Reduced Iron Overload with Pegcetacoplan Treatment in Eculizumab-Experienced Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Shammo Jamile , Yeh Michael , Hillmen Peter , Kuter David J 
Published: December 2024

Introduction: Although C5 inhibitors (eg, eculizumab) effectively treat intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH), extravascular hemolysis (EVH) and transfusion-dependent anemia may occur, causing transfusional iron overload (IO). EVH can also increase erythropoiesis which decreases hepcidin concentrations, thereby enhancing iron absorption and furthering IO. Increased ferritin, an established marker of IO, can occur with C5 inhibitors even without transfusions. In the Phase 3 PEGASUS trial (NCT03500549), pegcetacoplan, a complement C3/C3b inhibitor, increased hemoglobin concentrations and reduced transfusion needs in patients with PNH who had previously received eculizumab for 3-4 years. Approximately 75% of PEGASUS patients needed a transfusion the year before trial entry, likely due to treatment-related EVH. The current post hoc analysis investigated the effect of pegcetacoplan on iron regulation in eculizumab-experienced patients with IO at trial entry.
Methods: In PEGASUS, adults with PNH with residual anemia on C5 inhibitors received 4 weeks of eculizumab plus pegcetacoplan (run-in), then eculizumab or pegcetacoplan for 16 weeks. In the subsequent 32-week open-label period, patients continued pegcetacoplan for up to 52 weeks or switched from eculizumab to pegcetacoplan for up to 32 weeks of pegcetacoplan treatment. Baseline was prior to run-in for pegcetacoplan-randomized patients and week 20 (prior to pegcetacoplan initiation in the open-label period) for the eculizumab-randomized patients. Patients did not fast before blood sampling. The current analysis included all patients with baseline IO (defined as serum transferrin saturation ≥50%; conversely, IO is considered resolved when transferrin saturation is &lt;50%). Transfusion needs and IO status were measured before and during the trial.
Results: In PEGASUS, 27 evaluable patients receiving eculizumab had baseline IO. Patients with IO at baseline had a mean (standard deviation [SD]) transferrin saturation of 64.6% (11.4%) at baseline. Five patients with IO at baseline did not have IO data available after pegcetacoplan treatment. In patients with post-baseline IO data, IO resolved in 72.7% (16 of 22); IO had not resolved in 6 patients (27.3%). Of the 16 patients with resolved IO, most experienced IO resolution at 20 weeks of pegcetacoplan treatment (n=10; mean [SD] transferrin saturation 31.8% [12.1%]); 4 patients had IO resolution at 32 weeks (mean [SD] transferrin saturation 32.9% [10.1%]), 1 had IO resolution at 40 weeks (transferrin saturation 47.6%), and 1 had IO resolution at 52 weeks (transferrin saturation 39.7%). Of the 6 patients with unresolved IO, 2 had a high transfusion burden during PEGASUS (15 units each), with both patients experiencing breakthrough hemolysis (1 patient with 2 events, 1 patient with 1 event) accompanied by potential complement amplifying conditions. Patients with unresolved IO after pegcetacoplan treatment also had more active disease at baseline, evident by more red blood cell units transfused prior to baseline (22.7 units vs 16.1 units).
Conclusions: IO, as defined here, resolved with pegcetacoplan in 72.7% of patients with PNH who had ongoing anemia and baseline IO on eculizumab. This suggests that the EVH control and improved anemia afforded by pegcetacoplan can improve iron regulation in patients with PNH. Resolution of IO can be rapid as transferrin saturation &lt;50% was often reported at week 20, the earliest timepoint assessed. Patients with IO that did not resolve with pegcetacoplan had greater transfusion needs before the trial and 2 of these patients had a substantial transfusion burden during the trial; it is possible that the higher underlying disease activity and/or increased transfusion needs could have contributed to the ongoing IO.