Improvements in hematologic markers and decreases in fatigue with pegcetacoplan for patients with paroxysmal nocturnal hemoglobinuria and mild or moderate anemia (hemoglobin ≥10 g/dL) who had received eculizumab or were naive to complement inhibitors

Abstract

Background: Although complement component 5 inhibitors (C5is) eculizumab and ravulizumab improve paroxysmal nocturnal hemoglobinuria (PNH) outcomes, patients may experience persistent anemia. This post hoc analysis investigated whether the complement component 3-targeted therapy pegcetacoplan also improved hematologic outcomes and reduced fatigue in patients with PNH and mild/moderate anemia.

Methods: Patients with PNH and hemoglobin ≥10.0 g/dL at baseline of PADDOCK (N = 6), PRINCE (N = 8), and PEGASUS (N = 11) were included. Before receiving pegcetacoplan, PADDOCK and PRINCE patients were C5i-naive; PEGASUS patients had hemoglobin <10.5 g/dL despite stably dosed eculizumab. Hemoglobin concentrations, percentages of patients with concentrations ≥12 g/dL, and sex-specific normalization were assessed at baseline and after 16 weeks of pegcetacoplan, as were absolute reticulocyte counts (ARCs) and normalization and fatigue scores and normalization.

Results: From baseline to week 16, mean (SD) hemoglobin concentrations increased in C5i-naive patients (PADDOCK: 10.5 [0.4] to 12.7 [1.1] g/dL; PRINCE: 11.3 [1.0] to 14.0 [1.3] g/dL) and those with suboptimal eculizumab responses (PEGASUS: 10.2 [0.2] to 12.8 [2.6] g/dL). Percentage of patients with hemoglobin ≥12 g/dL increased (PADDOCK: 0 to 60.0% [3 of 5 patients]; PRINCE: 25.0% [2 of 8] to 87.5% [7 of 8]; PEGASUS: 0 to 72.7% [8 of 11]). Sex-specific hemoglobin normalization at week 16 occurred in 40.0% (2 of 5) (PADDOCK), 62.5% (5 of 8) (PRINCE), and 63.6% (7 of 11) (PEGASUS). In all studies, mean ARCs decreased from above normal to normal and ARC normalization increased. Mean Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from below to above or near normal. Two patients had serious adverse events (PEGASUS: post-surgery sepsis, breakthrough hemolysis); breakthrough hemolysis resolved without study discontinuation.

Conclusion: Patients with PNH and mild/moderate anemia who were C5i-naive or who had suboptimal hemoglobin concentrations despite eculizumab treatment had improved hematologic outcomes and reduced fatigue after initiating or switching to pegcetacoplan.

Trial registration: Trial registration numbers: PADDOCK (NCT02588833), PRINCE (NCT04085601; EudraCT, 2018-004220-11), PEGASUS (NCT03500549).

Fig 1

Hemoglobin concentrations over time for patients with PNH and mild/moderate anemia (hemoglobin ≥10 g/dL) for individual patients and the total populations for the PADDOCK (A), PRINCE (B), and PEGASUS (C) trials. Gray lines represent individual patient hemoglobin concentrations and the red line represents the mean hemoglobin concentrations of patients with mild/moderate anemia in each trial. LLN, lower limit of normal; PNH, paroxysmal nocturnal hemoglobinuria. ^aLLN for female patients, 12 g/dL. ^bThis analysis was performed using week 16 as the baseline for patients who received eculizumab.

Fig 2

Percentage of patients with a hemoglobin concentration ≥12 g/dL (A) or sex-specific hemoglobin normalization (B) at baseline and after 16 weeks of pegcetacoplan for patients with PNH and mild or moderate anemia (hemoglobin ≥10 g/dL) in the PADDOCK, PRINCE, and PEGASUS trials. The hemoglobin response and normalization analyses included all patients in the post hoc analysis unless noted otherwise. Patients who received transfusions, withdrew from the study, or were missing data at each time point were classified as nonresponders. Sex-specific hemoglobin normalization was defined as hemoglobin concentrations greater than or equal to the sex-specific LLN (13.6 g/dL, male patients; 12.0 g/dL, female patients) and the absence of transfusions. LLN, lower limit of normal; PNH, paroxysmal nocturnal hemoglobinuria. ^aData from 1 patient who stopped dosing at day 29 and left the study per physician decision were not included in this analysis.

Fig 3

ARCs over time for patients with PNH and mild/moderate anemia (hemoglobin ≥10 g/dL) for individual patients and the total populations for the PADDOCK (A), PRINCE (B), and PEGASUS (C) trials. Gray lines represent individual patient ARCs and the red line represents the mean ARCs of patients with mild/moderate anemia in each trial. ARC, absolute reticulocyte count; LLN, lower limit of normal; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit of normal. ^aNormal reference ranges: 30–100×10⁹ cells/L. ^bThis analysis was performed using week 16 as the baseline for patients who received eculizumab.

Fig 4. ARC normalization at baseline and after 16 weeks of pegcetacoplan treatment are shown for patients with PNH and mild/moderate anemia (hemoglobin ≥10.0 g/dL) in the PADDOCK, PRINCE, and PEGASUS trials.

The normalization analysis included all patients in the post hoc analysis unless noted otherwise. Patients who received transfusions, withdrew from the study, or were missing data at each time point were classified as nonresponders. Normalization of ARC is defined as ≤ULN (120×10⁹ cells/L) and the absence of transfusions. ARC, absolute reticulocyte count; LLN, lower limit of normal; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit of normal. ^aData from 1 patient who stopped dosing at day 29 and left the study per physician decision were not included in this analysis.

Fig 5

LDH concentrations over time for patients with PNH and mild/moderate anemia (hemoglobin ≥10 g/dL) for individual patients and the total populations for the PADDOCK (A), PRINCE (B), and PEGASUS (C) trials. Gray lines represent individual patient LDH concentrations and the red line represents the mean LDH concentration of patients with mild/moderate anemia in each trial. LDH, lactate dehydrogenase; LLN, lower limit of normal; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit of normal. ^aNormal reference range: 113–226 U/L. ^bThis analysis was performed using week 16 as the baseline for patients who received eculizumab.

Fig 6. LDH analysis at baseline and after 16 weeks of pegcetacoplan treatment for patients with PNH and mild/moderate anemia (hemoglobin ≥10.0 g/dL) in the PADDOCK, PRINCE, and PEGASUS trials.

The normalization analysis included all patients in the post hoc analysis unless noted otherwise. Patients who received transfusions, withdrew from the study, or were missing data at each time point were classified as nonresponders. Normalization of LDH is defined as ≤226 U/L and the absence of transfusions. LDH, lactate dehydrogenase; LLN, lower limit of normal; PNH, paroxysmal nocturnal hemoglobinuria; ULN, upper limit of normal. ^aData from 1 patient who stopped dosing at day 29 and left the study per physician decision were not included in this analysis.

Fig 7

FACIT-Fatigue scores over time for patients with PNH and mild/moderate anemia (hemoglobin ≥10 g/dL) for individual patients and the total populations for the PADDOCK (A), PRINCE (B), and PEGASUS (C) trials. Gray lines represent individual patient FACIT-Fatigue scores and the red line represents the mean FACIT-Fatigue scores of patients with mild/moderate anemia in each trial. FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue; PNH, paroxysmal nocturnal hemoglobinuria. ^aGeneral population norm: 43.6. Defined by Cella et al [28]. ^bThis analysis was performed using week 16 as the baseline for patients who received eculizumab.

Fig 8. FACIT-Fatigue score normalization at baseline and after 16 weeks of pegcetacoplan treatment are shown for patients with PNH and mild/moderate anemia (hemoglobin ≥10.0 g/dL) in the PADDOCK, PRINCE, and PEGASUS trials.

The normalization analysis included all patients in the post hoc analysis unless noted otherwise. Patients who received transfusions, withdrew from the study, or were missing data at each time point were classified as nonresponders. Normalization of FACIT-Fatigue was defined as an increase in FACIT-Fatigue score to greater than or equal the general population mean of 43.6 [28] and the absence of transfusions. FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue; PNH, paroxysmal nocturnal hemoglobinuria. ^aData from 1 patient who stopped dosing at day 29 and left the study per physician decision were not included in this analysis.