Pegcetacoplan has been found to be clinically beneficial as a first-line treatment for complement inhibitor-naïve patients with paroxysmal nocturnal hemoglobinuria (PNH), researchers reported in Advances in Therapy.

Eculizumab and ravulizumab, both C5 complement inhibitors, were approved for use as first-line therapy for PNH in 2007 and 2008, respectively. Evidence demonstrates that both drugs can significantly ameliorate many of the symptoms experienced by patients with PNH. Nonetheless, in real-world settings, many patients with PNH who receive either drug still complain of persistent symptoms.

Pegcetacoplan, marketed as Empaveli®, is a C3 complement inhibitor recently approved for treating complement inhibitor-naïve adults with PNH. Theoretically, C3 inhibition should have broader effects than C5 inhibition, given that C3 acts upstream of C5 in the complement cascade. In the phase 3 PEGASUS trial, pegcetacoplan was found to be superior to eculizumab in improving hemoglobin levels in patients who were previously on eculizumab.

However, researchers have yet to conduct head-to-head studies comparing these 3 drugs in complement inhibitor-naïve patients with PNH. In the absence of a direct comparison, researchers used data from the pegcetacoplan arm of the PRINCE trial (a phase 3 study investigating the merits of the drug in complement inhibitor-naïve patients) and the ALXN1210-PNH-302 trial (a phase 3 study investigating the merits of ravulizumab vs eculizumab in patients previously treated with eculizumab). 

Read more about PNH etiology 

Study endpoints included changes in lactate dehydrogenase levels, changes in hemoglobin levels, the rate of transfusion avoidance, the rate of breakthrough hemolysis, and the risk of adverse vascular events. 

“Patients treated with pegcetacoplan had greater improvements in clinical, hematologic, and [quality of life] outcomes than those treated with either ravulizumab or eculizumab in this analysis,” the authors of the study concluded. 

PNH, driven by the pathological activation of the complement system, is a rare and debilitating disease. In 2017, its estimated prevalence in the United States alone was around 13 per 1 million persons. The introduction of complement inhibitors has drastically improved survival; before their availability, the median survival time was only 22 years. 


Wong R, Fishman J, Wilson K, et al. Comparative effectiveness of pegcetacoplan versus ravulizumab and eculizumab in complement inhibitor-naïve patients with paroxysmal nocturnal hemoglobinuria: a matching-adjusted indirect comparison. Adv Ther. Published online February 7, 2023. doi:10.1007/s12325-023-02438-9