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

Context: 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. Objective: 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. Design: 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 Transfusion recipients (hemoglobin/LDH endpoints only), patients withdrawn or lost to follow-up, or control-escape patients (PRINCE) were considered not normalized.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). Results: 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. Conclusions: 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.