A First Report from the COMPLETE Study on the Real-World Effectiveness of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is caused by complement-mediated hemolysis, resulting in increased thrombosis risk and a substantial symptom burden. Complement C5 inhibitors (C5i) reduce intravascular hemolysis (IVH); however, hemolysis and anemia can persist with C5i in up to 91% of patients (pts), which may lead to transfusion dependence and impaired quality of life (Panse et al. 2022). Pegcetacoplan is a novel complement C3 and C3b inhibitor that targets IVH without inducing extravascular hemolysis. In Phase 3 trials, pegcetacoplan significantly improved hemoglobin (Hb) levels and other clinical parameters in C5i-experienced (PEGASUS) and -naïve (PRINCE) adult PNH pts. Pegcetacoplan was approved by FDA in 2021 for adult PNH pts and by EMA in 2021 for adult PNH pts who are anemic after C5i treatment for ≥3 months, expanding to any adult pts with hemolytic anemia in 2024. Aim Describe real-world effectiveness of pegcetacoplan in the treatment of adult PNH pts. Methods COMPLETE (NCT05776472) is an ongoing Phase 4, multicenter, observational study aiming to recruit 200 pts from 80 sites in Europe, Saudi Arabia, Canada, and Australia. The study includes C5i-experienced and -naïve adult PNH pts who started pegcetacoplan before enrollment or were prescribed pegcetacoplan at enrollment. The primary endpoint is change in Hb level from pegcetacoplan start to 6 months. Changes in lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), bilirubin, and ferritin, as well as alleviation of anemia (achievement of Hb ≥12 g/dL or Hb increase of ≥2 g/dL) are evaluated from treatment initiation and at 6-month intervals until the end of study. The annualized number and units of red blood cell transfusions (RBCT) are examined. Adverse events including acute hemolytic (AH) events are recorded. The main part of the study includes a prospective observation period of 24 months. The study also collects retrospective pegcetacoplan treatment data and is supplemented by retrospective data for up to 12 months before pegcetacoplan start. Results As of 16 Jun 2024, 32 eligible pts were enrolled from 13 sites in 6 countries. At baseline (pegcetacoplan initiation), median age was 57.4 years (interquartile range [IQR] 35.2-68.9) and 46.9% of pts were female. Before pegcetacoplan initiation, aplastic anemia was recorded in 12 pts. Median time from PNH diagnosis to pegcetacoplan initiation was 52.6 months (IQR 27.4-119.9). 94% (30/32) of pts were previously treated with a C5i. 87% (20/23) of pts had Hb <10.5 g/dL and median Hb was 9.4 g/dL (IQR 8.6-10.0). Median LDH was 299.5 U/L (IQR 222.0-414.0), median total bilirubin was 23.9 µmol/L (IQR 18.4-41.6), median ARC was 187.9×109/L (IQR 130.8-220.0), and median ferritin was 622 µg/L (IQR 189-1262). Pts received pegcetacoplan 1080 mg twice weekly for a median of 11.4 months (range: 1.2-18.0, IQR 7.1-14.0). From baseline to 6 months, median increase in Hb (n=20) was 2.2 g/dL (IQR 0.6-3.1; median Hb at 6 months was 11.1 g/dL [n=24]), and in 11 pts (55%) Hb increased by ≥2 g/dL. No pt (0%, n=20) at baseline vs 8 pts (33%, n=24) at 6 months had Hb ≥12 g/dL. Median (IQR) changes in other hematologic parameters at 6 months were: LDH (n=13) decreased by 106.0 U/L (19.0-225.0), total bilirubin (n=18) decreased by 11.1 µmol/L (3.0-47.7), ARC (n=17) decreased by 81.0×109/L (60.0-135.0), and ferritin (n=9) decreased by 64 µg/L (29-257). The median (IQR) number of annualized RBCT (n=31) was 0 (0-3) in the ≤12 months before pegcetacoplan start (n=10 pts had RBCT) vs 0 (0-0) in the ≤12 months following pegcetacoplan start. During pegcetacoplan, 7 pts had RBCT. AH events requiring additional intervention (n=24) were seen in 4 pts (16.7%) at 6 months. Two serious adverse events (SAEs) unrelated to pegcetacoplan and 2 treatment discontinuations were reported. Conclusions The COMPLETE study started in 2023 and is enrolling a wide range of pts reflecting the real-world treatment landscape in PNH. Baseline data highlight a need for improved treatment. After 6 months of pegcetacoplan treatment, pts experienced rapid improvements in hematologic parameters, consistent with benefits observed in clinical trials. Median (IQR) percentage increase in Hb was 24.2% (5.4%-34.1%) and 55% of pts had a Hb increase of ≥2 g/dL. There were no pegcetacoplan-related SAEs. As the study progresses, additional data will expand our understanding of the real-world effectiveness of pegcetacoplan in PNH patients.

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