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Durable treatment effect with pegcetacoplan in patients with paroxysmal nocturnal haemoglobinuria and a suboptimal response to eculizumab

Results of the PEGASUS trial previously demonstrated that pegcetacoplan was superior to eculizumab in patients with paroxysmal nocturnal haemoglobinuria. In a continuation phase of this trial, in which patients in the eculizumab arm crossed over to the pegcetacoplan arm, patients with a suboptimal response on prior eculizumab treatment experienced durable treatment effect in all efficacy parameters at week 48. The safety profile of pegcetacoplan remained consistent with previously reported data.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, potentially life-threatening  haematologic disease characterised by haemolysis, thrombosis, and bone marrow dysfunction. While eculizumab, a C5 inhibitor, can prevent the intravascular haemolysis, it does not block C3-mediated extravascular haemolysis. Pegcetacoplan is a C3 inhibitor that can control both intravascular and extravascular haemolysis in PNH. In addition, pegcetacoplan was superior to eculizumab in improving haemoglobin levels and clinical outcomes at week 16 during the PEGASUS trial. An open-label period through week 48 was now used to evaluate the long-term efficacy and safety of pegcetacoplan.

PEGASUS study design

The PEGASUS trial recruited 80 patients (aged ≥18 year) with a confirmed diagnosis of PNH and haemoglobin levels <10.5 g/dL despite stable eculizumab treatment for at least three months. In order to be eligible, patients had to have a reticulocyte level above the upper limit of normal, with a platelet level of >50 x109/L and a neutrophil count of >0.5 x109/L. All patients completed a four-week run-in period with pegcetacoplan plus eculizumab before they were randomised (1:1) to monotherapy with pegcetacoplan (N= 41; 1,080 mg subcutaneously twice weekly) or eculizumab (N= 39, continued dosing regimen). The primary endpoint of the study was a change in baseline haemoglobin (Hb) level at week 16. After this timepoint, patients in the eculizumab arm could cross over to pegcetacoplan arm after where they first received a short period of eculizumab-pegcetacoplan combination therapy after which all patients continued a further 32-week open-label pegcetacoplan phase (OLP).

Sustained improvement in pegcetacoplan-treated patients

Patients who switched from eculizumab to pegcetacoplan (ECU-to-PEG) demonstrated an Hb improvement with mean Hb levels of 11.6 g/dL at week 48 (change from baseline [CFB] of 2.93 g/dL), while patients who continued on pegcetacoplan (PEG-to-PEG) maintained high Hb levels through the open-label phase with a mean Hb level of 11.3 g/dL at week 48 (CFB: 2.47 g/dL). Furthermore, pegcetacoplan-treated patients demonstrated a sustained improvement in key secondary efficacy endpoints including lactate dehydrogenase (LDH) levels and absolute reticulocyte count (ARC). While for LDH levels an overall decrease was observed in the PEG-to-PEG group compared to baseline, a decrease from week 17 to week 48 was observed in the ECU-to-PEG arm. With respect to ARC, no significant difference between week 16 and week 48 was reported in the PEG-to-PEG arm (p= 0.31). In contrast, for patients in the ECU-to-PEG arm, a significant decrease at week 48 as compared to week 16 was noted (p< 0.0001). Remarkably, while at baseline only 25% of enrolled patients were transfusion-free during the prior twelve months, over 70% of PEG-to-PEG and ECU-to-PEG patients were transfusion-free at week 48. A sustained clinically meaningful improvement (≥ 3 point increase in FACIT-Fatigue score) in fatigue symptoms was reported in PEG-to-PEG patients through week 48. For patients treated with ECU-to-PEG, a significant improvement in fatigue symptoms in week 48 vs. week 16 was observed (p< 0.0001). Mechanistically spoken, it should be noted that pegcetacoplan decreased the C3 loading and increased the PNH clone size. At week 48, the summed mean of PNH red blood cell clonal distribution represented nearly 90% of overall PNH red blood cells for patients in both PEG-to-PEG and ECU-to-PEG groups.

The incidence of serious treatment-emergent adverse events (TEAEs) was similar in the randomised controlled trial phase (RCP) and in the OLP. In the OLP, no encapsulated bacterial infections were observed and five patients had infections classified as serious adverse events (SAEs). Three patients had one sepsis SAE and one of these patients withdrew from treatment due to sepsis. Furthermore, two patients experienced serious hypersensitivity and two thrombotic events were reported. Both were deemed unrelated to pegcetacoplan and neither thrombotic event led to study discontinuation. Six patients discontinued due to haemolytic events: five classified by the treating physician as “haemolysis” and one as “haemolytic anaemia.” Overall, 13 patients discontinued PEG: 3 in RCP, 10 in OLP due to TEAEs (7 in ECU-to-PEG, 3 in PEG-to-PEG).


These data demonstrate that pegcetacoplan-treated PNH patients experienced sustained improvements related to disease characteristics through 48 weeks of treatment. In addition, the safety profile of pegcetacoplan demonstrates a favourable risk-benefit balance during the PEGASUS study. Authors conclude that pegcetacoplan can control both intravascular and extravascular haemolysis in patients with PNH and may represent a promising new therapeutic option for the disease.


Peffault de Latour R, et al. Forty-eight week efficacy and safety of pegcetacoplan in adult patients with paroxysmal nocturnal hemoglobinuria and suboptimal response to prior eculizumab treatment. Presented at EHA 2021; abstract S174.

Speaker Régis Peffault de Latour

Régis Peffault de Latour

Régis Peffault de Latour, MD, PhD, Hôpitaux de Paris, Université de Paris, Paris, France


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