MDS-111 Hemoglobin, Lactate Dehydrogenase, and FACIT-Fatigue Normalization in Pegcetacoplan-Treated Patients With Paroxysmal Nocturnal Hemoglobinuria from Two Phase 3 Clinical Trials

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease involving complement-mediated hemolysis. Pegcetacoplan is the first FDA/EMA-approved C3 complement-inhibitor for adults with PNH. We report hemoglobin, lactate dehydrogenase (LDH), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue normalization rates in the phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. The PEGASUS study (2018-2020) randomized patients with hemoglobin levels <10.5 g/dL at screening despite stable eculizumab treatment (≥3-months) 1:1 to pegcetacoplan (n=41) or eculizumab (n=39) for the 16-week randomized controlled period (RCP). Eculizumab-treated patients switched to pegcetacoplan during the open-label period through Week 48. The 26-week PRINCE study (2019-2021) randomized complement-inhibitor naive patients 2:1 to pegcetacoplan (n=35) or control treatment ([n=18] without complement-inhibitors: eculizumab/ravulizumab). Normalization was defined separately as hemoglobin ≥gender lower limit of normal, LDH ≤upper limit of normal, and FACIT-Fatigue scores ≥population norm (43.6). Transfusion recipients (hemoglobin/LDH endpoints only), patients withdrawn or lost to follow-up, or control-escape patients (PRINCE) were considered not normalized. Safety endpoints included incidences of adverse events (AEs). Pegcetacoplan demonstrated rapid treatment effects in both studies; Week 2 hemoglobin normalization rates were 43.9% (PEGASUS, baseline 0%) and 22.9% (PRINCE, baseline 2.9%) and Week 2 LDH normalization rates were 87.8% (PEGASUS, baseline 41.5%) and 51.4% (PRINCE, baseline 0%). At Week 16 (PEGASUS) and Week 26 (PRINCE), higher normalization rates were achieved with pegcetacoplan versus respective comparator treatments in hemoglobin (PEGASUS: 34.1% versus 0%; PRINCE: 45.7% versus 0%), LDH (PEGASUS: 70.7% versus 15.4%; PRINCE: 65.7% versus 0%), and FACIT-Fatigue (PEGASUS: 48.8% versus 10.3%; PRINCE: 60.0% versus 11.1%). Numerically similar results were observed at Week 48 in PEGASUS patients randomized to pegcetacoplan or switched from eculizumab to pegcetacoplan. Common AEs in pegcetacoplan-treated patients were injection site reactions (ISRs), diarrhea, abdominal pain, nasopharyngitis, upper respiratory tract infection, hemolysis, cough, and headache for PEGASUS, and ISRs, hypokalemia, and dizziness for PRINCE. Pegcetacoplan rapidly enables higher rates of hemoglobin and LDH normalization, and improvements in FACIT-Fatigue scores compared to eculizumab and control treatment. This further supports the rapid treatment effect of pegcetacoplan in improving clinical parameters and health-related quality of life with a favorable safety profile.