Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial

Latour, Régis Peffault de; Szer, Jeff; Weitz, Ilene C.; Röth, Alexander; Höchsmann, Britta; Panse, Jens; Usuki, Kensuke; Griffin, Morag; Kiladjian, Jean‐Jacques; Castro, Carlos M. de; Nishimori, Hisakazu; Ajayi, Temitayo; Al‐Adhami, Mohammed; Deschatelets, Pascal; Francois, Cedric; Grossi, F; Risitano, Antonio M.; Hillmen, Peter

doi:10.1016/s2352-3026(22)00210-1

Cited by 40 publications

(103 citation statements)

References 29 publications

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“…The rate of transfusion avoidance was 35/41 (85.4%) in pegcetacoplan arm and 6/39 (15.4%) in the eculizumab arm, and the proportions of patients achieving hemoglobin normalization were 34.1% and 0% in pegcetacoplan and eculizumab arms, respectively 91 . The long‐term analysis at 48 weeks (in the open‐label part of the study) confirmed the hemoglobin gain in comparison to baseline in patients randomized to pegcetacoplan (+2.47 ± 1.72 g/dL; n = 33), and patients switching to open‐label pegcetacoplan after being initially randomized to eculizumab achieved a similar hemoglobin gain (+2.93 ± 2.09 g/dL, n = 30) 92 . Transfusion avoidance was overlapping between the two treatment arms (73% in the pegcetacoplan‐pegcetacoplan arm and 72% in the eculizumab‐pegcetacoplan arm) 92 .…”

Section: Inhibitors Of the Alternative Pathway: Clinical Data In Pnhmentioning

confidence: 59%

“…tion (n = 1). 92 Looking specifically for breakthrough hemolysis, the cumulative discontinuation rate through the 48 week study period was 7.5%. 92 Irrespective of treatment discontinuation, the rate of breakthrough hemolysis in the pegcetacoplan was 10% (n = 4) at week 14, compared to 23% (n = 9) in the eculizumab arm, 91 even if it was suggested that the clinical severity of these events was quite different in the two treatment arms.…”

Section: Injection Site Reaction Was the Most Frequent Treatment Emer...mentioning

confidence: 99%

“…Hemolysis was the only recurrent serious adverse event, leading to treatment discontinuation in 3 patients within week 16 91 . Ten additional patients discontinued pegcetacoplan switching back to eculizumab during the open‐label period of the study, due to breakthrough hemolysis (n = 3), pancytopenia/aplastic anemia (n = 2), hematological cancers (n = 2), mesenteric ischemia (n = 1), hypersensitivity pneumonia (n = 1), and fatal SARS‐CoV‐2 infection (n = 1) 92 . Looking specifically for breakthrough hemolysis, the cumulative discontinuation rate through the 48 week study period was 7.5% 92 .…”

Section: Inhibitors Of the Alternative Pathway: Clinical Data In Pnhmentioning

confidence: 99%

“…Ten additional patients discontinued pegcetacoplan switching back to eculizumab during the open‐label period of the study, due to breakthrough hemolysis (n = 3), pancytopenia/aplastic anemia (n = 2), hematological cancers (n = 2), mesenteric ischemia (n = 1), hypersensitivity pneumonia (n = 1), and fatal SARS‐CoV‐2 infection (n = 1) 92 . Looking specifically for breakthrough hemolysis, the cumulative discontinuation rate through the 48 week study period was 7.5% 92 . Irrespective of treatment discontinuation, the rate of breakthrough hemolysis in the pegcetacoplan was 10% (n = 4) at week 14, compared to 23% (n = 9) in the eculizumab arm, 91 even if it was suggested that the clinical severity of these events was quite different in the two treatment arms 93,94 .…”

Section: Inhibitors Of the Alternative Pathway: Clinical Data In Pnhmentioning

confidence: 99%

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The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target

Risitano

Frieri

Urciuoli

et al. 2022

Immunological Reviews

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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal, not malignant, hematological disease characterized by intravascular hemolysis, thrombophilia and bone marrow failure. While this latter presentation is due to a T-cell mediated auto-immune disorder resembling acquired aplastic anemia, the first two clinical presentations are largely driven by the complement pathway. Indeed, PNH is characterized by a broad impairment of complement regulation on affected cells, which is due to the lack of the complement regulators CD55 and CD59. The deficiency of these two proteins from PNH blood cells is due to the somatic mutation in the phosphatidylinositol Nacetylglucosaminyltransferase subunit A gene causing the disease, which impairs the surface expression of all proteins linked via the glycosylphosphatidylinositol anchor.The lack of the complement regulators CD55 and CD59 on PNH erythrocytes accounts for the hallmark of PNH, which is the chronic, complement-mediated intravascular hemolysis. This hemolysis results from the impaired regulation of the alternative pathway upstream in the complement cascade, as well as of the downstream terminal pathway. PNH represented the first indication for the development of anticomplement agents, and the therapeutic interception of the complement cascade at the level of C5 led to remarkable changes in the natural history of the disease. Nevertheless, the clinical use of an inhibitor of the terminal pathway highlighted the broader derangement of complement regulation in PNH, shedding light on the pivotal role of the complement alternative pathway. Here we review the current understanding of the role of the alternative pathway in PNH, including the emergence of C3-mediated extravascular hemolysis in PNH patients on anti-C5 therapies. These observations provide the rationale for the development of novel complement inhibitors for the treatment of PNH. Recent preclinical and clinical data on proximal complement inhibitors intercepting the alternative pathway with the aim of improving the treatment of PNH are discussed, together with their clinical implications which are animating a lively debate in the scientific community. This article is part of a series of reviews covering The Alternative Pathway or Amplification Loop of Complement appearing in Volume 313 of Immunological Reviews.

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Section: Inhibitors Of the Alternative Pathway: Clinical Data In Pnhmentioning

confidence: 59%

Section: Injection Site Reaction Was the Most Frequent Treatment Emer...mentioning

confidence: 99%

Section: Inhibitors Of the Alternative Pathway: Clinical Data In Pnhmentioning

confidence: 99%

Section: Inhibitors Of the Alternative Pathway: Clinical Data In Pnhmentioning

confidence: 99%

See 2 more Smart Citations

The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target

Risitano

Frieri

Urciuoli

et al. 2022

Immunological Reviews

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“…The PEGASUS trial randomized patients with PNH treated with eculizumab but who remained anemic, Hemoglobin < 10, or transfusion dependent were entered into 2 groups. Both groups received PEG + eculizumab for 4 weeks, then randomized to receive PEG alone vs eculizumab (ECU) alone for 16 weeks 21 , 22 The trial demonstrated superiority PEG to eculizumab in the reduction of hemolysis and transfusion avoidance. PEG was superior to the control for the coprimary endpoints of hemoglobin stabilization as well the change from baseline in LDH levels through Week 26 ( Figure 2 ).…”

Section: Pegasusmentioning

confidence: 99%

Pegcetacoplan: A New Opportunity for Complement Inhibition in PNH

Weitz¹

2023

JBM

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Pegcetacoplan is the newest inhibitor of the complement system to be approved by the FDA and EMA for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). The cyclic peptide inhibitor of C3 was evaluated in several clinical trials in PHN leading to its approval. The focus of this paper will review the efficacy and safety of Pegcetacoplan (PEG), and considerations for use in patients with PNH.

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Paroxysmal nocturnal hemoglobinuria: Where we stand

Panse

2023

American J Hematol

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For the last 20 years, therapy of paroxysmal nocturnal hemoglobinuria (PNH) relied-up until recently-on antibody based terminal complement inhibitionon. PNH pathophysiology-a mutational defect leading to partial or complete absence of complement-regulatory proteins on blood cells-leads to intravascular hemolysis and consequences such as thrombosis and other sequelae. A plethora of new drugs interfering with the proximal and terminal complement cascade are under recent development and the first "proof-of-pinciple" proximal complement inhibitor targeting C3 has been approved in 2021. "PNH: where we stand" will try to give a brief account on where we came from and where we stand focusing on approved therapeutic options. The associated improvements as well as potential consequences of actual and future treatments as well as their impact on the disease will continue to necessitate academic and scientific focus on improving treatment options as well as on side effects and outcomes relevant to individual patient lives and circumstances in order to develop effective, safe, and available treatment for all hemolytic PNH patients globally.Note: Due to space limitation the author mostly cites reviews and overviews, giving readers the chance to easily find continuative summaries of potentially interesting topics. He therefore does apologize

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Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial

Cited by 40 publications

References 29 publications

The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target

The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target

Pegcetacoplan: A New Opportunity for Complement Inhibition in PNH

Paroxysmal nocturnal hemoglobinuria: Where we stand

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