Release More Inhibitions? Pegcetacoplan Treatment for Patients With Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder of hematopoietic stem cells that manifests as hemolytic anemia, bone marrow failure, smooth muscle dystonia, and thrombosis.¹  In patients with PNH, a deficiency of the glycosylphosphatidylinositol (GPI) -anchored complement regulatory proteins CD55 and CD59 due to somatic mutation of the phosphatidylinositol glycan A (PIGA) gene, leads to complement-mediated lysis of PNH erythrocytes.²  Eculizumab and ravulizumab (with its four-fold longer half-life) are humanized monoclonal antibodies against complement C5 that inhibit terminal complement and significantly reduce intravascular hemolysis and thrombosis, the leading cause of death in patients with PNH.^3,4  Although patients with PNH on terminal complement inhibitors have a normal life expectancy, up to 20 percent of patients require transfusion support.⁵  Extravascular hemolysis due to opsonization of PNH erythrocytes with complement C3 accounts for persistent anemia in some patients.⁶  New complement inhibitors are under investigation to treat PNH including pegcetacoplan, a C3 inhibitor (Figure) administered twice weekly as a subcutaneous infusion.

Dr. Peter Hillmen and colleagues conducted a phase III open-label, controlled trial comparing pegcetacoplan to eculizumab in 80 patients aged 18 years and older with PNH. All patients had hemoglobin of less than 10.5 g/dL despite eculizumab therapy for at least three months. After a four-week run-in phase when all patients received pegcetacoplan 1,080 mg twice per week in addition to eculizumab, patients were randomized to receive pegcetacoplan (41 patients) or eculizumab (39 patients) monotherapy. The primary outcome measured was the mean change in hemoglobin from baseline to week 16 with data censored after the first red cell transfusion. Secondary outcomes include relevant lab markers of hemolysis as well as patient-reported fatigue metrics.

At baseline, the mean hemoglobin across both treatment groups was 8.7 g/dL (range, 6.0-10.8 g/dL), and more than 50 percent of patients received four or more transfusions in the previous year. During the 16-week randomization period, patients receiving pegcetacoplan had an average increase in hemoglobin from baseline (+2.27 g/dL vs. -1.47 g/dL in the eculizumab group). A statistically significant reduction in transfusion requirements was observed in the pegcetacoplan group (85% transfusion independence in patients receiving pegcetacoplan vs. 15% in eculizumab). Noninferiority was observed for change in absolute reticulocyte count but not for change in lactate dehydrogenase (LDH). Fatigue metrics improved in the pegcetacoplan arm.

Common adverse events associated with pegcetacoplan as compared to eculizumab included injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), and infections (29% vs. 26%). Of note, patients receiving pegcetacoplan may develop meningococcal and other serious infections from encapsulated bacteria; accordingly, appropriate vaccination prior to treatment initiation, or alternatively, continual antibiotic prophylaxis, is recommended. Although breakthrough hemolysis was observed more frequently in patients receiving eculizumab, three patients in the pegcetacoplan group discontinued therapy due to breakthrough hemolysis with significantly elevated LDH greater than three times the upper limit of normal. There were no instances of thromboembolism, meningitis, or death in either treatment group.