Pegcetacoplan Versus Eculizumab for Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, non-malignant hematologic disease characterized by complement-mediated red blood cell hemolysis, and the current standard of care for this condition is C5 inhibition, such as eculizumab. Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both intravascular hemolysis (IVH) and extravascular hemolysis (EVH). 

A study presented at the 2020 ASH Annual Meeting compared pegcetacoplan versus eculizumab for patients with PNH and found that pegcetacoplan led to better hematologic responses in a greater proportion of patients.

In the randomized, open-label, active-comparator controlled, phase III PEGASUS trial, patients were randomized to receive pegcetacoplan (n=41) or eculizumab (n=39) in the intention-to-treat population. Four patients in the pegcetacoplan arm and one patient in the eculizumab arm were not evaluable for analysis. 

Hematologic response (based on week 16 data) was defined as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count.

In the pegcetacoplan arm, 61.0% of patients (n=25) achieved at least a good hematologic response compared with 5.1% (n=2) in the eculizumab arm. At week 16, the following responses were observed in the pegcetacoplan and eculizumab groups: complete response, 36.6% and 0%; good response, 24.4% and 5.1%; partial response, 12.2% and 33.3%; minor response, 2.4% and 23.1%; and no response, 0% and 28.2%, respectively.

Nine patients (six from the pegcetacoplan arm and three from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16; these nine patients were manually categorized identically by the lead and senior author in a blinded, independent manner but were not included among these data. The addition of the nine manually categorized patients did not significantly alter the proportions reported, according to the study authors.

Factors that may have contributed to heterogeneity of hematologic response to treatment were impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure did not appear to be a factor for heterogeneity of response, and researchers observed no difference in LDH, “suggesting that the major factor accounting for the difference between the two arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells).”

“These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematologic improvement in the treatment of PNH,” the researchers concluded.


Risitano A, Weitz IC, de Castro CM, et al. Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS). Abstract 2588. Presented at the 62nd American Society of Hematology Annual Meeting & Exposition, Dec. 2-11, 2020.