Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, serious hematologic condition in which a somatic mutation in bone marrow stem cells leads to uncontrolled complement-mediated hemolysis. In addition to the primary clinical manifestation of chronic intravascular hemolysis, PNH is associated with thrombosis, anemia, dark urine, shortness of breath, and fatigue. Complement-targeted therapy for PNH was introduced with the C5 inhibitor eculizumab in 2007. Pegcetacoplan, approved in 2021, acts upstream in the complement cascade by binding to C3 and C3b and blocking downstream activity, thereby preventing both intravascular and extravascular hemolysis. The objective of the pegcetacoplan silo within the International PNH Interest Group (IPIG) PNH Registry is to evaluate the long-term, real-world effectiveness and safety of pegcetacoplan in PNH. Methods The IPIG PNH Registry is a multinational, multicenter, observational, non-interventional study to prospectively collect clinical outcomes, patient-reported outcomes, health-resource utilization, and long-term safety data for patients with PNH. All patients with PNH confirmed by flow cytometry are eligible to participate in the core IPIG PNH Registry, which is divided into treatment-specific silos. The pegcetacoplan silo consisted of patients in the Core PNH Registry who were receiving pegcetacoplan, had discontinued pegcetacoplan within the last 12 weeks, or had received pegcetacoplan during pregnancy. Patients who had participated in any clinical interventional study for pegcetacoplan were not eligible. Patients' visit schedules follow the standard of care, with patient data collected at the time of registry enrollment and approximately every 6 months thereafter. Historical data from diagnosis were collected for individual patients. Patients will remain in the pegcetacoplan silo until the earliest of the following: 12 weeks after pegcetacoplan treatment discontinuation, discontinuation from the registry, or the end of the IPIG PNH Registry. Here we report interim results from May 28, 2024 (first patient in) to January 8, 2025 (interim data cut-off). Results At the data-cutoff, 24 patients with PNH were enrolled in the pegcetacoplan silo in 3 sites in the United States (n=1), the United Kingdom (n=22), and Germany (n=1 patient) and all patients were actively receiving pegcetacoplan. At baseline, the mean (SD) patient age was 56.0 (16.3) years. Most patients (58.3%) were men; the most common race was White (70.8%), followed by unknown (16.7%) and Black (12.5%). The mean (SD) time since PNH diagnosis was 10.6 (12.5) years. Of the 24 enrolled patients, 23 had prior experience with anti-complement therapies, most commonly eculizumab (66.7%) and/or ravulizumab (62.5%) in the clinical setting. All 24 patients were receiving pegcetacoplan subcutaneously at a dosage of 1080 mg twice weekly. The mean (SD) pegcetacoplan treatment duration was ~2 years (770.4 649.32 days). Clinical events of interest during the treatment period included infections (15 events in 9 patients 37.5%: 9 COVID-19 in 8 patients, 1 neutropenic sepsis, 1 pneumonia, 1 respiratory tract infection, 1 sepsis, 1 upper respiratory tract infection, 1 viral infection), potential breakthrough hemolysis (11 events in 4 patients 16.7%; 2 started before enrollment; 3 associated with complement-amplifying conditions), and chronic kidney disease (1 patient 4.2%). Potential breakthrough hemolysis was defined as ≥1 new or worsening sign or symptom of intravascular hemolysis and elevated lactate dehydrogenase (≥2 × upper limit of normal ULN) after prior reduction to 1.5 × ULN on therapy). Red blood cell transfusions were reported in 3 patients (12.5%; 14 transfusions total) during the treatment period. While on treatment, 8 infections in 3 patients (12.5%) required hospitalization of 2–8 days (respiratory tract infection, COVID-19, upper respiratory tract infection). No major adverse vascular events, no autoimmune diseases, no encapsulated bacterial infections were reported during the treatment period. No deaths were reported. There were no pregnancies or women currently breastfeeding reported during the treatment period. Conclusions As of data cut-off, 24 patients were enrolled in the pegcetacoplan silo of the IPIG PNH Registry. In this first interim report, safety results with pegcetacoplan were consistent with previously reported clinical trial data and no new safety signals were detected.
Carlos de Castro (Mon,) studied this question.