What is PNH?

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and a heightened risk of thrombosis.¹ This non-malignant disease arises from mutations in the phosphatidylinositol glycan class A (PIGA) gene, which disrupts the synthesis of glycosylphosphatidylinositol (GPI) anchor proteins.¹ The deficiency of two of these proteins, CD55 and CD59, leaves red blood cells susceptible to complement activation and lysis, and accounts for the majority of the commonly observed clinical manifestations of PNH.¹ The pathophysiology of the disease drives the classical triad of clinical features: hemolytic anemia, a prothrombotic state, and varying degrees of bone marrow dysfunction.² Thrombosis, especially in intra-abdominal sites (hepatic, portal, etc.) or cerebral veins, is a significant cause of morbidity and mortality in PNH.¹

The diagnosis of PNH

Diagnosing PNH relies on high-sensitivity flow cytometry, which detects the absence or reduction of GPI-anchored proteins on peripheral blood cells once they have been stained with monoclonal antibodies and fluorescent aerolysin reagent (FLAER).¹ Clinically, patients with PNH may present with fatigue, dyspnea, dark urine (classically more noticeable in the morning), abdominal pain, and erectile dysfunction.¹ Additionally, cytopenias are common, ranging from mild to severe.²

Based on clinical presentation and laboratory results, PNH can be categorized into one of three types based on a classification scheme proposed by the International PNH Interest Group. These include classical PNH, PNH in the context of another bone marrow disorder, and subclinical PNH, characterized by a small PNH clone size with no evidence of hemolysis or thrombosis.³ The most common bone marrow disorders occurring with PNH include aplastic anemia (AA), myelodysplastic syndrome (MDS), and primary myelofibrosis (PMF).¹

The current treatment landscape in PNH: complement inhibitors and alloSCT

Over the last two decades, the treatment landscape for PNH has undergone significant changes due to an improved understanding of the role of the complement cascade in disease pathobiology. The standard of care for PNH centers on complement inhibition, which has significantly improved outcomes by reducing hemolysis, lowering the risk of thrombosis, and enhancing survival.⁴

In 2007, the first complement inhibitor, eculizumab, was approved by the Food and Drug Administration (FDA) for patients with PNH.⁴ Eculizumab remains a mainstay in the treatment of the disease; however, in 2018, a longer-acting C5 inhibitor named ravulizumab was approved.⁴ This agent requires less frequent infusions, due to having a 4x longer half-life than eculizumab, reducing the risk of patients experiencing breakthrough hemolysis and decreasing healthcare utilization.⁴ A third ​​C5 inhibitor, crovalimab, was approved in 2024. Due to its enhanced recycling, crovalimab requires lower and less-frequent doses and can be administered subcutaneously every four weeks.

Earlier this year, at the 2nd International PNH Interest Group (IPIG) Conference in Paris, France, we spoke with Austin Kulasekararaj, MBBS, MD, MRCP, FRCPath, of King’s College Hospital NHS Foundation Trust, London, UK, who outlined the role of ravulizumab in PNH treatment. He noted that “[ravulizumab] was definitely a step up from pre-existing eculizumab, and nowadays the standard of care C5 inhibition is mostly ravulizumab in countries with approval of this drug.”

At the same meeting, we spoke with Catherine Flynn, MD, of St James’s Hospital, Dublin, Ireland, who discussed the difference between crovalimab and eculizumab, highlighting that crovalimab is “a game changer in terms of the fact that it can be self-administered at home without the supervision of a nurse.”

Although the advent of C5 inhibitors revolutionized PNH treatment, these agents do not entirely prevent extravascular hemolysis, prompting the development of proximal complement inhibitors targeting C3 or factor B/D.⁵ In 2021, pegcetacoplan, a complement protein C3 inhibitor, was approved based on findings from the PEGASUS and PRINCE trials (NCT03500549; NCT04085601), in which the agent showed improvements in efficacy outcomes compared with eculizumab or supportive care.⁴ Furthermore, iptacopan, an oral Factor B inhibitor approved in 2023, has been used both as monotherapy and in combination with eculizumab to increase hemoglobin level without the need for transfusion.⁴ Finally, danicopan, an oral factor D inhibitor, has been investigated as an add-on to C5 inhibition to improve hemoglobin concentration in patients with PNH and clinically significant extravascular hemolysis, and was FDA approved in 2024.⁴

At IPIG 2025, Jens Panse, MD, of Aachen University Hospital, Aachen, Germany, discussed the complexities of switching patients with PNH from C5 inhibitors to proximal complement inhibitors. Dr Panse states: “Besides the efficacy of the drug, the question also is, is this the ideal patient for the specific drug? So it’s the mantra of personalized medicine – basically, right patient, right drug at the right time.”

Despite the availability of these agents, allogeneic stem cell transplantation (alloSCT) remains the only curative option for patients with PNH, as it can eradicate the PNH clone in both classical PNH and AA with PNH.⁶ However, with the advent of effective, non-transplant therapies, its use has decreased, with alloSCT now reserved for patients with severe marrow failure or refractory disease due to the high risk of morbidity and mortality.⁶

In patients with PNH, supportive care remains essential, particularly in resource-limited settings in which access to novel therapies is limited. Patients with iron deficiency require iron and folic acid supplementation, while those with severe anemia may require transfusion support and iron chelation.⁷ Complement inhibition significantly elevates the risk of life-threatening and fatal meningococcal infection; therefore, all patients should be vaccinated against meningococcal subtypes and receive antimicrobial prophylaxis for at least 14 days following vaccination.⁷

Novel therapeutic approaches being explored for PNH

Despite recent therapeutic advances in PNH, novel approaches are being developed to further improve patient outcomes. Mannan-binding lectin-associated serine protease-3 (MASP-3) presents a potential novel target in PNH, and the MASP-3 inhibitor zaltenibart is under investigation in a Phase II proof-of-concept clinical trial (NCT05972967) in patients with a suboptimal response to ravulizumab.⁴ The agent is also set to be assessed in two large-scale Phase III trials, one in patients not receiving complement inhibitor therapy, and the other in patients who are suboptimal responders to eculizumab or ravulizumab.⁸ Zaltenibart is expected to confer enhanced efficacy to anti-C5 therapies, due to its ability to prevent both intravascular and extravascular hemolysis.⁴ Additionally, KP104, a bifunctional monoclonal antibody that simultaneously inhibits C5 and activates factor H, is being evaluated in an ongoing Phase II study (NCT05476887) and represents a promising novel approach for the management of PNH.⁴ 

In conclusion, significant recent progress has been made in the treatment of PNH. Treatment strategies are becoming increasingly individualized, balancing disease severity, thrombotic risk, and patient quality of life. However, the risk of breakthrough hemolysis remains with currently approved agents, underscoring the need for ongoing therapeutic innovations.

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