience with eculizumab and ravulizumab. Clinicians should rely on careful assessment of the potential benefits and risks of complement inhibitors for each patient and monitor patients to effectively mitigate the risk of meningococcal infection.

Supporting information

Acknowledgments

We thank Hua Zhang and Meghana Koneru (Alexion, AstraZeneca Rare Disease) for their valuable contributions to the analysis of the data. Medical writing and editorial support were provided by Judy Bloom, PhD, and Melissa Austin of Apollo Medical Communications, part of Helios Global Group, and funded by Alexion, AstraZeneca Rare Disease.