Pegcetacoplan Outperforms Eculizumab for Paroxysmal Nocturnal Hemoglobinuria

Results from the phase III PEGASUS trial suggest that the targeted C3 inhibitor pegcetacoplan improved hemoglobin levels better than eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were still anemic despite at least 3 months of eculizumab therapy. Treatment with pegcetacoplan also led to a greater proportion of patients able to avoid transfusion, according to findings presented as part of EHA25 Virtual, the 25th European Hematology Association Annual Congress, by Peter Hillmen, MD, of the St. James’s University Hospital in Leeds, U.K.

PNH is characterized by complement-mediated hemolysis, Dr. Hillmen explained. The FDA-approved C5 inhibitors eculizumab and ravulizumab reduce intravascular hemolysis, but not C3-mediated extravascular hemolysis. Pegcetacoplan is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, meaning it has the potential to block both intravascular and extravascular hemolysis.

The PEGASUS trial compared pegcetacoplan with eculizumab in adults with a confirmed PNH diagnosis and the following characteristics:

  • hemoglobin levels <10.5 g/dL (despite stable eculizumab for ≥3 months)
  • absolute reticulocyte count >1.0 times the upper limit of normal at screening
  • platelets >50×109/L
  • neutrophils >0.5×109/L

Patients completed a 4-week run-in period that included treatment with pegcetacoplan plus eculizumab. Following the run-in period, patients were randomized to receive either subcutaneous pegcetacoplan 1,080 mg administered twice weekly (n=41) or eculizumab (n=39).

A total of 37 patients and 38 patients in the pegcetacoplan and eculizumab arms, respectively, continued with the treatment for up to 16 weeks and were included in the follow-up analysis. Baseline characteristics were similar between the treatment arms, Dr. Hillmen reported. More than half of patients in each group had received 4 or more transfusions in the year prior to enrollment (51% in the pegcetacoplan group and 59% in the eculizumab group). Participants also had similar Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-f) scores.

The investigators reported that, from baseline to week 16, patients randomized to pegcetacoplan experienced an increase of hemoglobin from 8.7 g/dL to 11.5 g/dL. However, in the eculizumab group, patients experienced a decrease in hemoglobin from 8.7 g/dL to 8.6 g/dL. This translated to an adjusted treatment difference between the 2 groups of 3.84 g/dL (p<0.0001), in favor of pegcetacoplan.

This benefit was seen regardless of transfusion history. In patients who had a history of ≥4 transfusions in the 12 months before enrollment, treatment with pegcetacoplan improved hemoglobin levels by 6.13 g/dL; in patients with <4 transfusions, the improvement was 2.98 g/dL.

The researchers added that a higher proportion of patients treated with pegcetacoplan avoided transfusion during the treatment period (85% vs. 15%). Incidence of adverse events (AEs) were similar in the pegcetacoplan and eculizumab groups (88% and 87%, respectively). Similar proportions of patients also experienced serious AEs (17% and 18%). In the overall study population, most AEs were mild; the most common AEs included injection-site reactions (37% with pegcetacoplan vs. 3% with eculizumab) and diarrhea (22% with pegcetacoplan vs. 0% with eculizumab).

A higher proportion of patients in the eculizumab group experienced breakthrough hemolysis by week 16 (23% vs. 10%). Breakthrough hemolysis led to discontinuation in 3 patients in the pegcetacoplan arm. Researchers are now exploring whether dose modifications could control hemolysis.

Limitations of this study include the small sample sizes in both treatment arms, as well as the short follow-up. In addition, the study selected only patients in whom hemoglobin was <10.5 g/dL after ≥3 months of eculizumab, which made the lack of improvement in the patients randomized to eculizumab unsurprising. The ongoing phase III PRINCE study is evaluating pegcetacoplan in patients with PNH who are treatment-naïve; that study met accrual in early July 2020.

Study authors report relationships with Apellis Pharmaceuticals, which sponsored the trial.


Hillmen P, Szer J, Weitz I, et al. Results of the PEGASUS phase III randomized trial demonstrating superiority of the C3 inhibitor, pegcetacoplan, compared to eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Abstract S192. Presented as part of EHA25 Virtual, June 12, 2020.