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Paroxysmal Nocturnal Hemoglobinuria: Pathophysiology and Novel Therapeutic Approaches
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Paroxysmal Nocturnal Hemoglobinuria: Pathophysiology and Novel Therapeutic Approaches

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 2491

Special Issue Editor

Dr. Jun-Ichi Nishimura

E-Mail Website
Guest Editor
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Japan
Interests: hematology; bone marrow failure; hemolytic anemia; paroxysmal nocturnal hemoglobinuria; complement

Special Issue Information

Dear Colleagues,

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis caused by the clonal expansion of hematopoietic stem cells with a mutation in a gene involved in GPI-anchor synthesis, such as PIGA. At this moment, the mechanism of PNH clonal expansion is still not fully resolved. The anti-C5 antibody eculizumab (Soliris®), a terminal complement inhibitor, was developed as a therapeutic for PNH hemolysis, and it not only markedly inhibited hemolysis and prevented thrombosis, but it also dramatically improved both quality of life and prognosis. However, to overcome the new challenge of manifesting extravascular hemolysis via complement C3 opsonization, various proximal complement inhibitors targeting C3, Factor D, and Factor B are being developed.

This Special Issue focuses on the molecular pathogenesis of PNH and therapeutic strategies for novel anticomplement agents.

Dr. Jun-Ichi Nishimura
Guest Editor

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Keywords

  • paroxysmal nocturnal hemoglobinuria
  • complement
  • intravascular hemolysis
  • extravascular hemolysis
  • breakthrough hemolysis
  • terminal complement inhibitor
  • proxymal complement inhibitor

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Published Papers (3 papers)

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Research

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12 pages, 2268 KiB  
Article
Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function
by Jeff Szer, Jens Panse, Austin Kulasekararaj, Monika Oliver, Bruno Fattizzo, Jun-ichi Nishimura, Regina Horneff, Johan Szamosi and Régis Peffault de Latour
Int. J. Mol. Sci. 2024, 25(16), 8591; https://doi.org/10.3390/ijms25168591 - 6 Aug 2024
Cited by 1 | Viewed by 762
Abstract
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, potentially life-threatening haematological disease characterised by chronic complement-mediated haemolysis with multiple clinical consequences that impair quality of life. This post hoc analysis assessed haematological and clinical responses to the first targeted complement C3 inhibitor pegcetacoplan in [...] Read more.
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, potentially life-threatening haematological disease characterised by chronic complement-mediated haemolysis with multiple clinical consequences that impair quality of life. This post hoc analysis assessed haematological and clinical responses to the first targeted complement C3 inhibitor pegcetacoplan in patients with PNH and impaired bone marrow function in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. For patients with impaired bone marrow function, defined herein as haemoglobin <10 g/dL and absolute neutrophil count <1.5 × 109 cells/L, normalisation of the parameters may be difficult. Indeed, 20% and 43% had normalised haemoglobin in PEGASUS and PRINCE, respectively; 60% and 57% had normalised LDH, and 40% and 29% had normalised fatigue scores. A new set of parameters was applied using changes associated with clinically meaningful improvements, namely an increase in haemoglobin to ≥2 g/dL above baseline, decrease in LDH to ≤1.5× the upper limit of normal, and an increase in fatigue scores to ≥5 points above baseline. With these new parameters, 40% and 71% of PEGASUS and PRINCE patients had improved haemoglobin; 60% and 71% had an improvement in LDH, and 60% and 43% had an improvement in fatigue scores. Thus, even patients with impaired bone marrow function may achieve clinically meaningful improvements with pegcetacoplan. Full article
(This article belongs to the Special Issue Paroxysmal Nocturnal Hemoglobinuria: Pathophysiology and Novel Therapeutic Approaches)
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Review

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16 pages, 2705 KiB  
Review
Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors
by Peter Hillmen, Regina Horneff, Michael Yeh, Martin Kolev and Pascal Deschatelets
Int. J. Mol. Sci. 2024, 25(17), 9477; https://doi.org/10.3390/ijms25179477 - 31 Aug 2024
Viewed by 586
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, [...] Read more.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3/C3b-targeted therapy, pegcetacoplan. Full article
(This article belongs to the Special Issue Paroxysmal Nocturnal Hemoglobinuria: Pathophysiology and Novel Therapeutic Approaches)
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Other

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16 pages, 1798 KiB  
Perspective
Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval
by Regina Horneff, Barbara Czech, Michael Yeh and Elena Surova
Int. J. Mol. Sci. 2024, 25(16), 8698; https://doi.org/10.3390/ijms25168698 - 9 Aug 2024
Viewed by 719
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A [...] Read more.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients’ quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH. Full article
(This article belongs to the Special Issue Paroxysmal Nocturnal Hemoglobinuria: Pathophysiology and Novel Therapeutic Approaches)
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