Real-world effectiveness of pegcetacoplan in paroxysmal nocturnal hemoglobinuria: A systematic review of clinical and patient-reported outcomes

Abstract Background Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired, non-malignant hematological disorder that, if left untreated, can lead to significant morbidity and mortality. Pegcetacoplan (PEG), a complement 3/3b inhibitor (C3i) available since 2021, has demonstrated efficacy and safety in Phase 3 trials in both, complement 5 inhibitor-naïve (C5i-n) and C5i-experienced (C5i-e) patients with PNH. Real-world evidence (RWE) has provided further insights to inform clinical decision-making. This systematic literature review (SLR) summarizes the RWE for PEG in PNH. Methods The SLR (PROSPERO CRD420251043506) followed 2020 PRISMA guidelines and included RW studies of PEG (published in English; to April 2025) evaluating clinical and patient-reported outcomes in adults (age ≥18 years) with PNH. Results Searches of published articles and congress abstracts/presentations identified 409 records; 39 (including 13 full-text) from 28 studies met the review criteria. Four were multinational, 8 US, 12 EU, 1 UK, 1 Australian, 1 Japanese, 1 unspecified. Of 11 studies of n>1 pts reporting hemoglobin levels (Hb), 6 (n=4–39) reported median (mdn) Hb with baseline values 8.1–9.6 g/dL. Ending mdn Hb and maximum (max) PEG durations were 12.0 g/dL at 12 months (mos; 2 studies), 11.1–12.1 g/dL at 6 mos (3 studies), and 11.1 g/dL at 3 mos (1 study). In an n=63 study, mean (mn) baseline Hb of 7.4 in C5i-n increased to 11.7 g/dL after 8.4 mos max PEG duration, and mn baseline Hb of 9.1 g/dL in C5i-e to 11.3 g/dL after max 7.2 mos of PEG. In 4 other studies (n=48–70), ending mn Hb (max PEG duration) were 11.3 g/dL (7.2 mos), 11.5 g/dL (6.6 mos), 11.5 g/dL (5.9 mos), and 11.58 g/dL (3 mos) Seven studies reported absolute reticulocyte count (ARC; n=4–48) from baseline mdn 155–301×10⁹/L reduced to mdn 56–107×10⁹/L as early as 14 days from PEG initiation, with levels maintained to max PEG durations of 1–12 mos. Of 8 studies reporting lactate dehydrogenase (LDH; n=46–63), 7 showed reductions from baseline after PEG initiation (1 no change). Three studies reported mdn absolute LDH after max PEG durations, from baseline mdn 543.0 decreasing to 161.7 U/L after 3 mos, and baseline mdn 299.5–316.0 U/L to 193.5–187.0 U/L after 6 mos. Mn LDH in 2 studies decreased in C5i-n from 977.8 to 358.9 U/L after 8.4 mos, and 503.6 to 292.5 U/L in C5i-e after 7.2 mos. Four studies (n=4–63) reported LDH relative to upper limit of normal; 3 with reductions to normal levels and 1 with no changes. Six studies (n=23–70) reported reduced red blood cell transfusions (RBCt) after max PEG durations of 6 mos, ≤12 mos, or 16.7 mos (undefined in 1 study), and mdn durations of 3.0 and 10.2 mos. Case reports all consistently indicated improved outcomes after PEG initiation: increased Hb (8 studies), decreased ARC (4 studies) and LDH (4 studies), and no RBCt (3 studies). Fatigue improvement per the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale was reported in 1 study with scores increased from baseline (mn 28.4) to 3 mos (38.6), 6 mos (36.3), and 9 mos (34.9) of PEG treatment. Two studies reported FACIT-Fatigue scores of 34.6–40.1 in pts receiving PEG for ≥1 mo. EQ-5D mn utility scores (0.85–0.94) in 2 studies were comparable to population norms. On the Short-Form 36 Health Survey, mental and physical component scores were slightly lower than US norms. Two studies used Likert scales to assess health-related quality of life (HRQoL); 1 showed 27% overall improvement with PEG, while in the other, pts scored improvement as 4 (scale of 0 [none] to 5 [very much]). Two studies measured cognitive function (CF); 1 reported reduced frequency and severity of symptoms, 1 reported clinically meaningful improvement in PROMIS-CF scores after 3, 6, and 12 mos of PEG in 55.5%, 50.5%, and 46.7% of pts, respectively. Adherence was reported in 2 studies; 1 defined this as the pt taking medication exactly as prescribed, with rates of 95.1% overall, 90.1% in C5i-n, and 86.5% C5i-e. The other defined it as having ≥0.8 proportion of days covered, reporting a rate of 78.4%. Compliance (per dispense records) measured in 5 studies reported up to 97–100% compliance, with 96.6% pt and physician treatment satisfaction. Conclusions RWE indicates PEG is associated with improved hematological parameters, reduced RBCt dependence and fatigue, and enhanced HRQoL. These findings from studies with diverse cohorts support generalizability and are broadly comparable with clinical trial evidence.