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Pegcetacoplan superior to eculizumab in patients with paroxysmal nocturnal haemoglobinuria

The phase III, randomised, open-label, active-comparator controlled PEGASUS study evaluated the safety and efficacy of the investigational compound pegcetacoplan in adult patients with paroxysmal nocturnal haemoglobinuria (PNH). With a mean increase of 2.37 g/dL in the haemoglobin level, pegcetacoplan demonstrated superiority to eculizumab (ECU). In addition, pegcetacoplan also could improved clinical outcomes at week 16 with transfusion avoidance in 85% of patients. This efficacy of pegcetacoplan validates the prevention of both extravascular and intravascular haemolysis in PNH and paves the way towards new therapeutic options for patients with PNH.


In patients with PNH, intravascular haemolysis (IVH) is mediated by the membrane attack complex while extravascular haemolysis (EVH) is facilitated by C3 opsonisation. Both IVH and EVH can lead to anaemia with associated fatigue, dyspnoea and the need for transfusions. While the C5 inhibitor ECU was shown to prevent IVH, 70% of patients remain anaemic and 36% require at least one transfusion per year due to C3-mediated EVH. Pegcetacoplan (APL-2) is a C3 inhibitor and as such has the potential to control both IVH and EVH in patients with PNH.

The PEGASUS trial recruited 80 patients (aged ≥18 year) with a confirmed diagnosis of PNH and haemoglobin levels <10.5 g/dL (despite stable ECU treatment for ≥3 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 ECU before they randomized (1:1) to monotherapy with pegcetacoplan (N=41, 1080 mg subcutaneously 2x/week) or ECU (N=39, continuing current dosing regimen). The primary endpoint of the study was a change in baseline haemoglobin level at week 16. At week 16, patients in the ECU arm crossed over to the pegcetacoplan arm after a period of ECU-pegcetacoplan combination therapy and all patients continued a further 32-week open-label pegcetacoplan period. Baseline clinical and demographic characteristics were well balanced between both study arms with a mean haemoglobin level at study entry of 8.7 g/dL.


Looking at the change in haemoglobin level at week 16, pegcetacoplan proved to be superior to ECU, with an adjusted treatment difference of 3.84 g/dL (p<0.0001). In the pegcetacoplan arm, the least squares (LS) mean change at week 16 was 2.37 g/dL while this was -1.47 g/dL with ECU. This effect was similar for patients who had less than 4 transfusion events and for patients who had at least 4 transfusions. Transfusion avoidance was achieved in 85% of the patients who were treated with pegcetacoplan as compared to only 15% in the ECU arm. This corresponds to an adjusted risk difference of 63% (95% CI: 48-77%) and clearly demonstrates non-inferiority. Non-inferiority was also shown for reticulocyte counts, which decreased with pegcetacoplan and slightly increased with ECU (LS mean changes of -136 and 28 x 109/L, respectively). LS mean changes from baseline in lactate dehydrogenase (LDH) levels were -15 and -10 U/L, respectively. The Functional Assessment of Chronic Illness Therapy fatigue (FACIT-f) score increased with pegcetacoplan (+9.2) and decreased with ECU (-2.7). As the change in LDH did not meet non-inferiority criteria, changes in FACIT-f score were not tested for non-inferiority due to prespecified hierarchical testing. A normalisation of the hematologic markers haemoglobin, reticulocytes and LDH occurred in 34%, 78% and 70.7% of the patients in the pegcetacoplan arm, respectively, as compared to 0%, 2.6% and 15.4% for patients in the ECU arm. In addition, a clinically meaningful improvement on FACIT-f score (≥3 points from baseline) at 16 weeks was reported by 73.2% of the patients treated with pegcetacoplan, while this was the case for none of the patients who received ECU. Finally, C3 loading on PNH red blood cells was decreased (-17.9% C3d-positive type II + III PNH RBCs), while the PNH clone size was increased (+27.7% type II + III PNH RBCs) with pegcetacoplan. Only small changes in these measures were seen with ECU (-3.2% and -9.7%, respectively).

In total 87.8% of the patients in the pegcetacoplan arm and 87.2% of the patients in the ECU arm reported an adverse event (AE) and 17.1% and 15.4%, respectively, had serious AEs. Most AEs were mild. Treatment-emergent AEs of interest included injection site reactions (pegcetacoplan: 36.6%; ECU: 2.6%), diarrhoea (22.0% and 2.6%, respectively) and infections (29.3% and 25.6%, respectively).  By week 16, breakthrough haemolysis was reported in 4 (9.8%) patients with pegcetacoplan and 9 (23.1%) with ECU, leading to discontinuation in 3 patients on pegcetacoplan.


In this phase III trial in patients with PNH, pegcetacoplan demonstrated superiority to ECU in terms of a haemoglobin improvement at week 16. In addition, compared to ECU, pegcetacoplan also improved hematologic and clinical outcomes at week 16 with transfusion avoidance in most patients. The safety profile of pegcetacoplan was comparable to that of ECU.

Speaker Peter Hillmen

Peter Hillmen

Peter Hillmen, MD, PhD, Department of Haematology, St James’s University Hospital, Leeds, UK


See: Keyslides


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