Thrombosis and meningococcal infection rates in pegcetacoplan-treated patients with paroxysmal nocturnal hemoglobinuria in the clinical trial and postmarketing settings

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Complement component 5 (C5) inhibitors have decreased PNH-related thrombosis rates and reduced mortality compared with those of age-matched controls. A small but significantly increased risk of life-threatening Neisseria infections, especially N meningitidis, represents a long-term safety risk of complement inhibition. Objectives To evaluate the rates of thrombosis and meningococcal infections in patients with PNH treated with the complement component 3–targeted therapy pegcetacoplan. Methods Cumulative patient-year exposure to pegcetacoplan was calculated, and thrombotic events and meningococcal infections were reviewed in 7 clinical trials and in the postmarketing setting. The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis, and Haemophilus influenzae before pegcetacoplan use; the label allowed for prophylactic antibiotic use if pegcetacoplan must be administered before vaccination. Results As of November 13, 2022, 464 patients with PNH had 619.4 patient-years of pegcetacoplan exposure in completed/ongoing clinical trials and the postmarketing setting. Seven thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting. The overall thrombosis rate was 1.13 events per 100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; postmarketing: 0.95 events/100 patient-years in 210.0 years). No infections with meningococcal bacteria were reported. Conclusion Event rates for thrombosis were comparable between pegcetacoplan and previously reported rates of C5 inhibitors in patients with PNH, and no cases of meningococcal infection were reported with pegcetacoplan. Continued follow-up is required.


| I N T R O D U C T I O N
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis [1].Before complement inhibitor approval, thrombosis was the leading cause of death in PNH.Approximately 40% of patients experienced thrombotic events, which were fatal in almost 25% of cases [2,3].Thrombosis mechanisms in PNH are likely multifactorial and may include the effects of intravascular hemolysis, complementmediated leukocyte and platelet activation, inflammatory cytokines, and impaired fibrinolysis [4,5].The approval and use of complement component 5 (C5) inhibitors changed the course of PNH and decreased thrombosis rates in patients with PNH, improving survival to comparable levels in age-matched controls [6].In 195 patients who received the C5 inhibitor eculizumab in clinical trials between 2002 and 2005, thrombosis rates decreased from 7.37 events per 100 patient-years (1683 patient-years of exposure) without complement inhibition (ie, before eculizumab treatment) to 1.07 events per 100 patient-years (281 patient-years of exposure) with eculizumab [7].
The thrombosis rate with C5 inhibitor ravulizumab treatment was 1.21 events per 100 patient-years among 434 patients in the extension period (662 patient-years of exposure) [8].
Optimal PNH treatment must block complement activity enough to reduce the risk of thrombosis without compromising the complement system to an extent that would increase the risk of lifethreatening infections, especially Neisseria meningitidis [9].In a 10-year pharmacovigilance study of patients with PNH and atypical hemolytic uremic syndrome on eculizumab, the estimated meningococcal infection rate was 0.25 events per 100 patient-years (28,518 patient-years of global cumulative exposure to eculizumab) [10].PNH-directed treatment must reduce thrombotic events and control hemolysis while considering the infection risk.
Pegcetacoplan is the first complement component 3 (C3)targeted therapy approved in the United States for adults with PNH [11] and in Europe for adults with PNH who are anemic after receiving a C5 inhibitor for ≥3 months [12].Clinical trial evidence has shown that pegcetacoplan improves hematologic parameters and anemia-related PNH complications, such as transfusion requirements, fatigue, and quality of life [13][14][15].However, the longterm effects of pegcetacoplan on thrombosis and meningococcal infection risk have not been assessed.In this report, we evaluated the thrombosis and meningococcal infection rates among patients with PNH receiving pegcetacoplan in clinical trials and in real-world postmarketing settings.

Essentials
• Terminal complement inhibition lowers thrombosis risk in paroxysmal nocturnal hemoglobinuria.
• We assessed thrombosis and meningitis rates with pegcetacoplan, a proximal complement inhibitor.
• Thrombosis rates on pegcetacoplan were comparable with those of terminal complement inhibitors.
• No meningitis infections were reported with pegcetacoplan, but continued surveillance is needed.This analysis included all patients who received ≥1 dose(s) of pegcetacoplan in 7 clinical trials and in the postmarketing setting in the United States, Europe, and the rest of the world as of November 13, 2022.[18].Adolescents with PNH enrolled in the ongoing, phase 2, open-label PIONEER study (NCT04901936) [19] were also included.Adult patients (aged ≥18 years) in these studies were either anemic (hemoglobin of <10 g/dL [PHAROAH] [16] or <10.5 g/dL [PEGASUS] [13,14]) after receiving stable eculizumab dosing for ≥3 months or C5 inhibitor-naive (PALOMINO [17], PADDOCK [17], and PRINCE [15]); adolescent patients (aged 12-17 years) in PIONEER were anemic and were either C5 inhibitor-experienced or C5 inhibitor-naive [19].In the United States, pegcetacoplan is available only through a Risk Evaluation and Mitigation Strategy program, which provided the numbers of patients who received pegcetacoplan in the US postmarketing setting.In other parts of the world, sales data were obtained from the manufacturer and distributor (Swedish Orphan Biovitrum AB), including the numbers of patients exposed to pegcetacoplan.

Adults with PNH
The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B before pegcetacoplan initiation; if pegcetacoplan had to be administered before vaccination, the labels mandated prophylactic antibiotic use [11][12][13][14][15][16][17].Patients receiving anticoagulant medications at trial entry were allowed to continue taking them with pegcetacoplan.All protocols were approved by the institutional review board or the independent ethics committee at each participating trial site, and patients provided informed consent for their participation.All trials were conducted in accordance with the protocols, applicable regulations, and ethical principles in the Declaration of Helsinki and the Good Clinical Practice guidelines.
Cumulative patient-years of pegcetacoplan exposure were calculated as the sum of the total duration of an individual patient's exposure to pegcetacoplan in years.Postmarketing exposure duration was estimated assuming that each patient received 2 vials of pegcetacoplan per week (or 1 vial/3.5 d).Rates of thrombosis and meningococcal infection per 100 patient-years in clinical trials were based on the total number of events from the first pegcetacoplan dose to the last follow-up assessment.Thrombotic events (or history) in clinical trials were reported by system organ class and preferred term using the Medical Dictionary for Regulatory Activities High-Level Term of "pulmonary thrombotic and embolic conditions" and the Medical Dictionary for Regulatory Activities High-Level Group Term of "embolism and thrombosis," which included arterial and venous thrombotic events.Postmarketing rates were estimated based on safety reports of total number of thrombotic (arterial and venous) and meningococcal infection events in the Apellis/Swedish Orphan Biovitrum AB global safety database, which included solicited reports from patient support and market research programs; spontaneous reports from health care providers, consumers, and regulatory agencies; and reports extracted from the literature.Compliance in the US postmarketing setting was calculated as the proportion of days a patient had the drug in possession divided by the total number of days of follow-up using central pharmacy prescription refill data following standard recommended practice [20,21].Clinical trial data were used to describe the percentages of patients with ≥1 thrombotic event(s) before the trial initiation of pegcetacoplan therapy and the concomitant use of antithrombotic agents with pegcetacoplan therapy.
Continuous data were summarized using descriptive statistics (ie, n, means, SDs, medians, and ranges).Categorical data were summarized using counts and percentages.

| R E S U L T S A N D D I S C U S S I O N 3.1 | Patient characteristics
Baseline characteristics of adult patients with PNH who participated in the 5 completed pegcetacoplan trials are summarized in Table 1.
Patients were recruited across multiple centers over the world and displayed demographic and clinical characteristics representative of the local trial center and recruiting criteria (ie, C5i-experienced vs C5inaive).Among these patients, 22.6% (38/168) had ≥1 thrombotic event(s) before the trials; pegcetacoplan and antithrombotic treatments were received concurrently by 21.7% (35/161) of patients with available concomitant medication data.

| Overall pegcetacoplan exposure and compliance
Overall, 464 patients with PNH had a total of 619.2).Compliance in the US postmarketing setting was estimated to be 98% as of November 13, 2022.

| Incidence of thrombosis
A total of 7 thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting (Table 2).Of the 5 thrombotic events reported in the clinical trials, 1 patient in PHAROAH experienced an event of portal vein thrombosis in the setting of likely breakthrough hemolysis and sepsis that developed after placement of a kidney stent and a nephrostomy tube.Three patients in PEGASUS experienced events: 1 patient in the pegcetacoplan-to-pegcetacoplan group had a deep vein thrombosis associated with a peripherally  during the long-term, open-label extension trial within 3 weeks of discontinuing pegcetacoplan and switching to eculizumab in order to conceive (Table 3).None of these events were assessed as related to pegcetacoplan by study investigators, and all were resolved.
The calculated overall thrombosis rate was 1.13 events per 100 patient-years, with 1.22 events per 100 patient-years in 409.4 years of pegcetacoplan exposure in clinical trials and 0.95 events per 100 patient-years in 210.0 years of postmarketing pegcetacoplan exposure.One event of severe mesenteric ischemia in the eculizumab-topegcetacoplan group that was possibly related to pegcetacoplan and could have been due to thrombosis in the PEGASUS 48-week, open-label extension was not included [14].Some patients had a history of prior thrombosis (22.6%) and/or were concomitantly receiving antithrombotic agents (21.7%) with pegcetacoplan, which might have influenced patients' risk for thrombosis during the trials.Of the 4 patients who experienced a thrombotic event, 1 had a prior history of thrombosis and 3 were receiving concomitant antithrombotic therapy (Table 3).

Previous studies have shown decreased thrombosis rates with C5
inhibitors compared with those with supportive care without complement inhibitors.In 79 eculizumab-treated patients at a single center from May 2002 to July 2010, the thrombotic event rate decreased from 5.6 events per 100 patient-years before treatment to 0.8 events per 100 patient-years during treatment [6].A pooled analysis from the 3 clinical trials and the extension study of eculizumab showed that the thromboembolism rate during eculizumab treatment was reduced by 85% from a pretreatment rate of 7.37 events per 100 patient-years to 1.07 events per 100 patient-years [7].
A long-term safety analysis of 195 patients receiving eculizumab over 66 months reported an 82% reduction in the thromboembolism rate, from 11.13 events per 100 patient-years before treatment to 2.14 events per 100 patient-years during treatment (10 events/467.1 patient-years of exposure) [22].In a 2-year extension of 2 ravulizumab clinical trials, the thrombotic event rate was 1.21 events per 100 patient-years (8 events in 434 patients with 662 patient-years of exposure) [8].In a recent report of 509 patients with PNH receiving C5 inhibitors from May 2002 to July 2022 in the United Kingdom, 23 patients had a thrombotic event, consistent with a thrombosis rate of 0.73 events per 100 patient-years [23].

| Incidence of meningococcal infections
No cases of meningococcal infection occurred during any of the completed or ongoing pegcetacoplan clinical trials or in the postmarketing setting through November 13, 2022 (Table 2).By comparison, no meningococcal infections were reported in the 2-year extension study of ravulizumab (662 patient-years) [8], but 1 fatal case and 1 life-threatening case of meningococcal sepsis were reported in patients receiving ravulizumab for 2.2 years and 1 year, respectively [24,25].Several cases of encapsulated bacterial infections, including meningococcal infections, have also been reported in patients receiving eculizumab [26,27].In a recent international PNH registry study of patients with PNH who received meningococcal vaccination before being treated with eculizumab and were receiving prophylactic antibiotics during C5 inhibitor treatment, the meningococcal infection rate was 0.1 per 100 (95% CI, 0.0-0.4)patient-years [28].A pharmacovigilance analysis that evaluated eculizumab use in patients with PNH and atypical hemolytic uremic syndrome over 10 years found a meningococcal infection rate for patients with PNH of 0.25 per 100 patient-years (approximately 1000-2000 times higher than that of the general population), with a fatal meningococcal infection rate of 0.03 per 100 patient-years [10]  b Severity was quantified by study investigators.c Hb reference range is 12.0 to 16.9 g/dL for females and 13.6 to 18.0 g/dL for males unless noted otherwise.d LDH reference range is 113 to 226 U/L unless noted otherwise.e Reference ranges not specified.f Hb reference range is 13.5 to 18.0 g/dL.g LDH reference range is 120 to 246 U/L.h Patient later experienced a severe, serious event of mesenteric ischemia possibly related to pegcetacoplan (per investigator's assessment) on study days 220 to 233, which led to pegcetacoplan and study discontinuation.Patient recovered from intestinal ischemia on day 233.
who completed 1 of 5 trials (PHAROAH [phase 1b, NCT02264639] [16], PALOMINO [phase 2a, NCT03593200] [17], PADDOCK [phase 1b, NCT02588833] [17], PEGASUS [phase 3, NCT03500549] [13,14], and PRINCE [phase 3, NCT04085601] [15]) could enroll in an ongoing, long-term, rollover, open-label, extension trial (phase 3, NCT03531255) 4 patient-years of pegcetacoplan exposure in completed and ongoing clinical trials (170 patients and 409.4 patient-years of exposure) and in the postmarketing setting, including the United States, Europe, and the rest of the world (294 patients and 210.0 patient-years of exposure) as of November 13, 2022 (Table KELLY ET AL. inserted central catheter line in the setting of diffuse large B cell lymphoma during the 48-week, open-label extension period; 1 patient in the eculizumab-to-pegcetacoplan group had a jugular vein thrombosis (presumably associated with central catheter placement) in the setting of multiple complications post cholecystectomy after switching from eculizumab to pegcetacoplan during the 48-week, open-label extension T A B L E 1 Baseline characteristics of adult patients with PNH enrolled in pegcetacoplan clinical trials.
Pegcetacoplan exposure, thrombosis, and meningococcal infections in patients with paroxysmal nocturnal hemoglobinuria.a a Taken only during pegcetacoplan monotherapy in the 16-week randomized controlled period and the 32-week open-label period in PEGASUS.T A B L E 2 a As of November 13, 2022.bExposure and events were assessed during the completed clinical trial throughout the ongoing, long-term, rollover, open-label, and extension trial.cExposure and events reported through pharmacovigilance and postmarketing distribution programs in the United States, Europe, and the rest of the world.dRounded number.eOne patient experienced 2 events.period;and 1 patient in the pegcetacoplan-to-pegcetacoplan group experienced 2 events (deep vein thrombosis and venous embolism) Thrombotic events reported in pegcetacoplan clinical trials.a