Introduction: Pegcetacoplan, the first approved proximal complement C3 inhibitor, showed superiority to eculizumab in improving hemoglobin levels and clinical outcomes in the phase 3 PEGASUS study in patients with paroxysmal nocturnal hemoglobinuria (PNH) and inadequate response to eculizumab. Methods: This analysis evaluates the efficacy and safety of pegcetacoplan for Japanese patients in PEGASUS, as they are known for different clinicopathologic features compared to non-Asian patients. Ten Japanese patients were enrolled to receive pegcetacoplan (n = 5) or eculizumab (n = 5) during the 16-week randomized controlled period. All patients received pegcetacoplan monotherapy during the open-label period until week 48. Results: Treatment with pegcetacoplan improved hemoglobin with a mean change from baseline of 2.4 g/dL at week 16, which was sustained through 48 weeks. Pegcetacoplan-treated Japanese patients experienced sustained improvements in key secondary efficacy endpoints, including freedom from transfusion, lactate dehydrogenase level, reticulocyte count, and FACIT-Fatigue score. The safety profile was consistent with previously reported data from pegcetacoplan studies. No events of hemolysis, meningococcal infection, or thrombosis were reported in the Japanese population and all Japanese patients remained on treatment throughout the study. Conclusion: These data suggest that Japanese patients with PNH can be effectively and safely managed with pegcetacoplan.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening blood disorder where an acquired genetic mutation causes a patient’s complement system (a part of the immune system) to attack and destroy red blood cells, which can lead to symptoms including anemia and the formation of blood clots. For many years, the standard treatment for PNH has been complement 5 (C5) inhibitors, which target a downstream part of the complement signaling pathway. However, many PNH patients on C5 inhibitors continue to experience symptoms of the disease, including anemia and impaired quality of life (QoL). Recently, pegcetacoplan, a novel complement inhibitor targeting the complement 3 protein (an upstream part of the complement system) was shown to be superior to a C5 inhibitor in key patient outcome measures in the phase 3 clinical trial PEGASUS, including raising hemoglobin levels and improving QoL. Japanese patients with PNH are known to have different clinical and pathological features from non-Asian PNH patients. Here, we report findings of a post-hoc analysis which evaluated the efficacy, safety, and QoL in Japanese patients treated with pegcetacoplan in PEGASUS. Consistent with findings in the overall study population, our results show that Japanese PNH patients treated with pegcetacoplan derived durable treatment benefits across key outcome measures, including increasing hemoglobin levels and improving QoL scores. The safety outcomes were also similar between Japanese patients and the overall study population. Together, these findings indicate that Japanese PNH patients can be effectively and safely treated with the newly approved C3 inhibitor pegcetacoplan.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, rare, and potentially life-threatening hematological disease characterized by chronic complement-mediated hemolysis and thrombosis with a substantial patient burden [1, 2]. Patients with PNH classically present with anemia and associated fatigue, dyspnea, and the need for transfusions [1, 3, 4].

Terminal complement protein 5 (C5) inhibitors eculizumab and ravulizumab have substantially improved patient outcomes and survival [5, 6]. While C5 inhibitors reduce intravascular hemolysis (IVH), clinically relevant C3-mediated extravascular hemolysis (EVH) occurs in a substantial number of patients treated with C5 inhibitors, leading to heterogeneous hematological benefit [7‒9]. Persistently low hemoglobin levels and other symptoms due to ongoing IVH and emerging EVH impair the quality of life (QoL) of many patients receiving C5 inhibitors [4, 10‒13].

Pegcetacoplan, the first proximal C3 inhibitor developed to address both IVH and EVH [14], is approved by the Food and Drug Administration (FDA) for the treatment of adults with PNH and by the European Medicines Agency (EMA) for the treatment of adults with PNH who remain anemic after at least 3 months of C5 inhibitor therapy. In the PEGASUS phase 3 trial, pegcetacoplan was superior to eculizumab in improving change from baseline (CFB) to week 16 in hemoglobin levels in PNH patients with inadequate response to eculizumab treatment [15]. Long-term assessment of efficacy and safety of pegcetacoplan through 48 weeks demonstrated sustained improvements in hematological outcomes and QoL measures [16].

Japanese patients with PNH are known to have different clinicopathologic features from non-Asian patients, including lower rates of hemoglobinuria and thrombosis, higher rates of bone marrow aplasia, and older age at diagnosis [17, 18]. Furthermore, an analysis of the International PNH Registry found significantly higher PNH clone size in granulocytes, higher lactate dehydrogenase (LDH) levels, and lower hemoglobin levels in Asian compared to non-Asian patients with PNH [18]. Given the clinicopathologic differences observed in Japanese patients with PNH, the purpose of this post hoc analysis was to evaluate the efficacy, safety, and QoL outcomes in Japanese patients treated with pegcetacoplan monotherapy in the randomized controlled period (RCP), and during the open-label period (OLP) of the phase 3 PEGASUS clinical trial.

Study Design and Population

PEGASUS (ClinicalTrials.gov identifier: NCT03500549) was a phase 3, randomized, open-label, multicenter, active-comparator controlled study. Patients eligible for PEGASUS were ≥18 years old with a PNH diagnosis and hemoglobin level <10.5 g/dL despite receiving a stable dose of eculizumab for at least 3 months prior to screening. During the 4-week run-in phase, all patients continued to receive their current dose of eculizumab with the addition of twice weekly pegcetacoplan (1,080 mg, subcutaneous), before 1:1 randomization to either pegcetacoplan or eculizumab monotherapy during the RCP (Fig. 1). After the 16-week RCP, all patients received pegcetacoplan monotherapy in the OLP until week 48. Patients on pegcetacoplan monotherapy during the RCP continued pegcetacoplan (PEG-to-PEG group). Patients on eculizumab during the RCP completed a run-in period of 4 weeks with pegcetacoplan plus eculizumab (weeks 17–20) before starting pegcetacoplan monotherapy during the remaining OLP (weeks 21–48) (ECU-to-PEG group). The number of Japanese patients with PNH enrolled in the PEGASUS study was predetermined (n = 10) with an equal allocation to each treatment arm. PEGASUS was approved by the Institutional Review Board or Independent Ethics Committee at participating trial sites and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Informed consent was obtained from all patients.

Fig. 1.

PEGASUS study design. *Pegcetacoplan run-in periods: (1) before randomization, for both PEG-to-PEG and ECU-to-PEG treatment groups; and (2) at start of OLP, for the ECU-to-PEG treatment group only. ECU, eculizumab; PEG, pegcetacoplan; SC, subcutaneous.

Fig. 1.

PEGASUS study design. *Pegcetacoplan run-in periods: (1) before randomization, for both PEG-to-PEG and ECU-to-PEG treatment groups; and (2) at start of OLP, for the ECU-to-PEG treatment group only. ECU, eculizumab; PEG, pegcetacoplan; SC, subcutaneous.

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Outcome Measures

The primary endpoint of the study was CFB in hemoglobin level to week 16. Key safety endpoints included incidence and severity of adverse events (AEs). Safety data were evaluated for the overall pegcetacoplan group receiving pegcetacoplan monotherapy during the RCP and/or OLP, including all 10 Japanese patients. At week 48, mean hemoglobin level, freedom from transfusion, change from baseline in absolute reticulocyte count (ARC), LDH, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score were analyzed as key efficacy outcomes. An increase in FACIT-Fatigue score denotes a decrease in fatigue and a 5-point change is considered clinically meaningful [19]. Additional secondary outcomes on QoL included Linear Analog Scale Assessment (LASA) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 Scale (EORTC QLQ-C30). An increase in total LASA score and EORTC QLQ-C30 Global Health Status (GHS)/QoL denotes an improvement in overall QoL. A ≥10-point increase or decrease from baseline is indicative of a clinically meaningful change [20‒22].

Results for the overall PEGASUS study population for the RCP and OLP have been described previously [15, 16]. Efficacy and safety data on Japanese patients treated with pegcetacoplan during the RCP and OLP of the PEGASUS study were the focus of this analysis. Outcomes in Japanese patients were compared to data received from the overall population in the PEGASUS study. Due to the small sample size of the Japanese population (n = 10), no formal statistical testing was performed and descriptive statistics (mean, standard error for efficacy, and FACIT-Fatigue; mean and standard deviation for additional QoL data) were used to assess the data.

In total, 80 patients from 44 centers were enrolled in the PEGASUS trial and randomized 1:1 to pegcetacoplan (n = 41) or eculizumab (n = 39), of which 10 were Japanese patients (from 7 centers). Five Japanese patients were randomized to receive pegcetacoplan, and 5 patients received eculizumab. Patient demographics and baseline characteristics for Japanese patients and the overall study population are compared in Table 1.

Table 1.

Patient characteristics before start of the study in the overall PEGASUS study population and in Japanese patients

CharacteristicsPegcetacoplanEculizumab
overall (n = 41)Japanese (n = 5)overall (n = 39)Japanese (n = 5)
Mean age (range), yr 50.2 (19–81) 57.4 (43–76) 47.3 (23–78) 47.2 (23–72) 
Female sex, n (%) 27 (66) 4 (80) 22 (56) 4 (80) 
Weight, kg, mean (SD) 75.9 (18.8) 61.3 (9.4) 74.6 (16.6) 61.0 (14.1) 
Body mass index, kg/m2, mean (SD) 26.7 (4.3) 24.1 (3.3) 25.9 (4.3) 23.5 (3.0) 
No transfusions within previous 12 months, n (%) 10 (24) 3 (60) 10 (26) 2 (40) 
History of aplastic anemia, n (%) 11 (27) 2 (40) 9 (23) 2 (40) 
Median time since PNH diagnosis (range), yr 6.0 (1–31) 2.6 (1–18) 9.7 (1–38) 3.3 (2–12) 
Median duration of prior treatment with eculizumab (range), yr 4.4 (0.4–17.1) 1.7 (0.9–8.1) 3.4 (0.3–13.8) 1.1 (0.4–7.8) 
Eculizumab dose at screening, n (%) 
 900 mg every 2 weeks 26 (63) 5 (100) 30 (77) 5 (100) 
 1,200 mg every 2 weeks* 13 (32) 9 (23) 
 1,500 mg every 2 weeks 2 (5) 
Platelets, ×109/L, mean (SD) 166.6 (98.3) 228.8 (167.4) 146.9 (68.8) 164.2 (71.1) 
Hemoglobin, g/dL, mean (SD) 8.69 (1.08) 7.81 (0.64) 8.68 (0.89) 7.70 (0.79) 
Absolute reticulocyte count, ×109/L, mean (SD) Normal reference range 30–12015 217.5 (75.0) 155.0 (31.0) 216.2 (69.1) 184.0 (39.1) 
Lactate dehydrogenase, U/L, mean (SD) Normal reference range 113–22615 257.5 (97.6) 234.5 (57.1) 308.6 (284.8) 479.4 (627.5) 
FACIT-Fatigue score, mean (SD) 32.2 (11.4) 37.2 (8.4) 31.6 (12.5) 38.0 (12.3) 
CharacteristicsPegcetacoplanEculizumab
overall (n = 41)Japanese (n = 5)overall (n = 39)Japanese (n = 5)
Mean age (range), yr 50.2 (19–81) 57.4 (43–76) 47.3 (23–78) 47.2 (23–72) 
Female sex, n (%) 27 (66) 4 (80) 22 (56) 4 (80) 
Weight, kg, mean (SD) 75.9 (18.8) 61.3 (9.4) 74.6 (16.6) 61.0 (14.1) 
Body mass index, kg/m2, mean (SD) 26.7 (4.3) 24.1 (3.3) 25.9 (4.3) 23.5 (3.0) 
No transfusions within previous 12 months, n (%) 10 (24) 3 (60) 10 (26) 2 (40) 
History of aplastic anemia, n (%) 11 (27) 2 (40) 9 (23) 2 (40) 
Median time since PNH diagnosis (range), yr 6.0 (1–31) 2.6 (1–18) 9.7 (1–38) 3.3 (2–12) 
Median duration of prior treatment with eculizumab (range), yr 4.4 (0.4–17.1) 1.7 (0.9–8.1) 3.4 (0.3–13.8) 1.1 (0.4–7.8) 
Eculizumab dose at screening, n (%) 
 900 mg every 2 weeks 26 (63) 5 (100) 30 (77) 5 (100) 
 1,200 mg every 2 weeks* 13 (32) 9 (23) 
 1,500 mg every 2 weeks 2 (5) 
Platelets, ×109/L, mean (SD) 166.6 (98.3) 228.8 (167.4) 146.9 (68.8) 164.2 (71.1) 
Hemoglobin, g/dL, mean (SD) 8.69 (1.08) 7.81 (0.64) 8.68 (0.89) 7.70 (0.79) 
Absolute reticulocyte count, ×109/L, mean (SD) Normal reference range 30–12015 217.5 (75.0) 155.0 (31.0) 216.2 (69.1) 184.0 (39.1) 
Lactate dehydrogenase, U/L, mean (SD) Normal reference range 113–22615 257.5 (97.6) 234.5 (57.1) 308.6 (284.8) 479.4 (627.5) 
FACIT-Fatigue score, mean (SD) 32.2 (11.4) 37.2 (8.4) 31.6 (12.5) 38.0 (12.3) 

*One patient in the overall pegcetacoplan group received 900 mg of eculizumab every 11 days.

FACIT, Functional Assessment of Chronic Illness Therapy; PNH, paroxysmal nocturnal hemoglobinuria; SD, standard deviation; yr, years.

Efficacy

Pegcetacoplan treatment in the Japanese cohort resulted in a mean hemoglobin increase of 2.4 g/dL at week 16 from baseline (mean CFB with eculizumab: +0.2 g/dL), which was in the same range as for the overall PEGASUS population (mean CFB with pegcetacoplan: +2.37 g/dL) (Fig. 2). Japanese patients in the PEG-to-PEG group maintained improved hemoglobin levels throughout the OLP (mean CFB at week 48: +1.8 g/dL; mean CFB for PEG-to-PEG overall PEGASUS group at week 48: +2.47 g/dL). A substantial increase in hemoglobin during the OLP (mean CFB at week 48: +3.2 g/dL) was seen in Japanese patients in the ECU-to-PEG group, which was also seen in the ECU-to-PEG group of the overall PEGASUS population (mean CFB at week 48: +2.93 g/dL). Starting from a lower hemoglobin level at baseline the resulting hemoglobin value at week 48 appears lower in the Japanese population compared to the overall study population. However, the change from baseline is comparable in both cohorts. Hemoglobin changes by patient are shown in supplementary material (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000537696).

Fig. 2.

Hemoglobin levels through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). BL, baseline; ECU, eculizumab; Hb, hemoglobin; LLN, lower limits of normal; OLP, open-label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error, W, week.

Fig. 2.

Hemoglobin levels through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). BL, baseline; ECU, eculizumab; Hb, hemoglobin; LLN, lower limits of normal; OLP, open-label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error, W, week.

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Pegcetacoplan-treated Japanese patients experienced sustained improvements in key secondary efficacy outcomes. All Japanese patients (100%) were free from transfusions while on pegcetacoplan treatment. In all, 4 out of 5 Japanese patients received transfusions while treated with eculizumab during the RCP. None of the patients in the PEG-to-PEG group had any transfusion through 48 weeks. At week 48 in the overall PEGASUS population, 73% of patients in the PEG-to-PEG group (through 48 weeks) and 72% of patients in the ECU-to-PEG group (while treated with pegcetacoplan from week 17 until week 48) achieved freedom from transfusion (Fig. 3).

Fig. 3.

a, b Freedom from transfusion in the overall and Japanese population. Data for the ECU-to-PEG group at week 48 only reflect the time, while patients were treated with pegcetacoplan (weeks 17–48). CI, confidence interval; ECU, eculizumab; PEG, pegcetacoplan.

Fig. 3.

a, b Freedom from transfusion in the overall and Japanese population. Data for the ECU-to-PEG group at week 48 only reflect the time, while patients were treated with pegcetacoplan (weeks 17–48). CI, confidence interval; ECU, eculizumab; PEG, pegcetacoplan.

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Japanese patients treated with pegcetacoplan experienced a decrease in LDH at week 16 with a mean CFB of −61.1 U/L. This improvement was sustained through week 48 (mean LDH CFB: −53.9 U/L) and was comparable to the overall study population (mean LDH CFB at week 48: −41.5 U/L) (Fig. 4). LDH levels moderately decreased in Japanese patients under eculizumab treatment (mean CFB at week 16: −37.2 U/L) with a more pronounced decrease after switching to pegcetacoplan at week 16 (mean CFB at week 48: −337.0 U/L). A comparable trend was seen in the overall study population for the ECU-to-PEG treatment group (mean LDH CFB at week 16: −10 U/L; week 48: −105.3 U/L).

Fig. 4.

LDH levels through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). ECU, eculizumab; LDH, lactate dehydrogenase; LLN, lower limits of normal; OLP, open-label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error; ULN, upper limits of normal.

Fig. 4.

LDH levels through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). ECU, eculizumab; LDH, lactate dehydrogenase; LLN, lower limits of normal; OLP, open-label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error; ULN, upper limits of normal.

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Japanese patients treated with pegcetacoplan showed a decrease in ARC at week 16 with a mean CFB of −89.0 × 109 cells/L. The ARC improvement was sustained through week 48 (mean CFB −89.0 × 109 cells/L). The mean ARC CFB for the overall study population was −136 × 109 cells/L at week 16 and −135.6 × 109 cells/L at week 48 (Fig. 5). No or only marginal decreases in ARC were seen in Japanese patients under eculizumab treatment at week 16 (mean CFB: −2.0 × 109 cells/L). Mean ARC CFB at week 16 in the overall study population treated with eculizumab was +28 × 109 cells/L. ARC levels decreased upon switching to pegcetacoplan after week 16 in the Japanese ECU-to-PEG cohort (mean CFB at week 48: −114.0 × 109 cells/L) comparable to the overall study population (mean CFB at week 48: −128.2 × 109 cells/L).

Fig. 5.

ARC levels through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). ARC, absolute reticulocyte count; ECU, eculizumab; LLN, lower limits of normal; OLP, open-label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error; ULN, upper limits of normal.

Fig. 5.

ARC levels through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). ARC, absolute reticulocyte count; ECU, eculizumab; LLN, lower limits of normal; OLP, open-label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error; ULN, upper limits of normal.

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Pegcetacoplan treatment improved the FACIT-Fatigue score in Japanese patients (mean CFB +5.6) and in the overall study population (mean CFB + 9.2) at week 16, while eculizumab treatment led to minor or no improvements. At week 48, the improvement was sustained in the PEG-to-PEG group, while ECU-to-PEG patients improved after switching to pegcetacoplan (mean FACIT-Fatigue score CFB in Japanese patients: +6.4 and in overall study population: +9.6) (Fig. 6). LDH, ARC, and FACIT-Fatigue score changes from baseline by patient are shown in supplementary material (online suppl. Fig. S2–S4).

Fig. 6.

FACIT-Fatigue scores through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). All observed/uncensored for transfusion data. An increase in FACIT-Fatigue score denotes a decrease in fatigue. ECU, eculizumab; FACIT, Functional Assessment of Chronic Illness Therapy; OLP, open label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error.

Fig. 6.

FACIT-Fatigue scores through week 48 for overall (a) and Japanese population (b). Values for run-in period RCP (weeks 3, 2, day 1) for both groups and for the ECU-to-PEG group during OLP run-in (weeks 17, 18, 20) in the Japanese population are for all patients (PEG + ECU, n = 10). All observed/uncensored for transfusion data. An increase in FACIT-Fatigue score denotes a decrease in fatigue. ECU, eculizumab; FACIT, Functional Assessment of Chronic Illness Therapy; OLP, open label period; PEG, pegcetacoplan; RCP, randomized controlled period; SE, standard error.

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Additional QoL Measures

Total LASA score and EORTC QLQ-C30 Global Health Status/QoL at baseline, week 16, and week 48 for the overall PEGASUS and the Japanese population are shown in Table 2. Mean LASA scores were better for pegcetacoplan- versus eculizumab-treated Japanese patients at week 16 (203.4 vs. 166.2), comparable with the overall study population (213.4 vs. 148.1). At week 48, mean LASA scores for PEG-to-PEG patients were 189.6 and 216.0 for patients in the Japanese cohort and the overall study population, respectively. Japanese ECU-to-PEG patients showed an improvement in their total LASA score after switching to pegcetacoplan, which was maintained through week 48 (mean LASA score at week 16: 166.2 vs. week 48: 218.8) and comparable to the overall study population (mean LASA score at week 16: 148.1 vs. week 48: 218.4).

Table 2.

LASA and EORTC QLQ-C30 Global Health Status/QoL scores at baseline, week 16, and week 48 for the overall PEGASUS (A) and Japanese (B) populations

(A)PEG-to-PEG overall (n = 41)ECU-to-PEG overall (n = 39)
baselineweek 16week 48baselineweek 16week 48
LASA score 
 Total LASA score 161.00 (67.99) ↑213.37 (69.36) ↑215.97 (67.14) 156.66 (61.27) 148.14 (65.26) ↑218.41 (60.11) 
EORTC QLQ-C30 
 Global Health Status/QoL 56.30 (20.39) ↑70.83 (23.70) ↑73.06 (20.38) 56.53 (20.24) 52.31 (18.61) ↑73.51 (19.78) 
(A)PEG-to-PEG overall (n = 41)ECU-to-PEG overall (n = 39)
baselineweek 16week 48baselineweek 16week 48
LASA score 
 Total LASA score 161.00 (67.99) ↑213.37 (69.36) ↑215.97 (67.14) 156.66 (61.27) 148.14 (65.26) ↑218.41 (60.11) 
EORTC QLQ-C30 
 Global Health Status/QoL 56.30 (20.39) ↑70.83 (23.70) ↑73.06 (20.38) 56.53 (20.24) 52.31 (18.61) ↑73.51 (19.78) 
(B)PEG-to-PEG Japanese (n = 5)ECU-to-PEG Japanese (n = 5)
baselineweek 16week 48baselineweek 16week 48
LASA score 
 Total LASA score 189.00 (49.80) ↑203.40 (75.68) 189.60 (78.87) 175.00 (73.97) 166.20 (72.64) ↑218.80 (82.02) 
 ≥10-point increase*, n (%)  1 (20.0) 1 (20.0)  1 (20.0) 4 (80.0) 
EORTC QLQ-C30 
 Global Health Status/QoL 63.33 (18.26) 61.67 (32.06) 60.00 (22.36) 70.00 (12.64) 58.33 (20.41) 78.33 (21.731) 
 ≥10-point increase*, n (%)  2 (40.0)  3 (60.0) 
(B)PEG-to-PEG Japanese (n = 5)ECU-to-PEG Japanese (n = 5)
baselineweek 16week 48baselineweek 16week 48
LASA score 
 Total LASA score 189.00 (49.80) ↑203.40 (75.68) 189.60 (78.87) 175.00 (73.97) 166.20 (72.64) ↑218.80 (82.02) 
 ≥10-point increase*, n (%)  1 (20.0) 1 (20.0)  1 (20.0) 4 (80.0) 
EORTC QLQ-C30 
 Global Health Status/QoL 63.33 (18.26) 61.67 (32.06) 60.00 (22.36) 70.00 (12.64) 58.33 (20.41) 78.33 (21.731) 
 ≥10-point increase*, n (%)  2 (40.0)  3 (60.0) 

Results are given as mean (SD) unless indicated otherwise. ECU, eculizumab; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 Scale; LASA, Linear Analog Scale Assessment; PEG, pegcetacoplan; QoL, quality of life; SD, standard deviation.

↑ Arrow denotes a ≥10-point increase in change from baseline.

*Improvements of score from baseline. An increase in total LASA score and EORTC QLQ-C30 Global Health Status/QoL denotes an improvement in overall QoL.

At week 16, mean EORTC QLQ-C30 GHS/QoL scores for patients treated with pegcetacoplan were 61.7 and 70.8 for the Japanese cohort and overall study population, respectively; scores were sustained through week 48 (60.0 and 73.1, respectively). Japanese ECU-to-PEG patients demonstrated improvements in GHS/QoL after the switch to pegcetacoplan (mean GHS/QoL score at week 16: 58.3 vs. week 48: 78.3), which was comparable to the overall study population (mean GHS/QoL score at week 16: 52.3 vs. week 48: 73.5).

Trends seen in the total LASA and EORTC QLQ GHS/QoL score are also reflected in the number of Japanese patients achieving a 10-point improvement in these scores (Table 2). Details on EORTC QLQ-C30 Functional and Symptom Scores are shown in supplementary material (online suppl. Table S1).

Safety

Incidences of AEs and serious AEs were comparable between the overall and Japanese cohorts. No additional safety signs were identified. The results indicate a consistent safety profile with previously reported data for pegcetacoplan.

Every Japanese patient treated with pegcetacoplan monotherapy during the study (n = 10) experienced at least one AE. The most common AEs with pegcetacoplan monotherapy in the overall study population were injection site reactions, hemolysis, and diarrhea. Injection site reactions were the most frequently reported AEs in the Japanese patients treated with pegcetacoplan. Furthermore, Japanese patients reported injection site reactions more frequently compared to the overall study population; 6 of the 13 injection site erythema events and all injection site induration and swelling reported in the overall population occurred in Japanese patients. However, the majority of injection site reactions were rated as mild in severity and none of the events led to a serious AE or study discontinuation. Two of 10 patients experienced diarrhea. No hemolysis events were reported on pegcetacoplan monotherapy in the Japanese cohort (Table 3). All AEs in Japanese patients on pegcetacoplan monotherapy are shown in supplementary material (online suppl. Table S2).

Table 3.

AEs on pegcetacoplan monotherapy (RCP + OLP)

AEs by the preferred term, n (%)Overall study population (n = 80)Japanese population (n = 10)
Any AE 78 (97.5) 10 (100.0) 
Most common AEs* 
 Hemolysis 19 (23.8) 0 (0.0) 
 Diarrhea 17 (21.3) 2 (20.0) 
 Injection site erythema 13 (16.3) 6 (60.0) 
 Nasopharyngitis 14 (17.5) 3 (30.0) 
 Injection site induration 5 (6.3) 5 (50.0) 
 Injection site swelling 5 (6.3) 5 (50.0) 
 Back pain 5 (6.3) 3 (30.0) 
 Serious AEs 24 (30.0) 2 (20.0) 
AEs by the preferred term, n (%)Overall study population (n = 80)Japanese population (n = 10)
Any AE 78 (97.5) 10 (100.0) 
Most common AEs* 
 Hemolysis 19 (23.8) 0 (0.0) 
 Diarrhea 17 (21.3) 2 (20.0) 
 Injection site erythema 13 (16.3) 6 (60.0) 
 Nasopharyngitis 14 (17.5) 3 (30.0) 
 Injection site induration 5 (6.3) 5 (50.0) 
 Injection site swelling 5 (6.3) 5 (50.0) 
 Back pain 5 (6.3) 3 (30.0) 
 Serious AEs 24 (30.0) 2 (20.0) 

AE, adverse event; OLP, open-label period; RCP, randomized controlled period.

*Experienced by >15% of patients in the overall study population or >20% in the Japanese population.

Two patients within the Japanese cohort experienced serious AEs on pegcetacoplan monotherapy: 1 bacterial infection during the RCP and 1 gastroenteritis during the OLP. Neither of the two events was deemed related to pegcetacoplan. No meningococcal infection was reported for Japanese patients or in the overall study population. Two thrombotic events occurred in the overall study population, but none in the Japanese cohort. While overall 13 patients discontinued pegcetacoplan treatment, no Japanese patient withdrew from the PEGASUS study. In addition, none of the Japanese patients needed pegcetacoplan dose increases to manage the disease. No treatment-related deaths occurred in the study; there was one death in the overall study population due to COVID-19.

Japanese patients with PNH are known to have different clinicopathologic features from non-Asian patients [17, 18]. This post hoc analysis was conducted to evaluate the efficacy, safety, and QoL in Japanese patients treated with pegcetacoplan monotherapy in the phase 3 PEGASUS clinical trial.

In PEGASUS, pegcetacoplan provided a superior improvement in hemoglobin levels compared to eculizumab that was sustained over 48 weeks. Improvements in all other key hematological parameters as well as QoL were sustained in patients with difficult to control disease (hemoglobin levels <10.5 g/dL despite stable treatment with eculizumab for ≥3 months at baseline) [15, 16]. In accordance with the overall PEGASUS study population, Japanese patients on pegcetacoplan had durable treatment effects in all efficacy parameters at 48 weeks. Overall, mean CFB in hemoglobin, LDH, ARC, and FACIT-Fatigue score in the Japanese population were consistent with the overall study population. The results suggest that pegcetacoplan can effectively control both IVH and EVH in patients living with PNH, including Japanese patients.

Of note, while patients in the PEG-to-PEG arm received pegcetacoplan for 48 weeks, results on pegcetacoplan in the ECU-to-PEG arm only represent the 32-week OLP. A positive effect of pegcetacoplan on QoL could be demonstrated for the overall PEGASUS study population [23]. Compared to the overall PEGASUS population, improvements seen in the Japanese population for FACIT-Fatigue, LASA, and EORTC QLQ-C30 scores are numerically smaller. In a study analyzing the impact of Asian ethnicity on EORTC QLQ-C30 scores, the authors concluded that Asian ethnicity presented no systematic biases when compared to European and North American population norms with regard to EORTC QLQ-C30 scores in PNH [24].

A potential reason for the less pronounced QoL effect in Japanese patients in this analysis is their presentation with higher baseline scores. Although the FACIT-Fatigue score achieved was comparable to the overall study population, the absolute change was smaller. In addition, the small Japanese population was intrinsically sensitive to individual events that could heavily sway average outcomes. This is particularly true for QoL measures where a wide range of patient factors, including comorbidities, concomitant medications, and AEs, play a role [25‒27]. Taken together, this may explain the high variability seen in QoL scores, with mixed results in particular for the PEG-to-PEG arm. Despite these factors, the increased and sustained FACIT-Fatigue score achieved in the Japanese population is considered clinically meaningful [19]. The same trends can be seen in improvements in LASA and EORTC QLQ-C30 scores, with similar factors at play, including higher baseline scores in Japanese patients than the overall study population, leading to a less pronounced improvement in these outcome measures.

The safety profile of pegcetacoplan was consistent with previously reported data and was similar between Japanese patients and the overall study population. Japanese patients reported injection site reactions more frequently compared to the overall study population. Pegcetacoplan is administered as a 20-mL subcutaneous infusion and this volume may not be agreeable for some patients, e.g., patients with low body mass index. Although local reactions were observed with pegcetacoplan injection in the Japanese cohort in the PEGASUS study, which has a lower mean body mass index (BMI) compared to the overall study population, none of the local reactions led to a serious AE or study discontinuation.

A higher incidence of injection site reactions in Japanese study participants has also been reported following SARS-CoV-2 mRNA vaccination, with the authors concluding that this might be attributable, in part, to a higher awareness of injection site reactions in Japanese recipients as well as differences in weight [28]. In the overall population of the PEGASUS study, hemolysis was one of the most common AEs and 5 patients discontinued the study due to hemolysis (3 in the RCP, 2 in the OLP). No event of hemolysis was reported in the Japanese cohort (n = 10). Moreover, all Japanese patients remained on treatment throughout the study and no pegcetacoplan dose adjustments occurred.

The results presented agree with earlier assessments of complement inhibitor efficacy and safety in Japanese patients with PNH. The pivotal open-label, phase 2 AEGIS study evaluated the long-term efficacy and safety of eculizumab in Japanese patients with PNH. Eculizumab was able to reduce IVH and transfusion dependence as well as to improve anemia, fatigue, and dyspnea [29, 30]. In addition, eculizumab’s sustained effectiveness and safety were confirmed in a postmarketing surveillance analysis in 632 Japanese patients [31]. A subgroup analysis of two phase 3 studies with ravulizumab found consistent efficacy and safety outcomes in the Japanese and global patient population [32].

PNH is a rare disease, which explains the very low number of Japanese patients in this analysis. A small sample size affects the reliability of results due to higher variability. Other aspects, e.g., history of aplastic anemia in 40% of patients, add to the heterogeneity of this Japanese patient group. Therefore, outcomes might not be representative of the population data and conclusions should be drawn with caution. Confirmation of the presented results in larger studies or in the context of real-world data on Japanese patients is warranted.

The comparison of the demographics and baseline characteristics between the Japanese and overall study populations reveals a few noteworthy aspects. Japanese patients presented with a lower BMI compared to the overall PEGASUS population. A lower BMI in Asian versus non-Asian patients with PNH was also found in an analysis of ravulizumab phase 3 study data [24]. In general, the PEGASUS trial included patients with a BMI <35 kg/m2 based on preliminary data from pharmacokinetic modeling. There were some indications that subjects who had class 2 or greater obesity, which is defined as BMI of >35 kg/m2, may have lower drug exposure, which may result in possible underdosing of pegcetacoplan.

Differences in PNH management approaches in Japan compared to the USA or EU might have an influence on the pretreatment characteristics of the two cohorts. Japanese guidelines recommend transfusions to manage anemia at lower hemoglobin values (below 7 g/dL) [33] compared to EU or US practice, which might affect the proportion of patients being free of transfusions before study entry. In Japan, eculizumab is prescribed according to label dose (900 mg every 2 weeks) and dose adjustments are rare, possibly explaining why none of the Japanese patients had a higher-than-label dose.

A shorter median time since PNH diagnosis, and a median duration of prior treatment with eculizumab, in the Japanese population indicates that these patients had a shorter disease history compared to the overall study population, which might indicate a less severe disease. The Japanese cohort had lower mean hemoglobin levels at baseline compared to the overall study population, and mean hemoglobin at week 48 was also lower in the Japanese population compared to overall. However, the total CFB in hemoglobin is similar between the two cohorts after pegcetacoplan treatment.

Clinicopathologic differences in PNH patients between geographic regions have been previously reported and Japanese patients have demonstrated a higher rate of bone marrow aplasia compared to non-Asian patients [17]. A higher percentage of Japanese patients presented with a history of aplastic anemia in the current analysis, which might also explain the lower hemoglobin levels for the Japanese patients in this study. Japanese patients in this analysis presented with lower ARC levels at baseline, which is in line with a previous analysis of differences between Asian and non-Asian patients [17].

In conclusion, no evidence was found that pegcetacoplan was less effective in this small subgroup of Japanese patients compared to the overall PEGASUS study population, suggesting that Japanese patients with PNH can be effectively managed with pegcetacoplan due to the beneficial control of both IVH and EVH. Although injection site reactions with pegcetacoplan were observed more frequently in the Japanese cohort when compared to the overall population, the majority of these events were mild in severity and none led to a serious AE or study discontinuation. Overall, the safety profile was consistent with the safe use of pegcetacoplan in this patient cohort.

We thank the patients and their families for participating in this trial and the trial investigators and coordinators for their contributions to the trial. We thank Mohammed Al-Adhami, for significant reviews of the manuscript. We also thank Miriam Souto of nspm ltd. (Meggen, Switzerland) for providing medical writing support.

All patients provided written informed consent before enrollment. The trial was conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki and the protocol was approved by the relevant Institutional Review Board or Ethics Committee at each site. For the Japanese patients included in the presented substudy, the protocol was reviewed and approved by the Institutional Review Board (IRB) of Japanese Red Cross Nagoya Daiichi Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya, Aichi, 453-8511, Japan (approval number: 551); the IRB of Japanese Red Cross Nagoya Daini Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, Aichi, 466-8650, Japan (approval number: 30-6); the IRB of Juntendo University Hospital, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan (approval number: 2018-029); the IRB of Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan (approval number: 1728); and the NTT Medical Center Tokyo, Institutional Review Board, 5-9-22 Higashi-Gotanda, Shinagawa-ku, Tokyo 141-8625, Japan (approval number: 30-13).

HNi reports consultancy at Kyowa Kirin. HNa, SB, and TU declare that they have no conflicts of interest. KU reports consultancy Coat SymBio and Nippon Shinyaku; honoraria from Novartis, Astellas, Alexion, Eisai, MSD, Otsuka, Ono, Kyowa Kirin, Celgene, Daiichi Sankyo, Takeda, Nippon-Shinyaku, PharmaEssentia, Bristol-Myers Squibb, Yakult, Sanofi, Pfizer, AbbVie, and Chugai; grants from Astellas, AbbVie, Ono, Chugai, Bristol-Myers Squibb, Otsuka, Yakult, Agios, MSD, Aperi, Amgen, Alexion, Incyte, Eisai, Kyowa Kirin, Sanofi, SymBio, Celgene, Daichi Sankyo, Sumitomo-Dainippon, Nippon Shinyaku, Novartis, Mundi, Janssen, and Takeda; advisory board member at Alexion, Otsuka, Chugai, Sanofi, Takeda, Kyowa Kirin, Astellas, Swedish Orphan Biovitrum AB, and Alnylam Japan; board member of the Japan Adult Leukemia Study Group; and member of the finance committee and medical committee of Japanese Society of Hematology. JS reports employment and stockholder at Swedish Orphan Biovitrum AB. RPdL reports consultancy at and honoraria from Alexion, Apellis, Novartis, Swedish Orphan Biovitrum AB, and Pfizer; research support from MSD, Novartis, and Pfizer; AR reports research support from Roche; travel support from Alexion, AbbVie, and Swedish Orphan Biovitrum AB; lecture honoraria from Alexion, Amgen, Grifols, Roche, Sanofi, Swedish Orphan Biovitrum AB, and Novartis; and consultancy for Alexion, Apellis, BioCryst, Bioverativ, Kira, Novartis, Pfizer, and Sanofi. JP reports consultancy for Apellis Pharmaceuticals, Bristol-Myers Squibb, MSD, Samsung Bioepis, and Sanofi; speakers’ bureaus and advisory committees for Alexion (Astra Zeneca), Boehringer Ingelheim, Blueprint Medicines, Novartis, Pfizer, and Swedish Orphan Biovitrum AB.

This study was funded by Apellis Pharmaceuticals. The analysis was funded by Swedish Orphan Biovitrum AB. Medical writing support was funded by Swedish Orphan Biovitrum AB.

The trial was designed by the sponsor (Apellis Pharmaceuticals) and the academic authors. Trial investigators collected the data. Hisakazu Nishimori, Hideyuki Nakazawa, Shinobu Tamura, Toshiki Uchida, Kensuke Usuki, Johan Szamosi, Régis Peffault de Latour, Alexander Röth, and Jens Panse (the authors) contributed to the analysis or interpretation of the data in this post hoc analysis as well as revision of the manuscript. The authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol. Medical writing assistance was paid for by Swedish Orphan Biovitrum AB. Manuscript review was conducted by Swedish Orphan Biovitrum AB and Apellis Pharmaceuticals during the development process. Full editorial control of the manuscript was maintained by the authors, all of whom provided their final approval of the manuscript submitted for publication.

Additional Information

ClinicalTrials.gov identifier: NCT03500549.

Sobi is committed to responsible and ethical sharing of data on participant level and summary data for medicines and indications approved by EMA and/or FDA, while protecting individual participant integrity and compliance with applicable legislation. Data access will be granted in response to qualified research requests. All requests are evaluated by a cross‐functional panel of experts within Sobi, and a decision on sharing will be based on the scientific merit and feasibility of the research proposal, maintenance of personal integrity, and commitment to publication of the results. To request access to study data, a data sharing request form (available on www.sobi.com) should be sent to medical.info@sobi.com. Further information on Sobi’s data sharing policy and process for requesting access can be found at: https://www.sobi.com/en/policies. Further inquiries can be directed to medical.info@sobi.com.

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