Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

Abstract

BACKGROUND:

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis.

METHODS:

We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed.

RESULTS:

Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group.

CONCLUSIONS:

Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

• Authors: Peter Hillmen, Jeff Szer, Ilene Weitz, Alexander Röth, Britta Höchsmann, Jens Panse, Kensuke Usuki, Morag Griffin, Jean-Jacques Kiladjian, Carlos de Castro, Hisakazu Nishimori, Lisa Tan, Mohamed Hamdani, Pascal Deschatelets, Cedric Francois, Federico Grossi, Temitayo Ajayi, Antonio Risitano, Régis Peffault de la Tour
• Journal: The New England journal of medicine (N Engl J Med) Vol. 384 Issue 11 Pg. 1028-1037 (03 18 2021) ISSN: 1533-4406 [Electronic] United States
• PMID: 33730455 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Massachusetts Medical Society.

Chemical References

• Antibodies, Monoclonal, Humanized
• Complement C3
• Complement C5
• Complement Inactivating Agents
• Hemoglobins
• Peptides
• Peptides, Cyclic
• eculizumab
• pegcetacoplan

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Complement C3 (antagonists & inhibitors)
• Complement C5 (antagonists & inhibitors)
• Complement Inactivating Agents (adverse effects, therapeutic use)
• Diarrhea (chemically induced)
• Drug Therapy, Combination
• Erythrocyte Transfusion
• Hemoglobins (analysis)
• Hemoglobinuria, Paroxysmal (blood, drug therapy, therapy)
• Humans
• Injections, Subcutaneous (adverse effects)
• Middle Aged
• Peptides (adverse effects, therapeutic use)
• Peptides, Cyclic