Introduction PNH is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan (PEG), a C3/C3b inhibitor approved for adults with PNH, controls intravascular (IVH) without inducing extravascular hemolysis (EVH). In the pivotal phase 3 trials PEGASUS (NCT03500549) and PRINCE (NCT04085601) clinical improvements were shown in PNH patients (pts) with (HAA) and without a history of aplastic anemia (NoHAA) (Usuki et al JSH 2022; Bogdanovic et al, EHA 2023). Here we present interim data from the Phase 4 COMPLETE study (NCT05776472) on the real-world effectiveness of PEG treatment in pts with HAA and NoHAA.

Methods COMPLETE is a 36-month international, observational study enrolling 200 adult (≥18 years old) pts with PNH treated with PEG. It includes retrospective data collection up to 12 months prior to PEG initiation. The primary objective is to evaluate hemoglobin (Hb) level at 6 months after PEG initiation. Secondary objectives include assessing changes in lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and improvement in Hb (defined as achieving ≥12 g/dL or an increase ≥2 g/dL from baseline) from the start of PEG treatment and every 6 months. Transfusion (Tx) support requirements and adverse events (AEs) are recorded. Baseline characteristics have been previously presented (Peffault de Latour et al, EHA 2025). Baseline disease characteristics (Hb, ARC, LDH) were comparable between the HAA and NoHAA cohorts.

Results As of 12 January 2025, 70 pts were recruited: 24 had a confirmed HAA, 43 had NoHAA and 3 were missing data on Aplastic Anemia (AA) history. The median (IQR) duration of PEG treatment was 11.7 months (6.0- 20.9) in the HAA group and 17.3 months (10.1- 23.0) in the NoHAA group. A total of 15 pts in the HAA group and 32 pts in the NoHAA group were included in the 6-month analysis.

At 6 months after PEG initiation, median Hb increase was 2.0 g/dL (IQR: 0.9- 3.0) in the HAA group and 2.6 g/dL (IQR: 0.8- 3.5) in the NoHAA group, rising from baseline values of 8.7 g/dL (IQR: 8.3- 10.0) and 9.4 g/dL (IQR: 8.8- 10.3), respectively (pts with available Hb data at 6 months: HAA, N=14; NoHAA, N=31). Median Hb at 6 months was 11.2 g/dL (IQR: 10.3- 12.5) in the HAA group and 11.7 g/dL (IQR: 10.5- 13.0) in the NoHAA group. At 6 months, 33.3% (5/15) in the HAA group achieved Hb levels ≥12 g/dL (0% at baseline) versus 46.9% (15/32) of pts in the NoHAA group (6.5% at baseline). These improvements were maintained at 12 months with median Hb levels of 11.5 g/dL (IQR: 10.9- 12.3, N=8) and 11.2 g/dL (IQR: 9.2- 12.2, N=19) in the HAA and NoHAA groups, respectively.

A clinically meaningful Hb increase was accompanied by corresponding benefits in LDH, ARCs, and Tx needs regardless of prior AA history. For the HAA group, the median LDH improved from 340.0 U/L (IQR: 303.0- 369.0, N=13) to 192.0 U/L (IQR: 161.0- 238.0, N=14) and ARC from 174×10⁹ cells/L (IQR: 145- 205) to 96x10⁹ cells/L (IQR: 62.0- 118.7, N=14) from baseline to 6 months. For the NoHAA group, the median LDH improved from 291.0 U/L (IQR: 228.0- 365.0, N=28) to 227.0 U/L (IQR:180.0-265.0, N=29), and ARC from 217×10⁹ cells/L (IQR: 171- 265, N=25) to 105 x10⁹ cells/L (IQR: 81.8- 136.6, N=29) from baseline to 6 months. In the HAA group, during the first 12 months on PEG treatment 12.5% (3/24) pts received RBC Tx compared to 29.2% (7/24) in the year prior to PEG initiation. In the NoHAA group, 18.6% (8/43) of pts received RBC Tx during the first 12 months of PEG treatment, compared to 27.9% (12/43) in the year prior to initiation.

No hemolytic events requiring additional intervention were reported at 6 and 12 months in the HAA group, compared to 6 of 32 pts at 6 months and 6 of 28 pts at 12 months, in the NoHAA group. Up to the data cut, 4 serious adverse events (SAEs) occurred in 3 HAA pts; 1 SAE (headache) was deemed related to PEG and led to discontinuation. In the NoHAA group, 3 SAEs were reported in 3 pts, all unrelated to PEG, with no treatment discontinuations.

Conclusions PEG treatment led to sustained improvements in markers of hemolytic anemia, Hb, LDH and ARC, and decreased RBC transfusion requirements in pts with PNH in real world settings, regardless of history of AA. The safety profile was consistent with previous findings, with SAEs being infrequent and largely unrelated to PEG. These findings confirm the meaningful clinical benefits of PEG in managing PNH and demonstrate its effectiveness across diverse patient populations.

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2025
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