Paroxysmal nocturnal haemoglobinuria is an ultra-rare disease that imposes significant medical and psychological burdens on patients. Mainstay treatment with complement inhibitors has improved patient outcomes but unmet needs remain. Dr João Gonçalves PhD explains how the treatment landscape is evolving to encompass different therapeutic targets and modalities, including danicopan, to provide a personalised, person-centred approach to management.
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening haematologic disorder characterised by complement-mediated haemolysis of red blood cells. The disease results from a somatic mutation in the phosphatidyl inositol glycan A (PIG-A) gene, leading to the absence of glycosylphosphatidylinositol-anchored proteins, particularly CD55 and CD59, on the surface of erythrocytes.
The loss of these regulatory proteins results in uncontrolled activation of the complement system, particularly the terminal pathway, which drives intravascular haemolysis and promotes a prothrombotic state.1–3
Paroxysmal nocturnal haemoglobinuria presentation
PNH presents with a characteristic triad of haemolytic anaemia, cytopaenia and thrombosis. Haemolysis leads to symptoms such as fatigue, haemoglobinuria and abdominal pain. Additionally, the haemolysis-related iron loss can exacerbate anaemia, further reducing patients’ quality of life. Cytopaenia in PNH patients is often due to associated bone marrow failure, which might coexist with aplastic anaemia or myelodysplastic syndromes.4,5
Thrombosis is a significant cause of morbidity and mortality in PNH, with patients exhibiting an increased risk of life-threatening thromboembolic events such as stroke, deep vein thrombosis and pulmonary embolism. The underlying mechanisms involve complement activation-induced platelet dysfunction, haemolysis-driven nitric oxide depletion and endothelial damage.6,7
The chronic nature of PNH significantly affects patients’ quality of life and health outcomes. Frequent medical interventions, including blood transfusions, anticoagulation therapy and hospitalisation for thromboembolic events, contribute to a substantial burden on healthcare systems.7,8
Additionally, the psychological impact of PNH, including increased anxiety and depression, complicates clinical management and highlights the need for effective, long-term therapeutic strategies.6
PNH management challenges
The advent of complement inhibitors, such as the monoclonal antibodies eculizumab and ravulizumab, has revolutionised PNH treatment by significantly reducing intravascular haemolysis and improving survival rates.
These drugs target C5 in the complement cascade, preventing the formation of the membrane attack complex and mitigating erythrocyte destruction.9,10 However, despite their efficacy, 11–27% of patients continue to experience breakthrough haemolysis, primarily attributed to extravascular haemolysis mediated by the alternative complement pathway.11–13
While C5 inhibitors have successfully addressed intravascular haemolysis, they do not entirely prevent C3-mediated extravascular haemolysis, which remains a significant challenge for some patients.
Next-generation therapies and personalising treatment
The persistence of anaemia in patients treated with ravulizumab or eculizumab underscores the need for targeting upstream mechanisms of complement activation. This has driven the development of next-generation therapies that address the alternative complement pathway, offering a more comprehensive treatment strategy.12,13
A promising addition to the PNH therapeutic landscape is danicopan, an oral complement factor D inhibitor that selectively targets the alternative complement pathway.
Unlike C5 inhibitors, danicopan acts upstream in the complement cascade, preventing C3-mediated extravascular haemolysis while preserving the efficacy of C5 blockade.14,15 This dual mechanism of action is particularly relevant for patients experiencing persistent anaemia or breakthrough haemolysis despite treatment with eculizumab or ravulizumab.13,14,16
Clinical studies have demonstrated that danicopan effectively reduces haemolysis and improves haemoglobin levels in patients with PNH inadequately controlled on C5 inhibitors.9,14 Oral administration provides a significant advantage over intravenous therapies, enhancing patient adherence and convenience.13,14
Given that frequent infusions pose a barrier to optimal management in PNH, oral administration could transform the treatment experience, reducing healthcare burden and improving patient satisfaction.7,8
The introduction of factor D inhibitors signals a shift towards personalised, multi-targeted complement inhibition strategies. Future research may explore combination therapies that further refine complement regulation, addressing both intravascular and extravascular haemolysis more effectively.
Additionally, gene therapies and haematopoietic stem cell transplantation remain areas of interest, particularly for patients with severe bone marrow failure syndromes.9
Conclusion
PNH is a complex and debilitating disorder that imposes significant clinical and psychological burdens on patients. Although C5 inhibitors have dramatically improved outcomes, breakthrough haemolysis and extravascular haemolysis remain challenges for some individuals.
The introduction of danicopan, targeting an alternative complement pathway to provide a more comprehensive therapeutic approach, represents a significant advance in treating PNH.
With its oral formulation, danicopan has the potential to enhance patient adherence, reduce treatment burden and improve overall quality of life. Future innovations in complement inhibition and emerging gene therapies will refine PNH management, offering new hope for patients suffering from this rare and potentially life-threatening disease.
Author
João Gonçalves PharmD PhD
Faculty of Pharmacy, University of Lisbon, Portugal
References
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