MDS-113 Pegcetacoplan Rapidly Stabilizes Complement-Inhibitor Naïve Patients With Paroxysmal Nocturnal Hemoglobinuria Experiencing Hemolysis With Acute Hemoglobin Decreases: A Post Hoc Analysis from the Phase 3 PRINCE Trial

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by chronic complement-mediated hemolysis. Pegcetacoplan is an FDA/EMA-approved C3 complement-inhibitor that provides broad hemolysis control in patients with PNH. In this time-aligned post hoc analysis the efficacy of pegcetacoplan in control rescue patients was evaluated in the phase 3, randomized, open-label PRINCE trial (NCT04085601). PRINCE (2019-2021) enrolled 53 adults (≥18 years), complement-inhibitor naïve (no prior eculizumab/ ravulizumab) patients with lactate dehydrogenase (LDH) ≥1.5x the upper limit of normal (ULN; ≥339 IU/L) and hemoglobin below the lower limits of normal (males: ≤13.6 g/dL; females: ≤12.0 g/dL). Patients were randomized 2:1 to receive pegcetacoplan or control treatment (excluding complement-inhibitors) for 26 weeks. Control patients could escape to pegcetacoplan treatment (rescue arm) with hemoglobin decreases ≥2 g/dL from baseline. A post hoc analysis was performed to time-align rescue patients with pegcetacoplan patients to compare mean LDH and hemoglobin changes over time. Safety endpoints included incidences of adverse events (AEs). Within the control arm, 61.0% (11/18) of patients experienced acute hemoglobin decreases ≥2 g/dL, allowing them to escape to the pegcetacoplan arm. After escaping to pegcetacoplan, rescue patients had a rapid response to pegcetacoplan with a substantial decrease in mean LDH levels by Week 1 (422.1 IU/L) achieving ≤1.5x ULN; by Week 2, mean LDH levels were in the normal range (186.6 IU/L), suggesting complete control of intravascular hemolysis. These levels were similar to pegcetacoplan patients at Week 4 (150.4 IU/L). Similar improvements in mean hemoglobin levels were seen in most rescue patients compared to pegcetacoplan patients. No deaths or serious AEs related to pegcetacoplan occurred or led to study drug discontinuation. Most common AEs were injection site reactions (pegcetacoplan [including rescue patients], 30.4%; control, 0.0%), hypokalemia (pegcetacoplan, 13.0%; control, 11.1%), dizziness (pegcetacoplan, 10.9%; control, 0.0%), and fever (pegcetacoplan, 8.7%; control, 0.0%). Pegcetacoplan treatment was able to rapidly stabilize complement-inhibitor naïve patients experiencing acute hemolysis by normalizing LDH and raising hemoglobin levels, such that over time the treatment effect was largely similar between pegcetacoplan and rescue patients. Pegcetacoplan represents a new effective therapeutic option with a favorable safety profile for patients with PNH.