Thrombosis and Encapsulated Bacterial Infection Rates in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Received Pegcetacoplan: Nearly 3 Years of Post-Marketing Experience
Authors: Gerber Gloria F. , Kelly Richard J. , Nishimori Hisakazu , Horneff Regina , Hillmen Peter , Uchendu Uchendu O. , Zhang Yiwei , Lallier Stacie , Panse Jens 
Published: December 2024

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis, aplasia, and thrombosis. Thrombosis was the leading cause of death in PNH before approval of complement inhibitors: thrombosis rates in patients treated with the C5 inhibitor (C5i) eculizumab in clinical trials decreased from 7.37/100 patient-years (py) before treatment to 1.07/100 py after treatment.[Hillmen et al. Blood. 2007;110:4123] Thrombosis rates were similar in clinical trials of the C5i ravulizumab (1.21/100 py),[Kulasekararaj et al. Eur J Haematol. 2022;109:205] and the first C3/C3b inhibitor approved for PNH, pegcetacoplan (1.22/100 py [Kelly et al. Res Pract Thromb Haemost. 2024;8:102416]). The real-world rate with C5is was 0.73/100 py.[Kelly et al. Blood. 2024;143:1157]) For reference, the rate of venous thrombotic events in the general population of the United States and Europe is ~0.1-0.2/100 py.[Lutsey, Zakai. Nat Rev Cardiol. 2023;20:248] Optimal PNH treatment must block complement activity enough to reduce risk of thrombosis without compromising the complement system to an extent that increases the risk of life-threatening infections, especially Neisseria meningitidis. To achieve this fine balance, risk-mitigating strategies for preventing infections are essential. Rates of N meningitidis infections are ~1000-2000-fold greater in C5i-treated patients with PNH than the general population, despite risk mitigation [McNamara et al. MMWR Morbid Mortal Wkly Rep. 2017;66:734]. Meningococcal infection rates in C5i-treated patients were 0.24/100 py in a 10-year pharmacovigilance analysis [Socié et al. Br J Haematol. 2019;185:297] and 0.35/100 py in a registry analysis.[Kelly et al. Blood. 2024;143:1157] Here we report the current real-world rates of thrombosis and encapsulated bacterial infections in patients with PNH treated with pegcetacoplan in the post-marketing setting as of May 13, 2024.
Methods: 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. Post-marketing exposure duration was estimated assuming each patient received 2 pegcetacoplan vials/week. Post-marketing thrombosis (arterial and venous) and encapsulated bacterial infections rates were estimated from the total events reported in the Apellis/Swedish Orphan Biovitrum AB global safety database, using solicited reports from patient support and market research programs; spontaneous reports from health care providers, consumers, and regulatory agencies; and reports from the literature. The label requires vaccination against N meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before pegcetacoplan use; the label recommends prophylactic antibiotics if pegcetacoplan is given before vaccination.
Results: Patients with PNH had 930.7 py of post-marketing pegcetacoplan exposure in the United States, Europe, and rest of the world as of May 13, 2024. Three thrombotic arterial and/or venous events occurred, resulting in a thrombosis rate of 0.32/100 py. Two were spontaneous reports and 1 was solicited; breakthrough hemolysis was present in 1 case whereas 2 cases had provoking risk factors; outcomes of these events were improving or resolving in 2 cases and unknown for 1 case at this time. No post-marketing encapsulated bacterial infections were reported across countries through May 13, 2024.
Conclusions: In nearly 3 years of post-marketing experience, patients receiving pegcetacoplan for PNH maintained a low thrombosis rate comparable to rates on C5is and had no encapsulated bacterial infections. These findings add 6 months of safety data to the literature, during which, 1 additional thrombotic event (3 total) but no encapsulated bacterial infections were reported. A potential confounder is that real-world data may be subject to underreporting. The lack of reported encapsulated bacterial infections may reflect effective risk mitigation strategies, including possible differences in prophylactic antibiotic usage and/or beneficial infection-prevention measures instituted during the Covid-19 pandemic. Continued follow-up is required, particularly surveillance for life-threatening events.