Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Historically, PNH was treated with C5 inhibitors (eculizumab [ECU)/ravulizumab). Despite their proven efficacy in the control of intravascular hemolysis (IVH), up to 72% of patients experience persistent hemolysis leading to suboptimal hemoglobin (Hb) levels and 36% require transfusions despite ECU treatment which results in a significant impact on the quality of life (QoL), including persistent fatigue. Pegcetacoplan (PEG) is an FDA/EMA-approved C3 complement-inhibitor that provides broad hemolysis control (including IVH and extravascular hemolysis) in patients with PNH. Aims: This analysis evaluates QoL measures in the Phase 3 PRINCE study (NCT04085601), a multicenter, randomized, open-label, controlled study evaluating the efficacy and safety of PEG compared to control treatment (CTRL; excluding complement-inhibitors) in complement-inhibitor naïve patients with PNH. Methods: PRINCE has been described previously and was superior for the coprimary endpoints of hemoglobin (Hb) stabilization (avoidance of >1 g/dL decrease in Hb from baseline), change from baseline in lactate dehydrogenase at 26 weeks and PEG-treated patients saw clinically meaningful increases in the FACIT-Fatigue scores (Wong SR, et al. Blood 2021; 138 [Supplement 1]: 606). Secondary endpoints specific to QoL measures included the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale (EORTC QLQ-C30), Linear Analog Scale Assessment (LASA) and The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). The EORTC QLQ-C30 contains 30 questions comprising 5 functional, 9 individual symptoms, and one global health status/QoL item(s), where a ≥10-point change in score is considered clinically meaningful. The LASA consists of 3 sections asking to rate the perceived level of functioning (scale 0-100, where a higher score corresponds to a better QoL) and contains specific domains for activity level, ability to carry out daily activities, and overall QoL. The FACIT-Fatigue is a 13-item Likert scaled instrument (scale 0-51), where a ≥3-point increase is considered clinically meaningful. Results: Relevant baseline characteristics for PRINCE are reported in Table A. Mean baseline scores of the EORTC QLQ-C30 functional and symptom scales were generally similar between groups (except for role and cognitive functioning and insomnia; Table B). After 26 weeks of PEG-treatment, patients displayed clinically meaningful improvements in most of the functional scales and the global health status/QoL at Week 26 as indicated by a ≥10-point score increase from baseline (Table B). Improvements in the symptom scales, including fatigue and dyspnea scales, were also observed in the PEG group at Week 26 as indicated by a reduction in the symptom score close to the general population norms (general population norm: fatigue: 24.1, dyspnea: 10.9). Mean total LASA scores increased in the patients receiving PEG treatment for 26 weeks (Table B). FACIT-Fatigue scores increased for PEG-treated patients to near the general population norm [43.6], supporting the gains shown in the EORTC QLQ-C30-Fatigue scale. Image:Summary/Conclusion: Substantial and clinically relevant improvements in QoL were consistently observed with PEG across both EORTC QLQ-C30, total LASA and FACIT-Fatigue scores and clinically significant improvements in fatigue and dyspnea are highly relevant to the symptomology of PNH.