Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for ≥3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomly assigned and stratified based on their number of transfusions (<4 or ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary end points were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n = 35) or control (n = 18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%; 95% confidence interval [CI], 57.2-89.0; P < .0001) and change from baseline in LDH (least square mean change: pegcetacoplan, -1870.5 U/L; control, -400.1 U/L; difference, -1470.4 U/L; 95% CI, -2113.4 to -827.3; P < .0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04085601.

Graphical abstract

Figure 1.

Trial profile. ∗ indicates the control group patients received supportive care (eg, transfusions, corticosteroids, and supplements [iron, folate, and vitamin B12]); †, patients assigned to the control group could escape to pegcetacoplan therapy if their hemoglobin levels were ≥2 g/dL below their baseline measurement or presented with a qualifying thromboembolic event secondary to PNH; ‡, 1 death occurred in the pegcetacoplan group related to septic shock in the context of bone marrow failure (both events were deemed unrelated to pegcetacoplan); and §, 1 death occurred in the control group related to respiratory failure and septic shock.

Figure 2.

Coprimary end points and hematologic parameters over time. (A) Coprimary end points of hemoglobin stabilization (defined as avoidance of >1-g/dL decrease in hemoglobin levels from baseline through week 26) and CFB in LDH levels at week 26 in patients in the pegcetacoplan group or control group. Reference range for normal LDH levels: 113 to 226 U/L. (B) Mean hemoglobin levels (±standard error [SE]) and (C) mean LDH over time (±SE) for patients in the pegcetacoplan group or control group. Reference range for normal hemoglobin levels: male, 13.6 to 18 g/dL; female, 12 to 16 g/dL. SE bars are not visible on data points representing mean values with small SE. ∗ indicates control group patients received supportive care (eg, transfusions, corticosteroids, and supplements [iron, folate, and vitamin B12]) and †, avoidance of >1-g/dL decrease in hemoglobin levels from baseline through week 26. Patients who received a transfusion, escaped from the control arm to pegcetacoplan treatment, withdrew from the study before week 26, or were lost to follow-up were categorized as failing to achieve hemoglobin stabilization. ‡ indicates from baseline to week 26.