Pegcetacoplan Outperforms Current Standard of Care in Paroxysmal Nocturnal Hemoglobinuria


The novel C3 inhibitor pegcetacoplan led to a significant improvement in hemoglobin level and other clinical outcomes at week 16 versus the current standard of care, eculizumab in patients with paroxysmal nocturnal hemoglobinuria.

Peter Hillmen, MD, PhD

The novel C3 inhibitor pegcetacoplan led to a significant improvement in hemoglobin level and other clinical outcomes at week 16 versus the current standard of care, eculizumab (Soliris) in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to findings from the phase 3 PEGASUS trial, presented ahead of the 2020 European Hematology Association Annual Congress.1

According to the change in hemoglobin level at week 16, pegcetacoplan led to an adjusted treatment difference of 3.84 g/L (95% CI, 2.33-5.34; P <.0001). The least squares (LS) mean (SE) changes were +2.37 (0.36) g/L with pegcetacoplan and -1.47 (0.67) g/L with eculizumab, both changed from a baseline level of 8.7 g/L.

“PEGASUS is the first randomized phase 3 trial of a proximal C3 inhibitor and shows a rapid and sustained improvement in hemoglobin, a reduction in ongoing breakdown of blood cells, a marked reduction in blood transfusions, and a marked improvement in fatigue,” lead study author, Peter Hillmen, MD, PhD, professor of experimental hematology and honorary consultant hematologist of St. James’s University Hospital in Leeds, wrote in the press release.

PNH is a rare chronic disease in which complement within the immune system destroys a patient’s blood cells. This results in severe anemia and fatigue, which often require blood transfusions, red or black urine, and potentially fatal blood clots in organs, including the liver.

Despite the availability of eculizumab, a C5 inhibitor, many patients with PNH remain anemic, fatigued and in need of transfusions. Pegcetacoplan is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation. Preliminary data from the phase 1b PHAROAH and PADDOCK trials showed an improvement in lactate dehydrogenase (LDH) and hemoglobin levels in patients who had a suboptimal response to eculizumab and in eculizumab-naïve patients, respectively.2

On February 11, 2019, the FDA granted a fast track designation to pegcetacoplan for the treatment of patients with PNH. The 2019 designation replaced the prior fast track designation that was granted on December 15, 2016 for the C3 inhibitor for the subset of patients with PNH who continue to experience hemolysis requiring blood transfusions, despite receiving therapy with eculizumab.2

In PEGASUS, 80 patients aged 18 years or older with a confirmed diagnosis of PNH, hemoglobin levels less than 10.5 g/L, reticulocytes greater than 1.0 x the upper limit of normal, platelets greater than 50 x 109/L, and neutrophils greater than 0.5 x 109/L were enrolled.

All patients completed a 4-week run-in period with pegcetacoplan plus eculizumab before they were randomized to 1080 mg of subcutaneous single-agent pegcetacoplan twice weekly (n = 41) or continued eculizumab (n = 39).

The primary end point of the trial was the change in hemoglobin level from baseline to week 16. Key secondary end points included transfusion avoidance, reticulocyte counts, lactate dehydrogenase levels, Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-f) score, and adverse effects (AEs). The evaluation of each secondary end point was contingent on meeting the primary efficacy end point.

Regarding the secondary end points, transfusion avoidance was achieved in 85% of patients (n = 35) with pegcetacoplan versus 15% of patients (n = 6) with eculizumab, with an adjusted risk difference of 63% (95% CI, 48%-77%).

Reticulocyte counts decreased with pegcetacoplan and increased with eculizumab (LS mean [SE] changes of -136 [6.5] and 28 [11.9] 109/L, respectively), translating to an adjusted risk difference of -164 (95% CI, -189.9 to -137.3).

LS mean changes in LDH levels were -15 (42.7) and -10 (71.0) U/L, respectively (95% CI, -181.3 to 172.0), failing to show noninferiority.

The FACIT-f assessment score increased with pegcetacoplan (9.2 [1.61]) and decreased with eculizumab (-2.7 [2.82]). However, noninferiority was not evaluated due to the prespecified hierarchical testing.

Additionally, the safety profile of pegcetacoplan was comparable with eculizumab. The rate of all-grade treatment-emergent AEs (TEAEs) was 87.8% (n = 36) in the pegcetacoplan arm versus 87.2% (n = 34) in the eculizumab arm. The rate of serious TEAEs was 17.1% (n = 7) and 15.4% (n = 6), respectively.

The majority of TRAEs were mild in the pegcetacoplan and eculizumab arms, respectively, and consisted of injection site reactions (36.6% vs 2.6%, respectively), diarrhea (22.0% vs 2.6%), and infections (29.3% vs 25.6%).

By week 16, 9.8% of patients (n = 4) in the pegcetacoplan arm and 23.1% of patients (n = 9) in the eculizumab arm developed hemolysis, leading to pegcetacoplan discontinuation.

In May 2020, Apellis Pharmaceuticals, Inc., the developer of the C3 inhibitor, announced plans to submit a new drug application for the drug as a treatment for patients with PNH in the second half of 2020. The submission will include the PEGASUS results.3


  1. Hillmen P, Szer J, Weltz I, et al. Results of the PEGASUS phase III randomized trial demonstrating superiority of the C3 inhibitor, pegcetacoplan, compared with eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Presented at: 2020 European Hematology Association Virtual Congress; June 11-21, 2020; Virtual. Abstract S192.
  2. APL-2 receives fast track designation the treatment of PNH. PEGASUS. Published February 11, 2019. Accessed June 11, 2020.
  3. Apellis announces plans to submit NDA for pegcetacoplan in paroxysmal nocturnal hemoglobinuria (PNH). BioSpace. Published May 21, 2020. Accessed June 11, 2020.
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