MDS-112 Normalization of Hematologic and Health-Related Quality of Life Markers in Patients With Paroxysmal Nocturnal Hemoglobinuria Treated With Pegcetacoplan and Baseline Hemoglobin at or Above 10 g/dL

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by chronic complement-mediated hemolysis. PNH-associated symptoms include anemia and fatigue, with patients requiring frequent blood transfusions. Pegcetacoplan is an FDA/EMA-approved C3 complement inhibitor for adults with PNH. Evaluate normalization rates of hematologic markers, fatigue, and safety after 16 weeks of pegcetacoplan monotherapy in a subgroup of patients with PNH and baseline hemoglobin levels ≥10.0 g/dL from the PEGASUS (NCT03500549), PADDOCK (NCT02588833), and PRINCE (NCT04085601) studies. PEGASUS (2018-2020) enrolled patients with hemoglobin levels <10.5 g/dL at screening despite stable eculizumab treatment (≥3 months) and randomized patients 1:1 to eculizumab or pegcetacoplan for the 16-week randomized controlled period (RCP). Eculizumab-treated patients in the RCP switched to pegcetacoplan through week 48 for the open-label period. PADDOCK (2015-2019) and PRINCE (2019-2021) evaluated pegcetacoplan in complement inhibitor-naïve patients. PRINCE compared pegcetacoplan to control (excluding eculizumab/ravulizumab) in patients with hemoglobin levels below gender-specific lower limits of normal. This post-hoc analysis included adults with PNH, baseline hemoglobin levels ≥10.0 g/dL, and no transfusions within 14 days of baseline. Hemoglobin, lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue normalization were evaluated after pegcetacoplan monotherapy for 16 weeks. Patients who withdrew or were lost to follow-up without efficacy data at specified timepoints were considered not normalized. Safety endpoints included incidences of adverse events (AEs). This analysis included 22 patients: 9 PEGASUS, 5 PADDOCK, and 8 PRINCE. Sixteen weeks of pegcetacoplan monotherapy led to increases in hemoglobin (PEGASUS: 66.7%; PADDOCK: 40.0%; PRINCE: 62.5%) and LDH (PEGASUS: 77.8%; PADDOCK: 60.0%; PRINCE: 100.0%) normalization rates, with similar results in ARC and FACIT-Fatigue. No serious AEs were reported in PADDOCK or PRINCE subgroups. One PEGASUS patient had a serious AE (breakthrough hemolysis; severe, unrelated to pegcetacoplan, resolved, no discontinuation) following upper respiratory infection. Injection site reactions and infections/infestations occurred at similar rates among subgroups. No thrombotic events occurred in this subgroup. Results suggest pegcetacoplan can be efficacious in patients with less severe anemia regardless of prior complement inhibitor treatment, further improving clinical markers of hemolysis and fatigue. The safety profile of pegcetacoplan was consistent with previous studies.