Among patients with paroxysmal nocturnal hemoglobinuria, pegcetacoplan may yield desirable efficacy and safety outcomes, according to research published in The Lancet Haematology.

Paroxysmal nocturnal hemoglobinuria is a rare, acquired, and life-threatening hematologic disease associated with PIGA mutations and consequent CD55 and CD59 deficiency. It is defined by complement-mediated hemolysis, thrombosis, and bone marrow failure; fatigue is also an associated symptom, which can impair patient quality of life.

The standard of care for paroxysmal nocturnal hemoglobinuria is C5 inhibitors, including eculizumab and ravulizumab. These treatments are approved by the US Food and Drug Administration for this disease, and have been repeatedly shown to reduce symptom burden and threat to life.

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There is, however, some evidence that C3-mediated problems may continue despite C5 inhibitor intervention in this patient population. Pegcetacoplan was the first C3 inhibitor to receive FDA approval for paroxysmal nocturnal hemoglobinuria in which anemia persists despite C5 therapy introduction; the drug has also shown evidence of superiority to eculizumab.

For the phase 3 PEGASUS study ( Identifier: NCT03500549), researchers evaluated the relative long-term safety and efficacy outcomes among patients with paroxysmal nocturnal hemoglobinuria who received pegcetacoplan for up to 48 weeks. In the present paper, the authors reported results from the open-label part of PEGASUS.

Overall, 80 patients were enrolled, among whom 41 were randomly assigned to receive pegcetacoplan, while 39 were randomly assigned to receive eculizumab. In the pegcetacoplan and eculizumab groups, the median ages were 53 and 47 years, respectively, 66% and 56% of patients were female sex, and the median durations of prior treatment with eculizumab were 4.4 and 3.4 years.

While patients in the pegcetacoplan arms had high hemoglobin concentrations at both 16 and 48 weeks (P =.14), those in the eculizumab arm had higher concentrations at 48 weeks (P <.0001). Scores on a fatigue-rating scale improved in all patients who received eculizumab or pegcetacoplan.

Common treatment-related adverse events among any patients who received pegcetacoplan were injection site reactions (26%), hemolysis (19%), nasopharyngitis (16%), and diarrhea (13%). A total of 4 of 18 patients in the overall study who had a serious treatment-related adverse event had an event deemed linked to pegcetacoplan. However, no treatment-related deaths were noted.

“As the first and only proximal complement inhibitor that can control both intravascular and extravascular haemolysis, pegcetacoplan has the potential to considerably improve haematological outcomes, benefit quality-of-life, and change treatment goals for patients with paroxysmal nocturnal haemoglobinuria,” the authors wrote.

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 


de Latour RP, Szer J, Weitz IC, et al. Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial. Lancet Haematol. 2022;9(9):e648-e659. doi:10.1016/S2352-3026(22)00210-1