Pegcetacoplan Improves Hematologic Response in PNH Treated With Eculizumab

For patients with paroxysmal nocturnal hemoglobinuria (PNH) who are receiving eculizumab yet have residual anemia, treatment with pegcetacoplan led to broad hemolysis control and improved hematologic response, according to results from a phase Ib study published in the American Journal of Hematology.

PNH is characterized by complement-mediated hemolysis, explained the authors, led by Carlos de Castro, MD, from Duke University School of Medicine in Durham, North Carolina. While the FDA-approved C5 inhibitor eculizumab reduces intravascular hemolysis, it does not target C3-mediated extravascular hemolysis. Pegcetacoplan binds specifically to C3 and C3b, meaning it has the potential to block both intravascular and extravascular hemolysis.

With this phase Ib trial, Dr. de Castro and researchers hypothesized that, in individuals with PNH who remained anemic during treatment with eculizumab, complement blockade with pegcetacoplan would improve hemoglobin (Hb) levels and provide more complete hemolysis control.

The trial consisted of four cohorts; the present report covers results from cohort 4, in which patients with PNH who were taking eculizumab received pegcetacoplan 270 mg/day, in multiple doses, for 28 days. Patients experiencing a clinical benefit from treatment continued receiving daily doses of pegcetacoplan for up to two years, after which they could either enter an eight-week follow-up period or enroll in an extension study evaluating the long-term safety and efficacy of pegcetacoplan. Any patient who discontinued eculizumab therapy continued to receive pegcetacoplan monotherapy.

Primary endpoints included the number and severity of treatment-emergent adverse events (AEs) and pegcetacoplan pharmacokinetic parameters. The investigators also analyzed pharmacodynamic endpoints such as Hb, lactate dehydrogenase (LDH), total bilirubin, and serum C3 levels. The number of packed red blood cell (RBC) transfusions administered during the study also was recorded.

At the time of this report, six patients had received treatment for up to two years, including four who were enrolled in the extension phase and had discontinued eculizumab. A total of 427 treatment-emergent AEs were reported, of which 68 were considered possibly related to the study drug. Of these, 48 were related to the injection site.

Two patients experienced a total of 12 serious AEs, of which eight were considered treatment emergent. These included:

  • pyrexia
  • anemia
  • lower gastrointestinal hemorrhage
  • pancreatitis
  • portal vein thrombosis
  • sepsis
  • urinary tract infection
  • alanine aminotransferase/aspartate aminotransferase elevation

Pharmacokinetic analyses revealed a dose-response relationship, the researchers reported, with higher pegcetacoplan serum concentration with increasing dose. Peak serum concentration was generally observed a week after dosing, reflecting a slow absorption phase by subcutaneous administration. An increase in serum C3 levels was observed in all participants, rising to 270% of baseline values by two years of treatment.

The investigators also observed improvements in hematologic response from baseline, including increased in Hb levels by day 29 of pegcetacoplan treatment and reductions in the need for RBC transfusions.

“The changes observed in biochemical markers over the course of this study support the broad control of hemolysis by pegcetacoplan, which allowed for a dose reduction in eculizumab therapy and, ultimately, a switch to pegcetacoplan monotherapy in all four subjects who completed the study,” the researchers wrote. These four patients also achieved transfusion avoidance.

The findings of this early-phase study are limited by its open-label design and small number of patients. The authors noted that pegcetacoplan is being evaluated patients with treatment-naïve PNH and other studies are evaluating the optimal dosing regimen.

Study authors report relationships with Apellis Pharmaceuticals, the manufacturer of pegcetacoplan.


de Castro C, Grossi F, Weitz IC, et al. C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab. Am J Hematol. 2020;95:1334-1343.