Pegcetacoplan versus Eculizumab in PNH

Ueda, Yutaka; Takamori, Hiroyuki; Nishimura, Junichi

doi:10.1056/nejmc2106424

Cited by 20 publications

(11 citation statements)

References 12 publications

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“…C3-targeted inhibitors and their transfer to the clinic are considered as promising ( 26 ). Indeed, C3 specific inhibitors using peptides and nanobodies platforms have been developed and clinical trials conducted in a large panel of diseases including periodontal inflammation and COVID-19 with AMY-101 ( 27 , 28 ), in paroxysmal nocturnal haemoglobinuria with pegcetacoplan ( 29 ), and in acute antibody-mediated graft injury and age-related macular degeneration with Cp40 ( 30 , 31 ). In addition to its anti-complement properties, M101 has original characteristics including oxygen carrier, anti-inflammatory, anti-bacterial, and superoxide dismutase antioxidant properties ( 32 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

The oxygen carrier M101 alleviates complement activation, which may be beneficial for donor organ preservation

Puissant‐Lubrano

Bouthemy²,

Congy‐Jolivet

et al. 2022

Front. Immunol.

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During organ transplantation, ischemia/reperfusion injury and pre-formed anti-HLA antibodies are the main cause of delayed graft function and recovery through the activation of the complement system. By supplying oxygen during transplantation, M101 is suspected to avoid complement activation, however, a direct effect exerted by M101 on this pathway is unknown. This was tested by using functional assays (lymphocytotoxic crossmatch test, C3d Luminex-based assay, 50% complement hemolysis [CH50], and 50% alternative complement pathway [AP50/AH50]), and quantitative assays (C3, C3a, C4, C5, C5a, C6, C7, C8, C9 and sC5b-9). M101 interferes with the anti-HLA lymphocytotoxic crossmatch assay, and this effect is complement-dependent as M101 inhibits the classical complement pathway (CH50) in a dose-dependent and stable manner. Such inhibition was independent from a proteolytic effect (fractions C3 to C9) but related to a dose-dependent inhibition of the C3 convertase as demonstrated by exploring downstream the release of the anaphylatoxins (C3a and C5a), C3d, and sC5b-9. The C3 convertase inhibition in the presence of M101 was further demonstrated in the AP50/AH50 assay. In conclusion, the use of M101 avoids the activation of the complement pathway, which constitutes an additional advantage for this extracellular hemoglobin to preserve grafts from ischemia/reperfusion injury and preformed anti-HLA antibodies.

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Section: Discussionmentioning

confidence: 99%

The oxygen carrier M101 alleviates complement activation, which may be beneficial for donor organ preservation

Puissant‐Lubrano

Bouthemy²,

Congy‐Jolivet

et al. 2022

Front. Immunol.

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Section: Discussionmentioning

confidence: 99%

“…38 It should be noted that patients enrolled in the PEGASUS study do not represent a broad population of patients with PNH and, as such, the conclusions drawn should be interpreted accordingly and cannot be extended to the full PNH population. [39][40][41] Additional studies will be needed to evaluate the long-term safety and efficacy of proximal complement inhibitors. 38 Baseline characteristics prior to C5 inhibition suggest that the cohort of patients in this study was representative of patients encountered in real-world clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Low Rate of Clinically Evident Extravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with a Complement C5 Inhibitor: Results from a Large, Multicenter, US Real-World Study

Shammo¹,

Gajra²,

Patel³

et al. 2022

JBM

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Purpose Most patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with a complement protein 5 (C5) inhibitor achieve full control of terminal complement activity and intravascular hemolysis. The minority remains anemic and transfusion dependent despite this control. Etiology for ongoing anemia is multifactorial and includes bone marrow failure, breakthrough hemolysis, extravascular hemolysis (EVH) and nutritional deficiencies. Patients and Methods To evaluate the potential etiologies of hemoglobin levels <10 g/dL despite receiving C5 inhibitor therapy, we performed a retrospective US chart review of adult patients with PNH and treated for at least 12 months with eculizumab (n=53), ravulizumab (n=32), or eculizumab followed by ravulizumab (n=15). Clinically evident EVH was defined as at least one transfusion, reticulocyte count ≥120×10 9 /L and hemoglobin level ≤9.5 g/dL. Safety data were not collected. Mean treatment duration was 26.5±17.2 months. Results Treatment with C5 inhibitors significantly improved hemoglobin, lactate dehydrogenase, and number of transfusions versus baseline. Among the patients with hemoglobin <10 g/dL during the last 6 months of treatment (n=38), one patient (eculizumab) had clinically evident EVH, and 10 patients had active concomitant bone marrow failure. Bone marrow failure was a major contributor to hemoglobin <10 g/dL and transfusion dependence; clinically evident EVH was uncommon. Conclusion A range of hematologic causes need to be considered when evaluating anemia in the presence of treatment with a C5 inhibitor.

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“…34 In a phase 3 open-label clinical trial, the new drug has been evaluated head-to-head with eculizumab in PNH patients registering suboptimal eculizumab responses (hemoglobin levels < 10.5 g/dL). 35 Pegcetacoplan administered subcutaneously twice weekly reached the primary endpoint of increase in hemoglobin levels from baseline to week 16 (adjusted mean difference of 3.84 g/dL, p<0.001). 34 Novel agents targeting other components of the complement system are currently under investigation in clinical trials with encouraging results.…”

Section: A Glimpse Into the Next Future: From Terminal To Proximal Complement Inhibitionmentioning

confidence: 95%

Current Opinions on the Clinical Utility of Ravulizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Gurnari¹,

Nautiyal²,

Pagliuca³

2021

TCRM

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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder of hematopoietic stem cells genetically defined by the acquisition of somatic mutations in the X-linked phosphatidylinositol glycan anchor biosynthesis, class A ( PIGA ) gene. PIGA is essential for the synthesis of glycosyl phosphatidylinositol (GPI) anchor proteins and its mutations result in a deficiency of such molecules on the membrane of blood cells derived from the mutant clone. In particular, the lack of the GPI-linked complement regulatory proteins CD55 and CD59 is responsible for the increased sensitivity of PNH erythrocytes to complement-mediated destruction. Indeed, the classical clinical picture of PNH includes signs and symptoms of intravascular hemolysis along with variable degrees of cytopenia and a strong tendency to thrombosis, hallmarks of the disease. Before the introduction of anti-complement inhibitors, PNH was characterized by a high mortality primarily due to thrombotic events. The approval of the terminal anti-complement inhibitor eculizumab in 2007 introduced a paradigm shift in the treatment of the disease with improvement of the chronic hemolytic process and dramatic reduction of the thrombotic rate. However, eculizumab has a relatively short half-life when considering a life-long treatment, with obvious consequences as to the quality of life of treated patients necessitating relatively frequent drug administrations. Moreover, up to 30% of PNH patients undergoing eculizumab therapy show a suboptimal response, continuing to require red cell transfusions because of extravascular hemolysis or breakthrough hemolytic episodes. In 2019, the FDA approved the second-generation C5 inhibitor ravulizumab, a long-lasting agent with a better control of disease manifestations. Herein, we discuss the use of ravulizumab in PNH, its differences with first-generation C5 inhibitors, the research evidence supporting the safety and efficacy of this drug and its impact on costs for health systems and quality of life of PNH patients.

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Pegcetacoplan versus Eculizumab in PNH

Cited by 20 publications

References 12 publications

The oxygen carrier M101 alleviates complement activation, which may be beneficial for donor organ preservation

The oxygen carrier M101 alleviates complement activation, which may be beneficial for donor organ preservation

Low Rate of Clinically Evident Extravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with a Complement C5 Inhibitor: Results from a Large, Multicenter, US Real-World Study

Current Opinions on the Clinical Utility of Ravulizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria

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