Clinical bottom line
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. Despite advances with complement C5 inhibitors, a subset of patients with relapsed or refractory disease remains challenging to manage. Emerging therapeutic strategies targeting proximal complement components, alternative pathways, or novel mechanisms offer promising avenues to improve disease control and patient outcomes. These approaches warrant cautious optimism but require further clinical validation to define their role in relapsed/refractory PNH management.
What the evidence shows
Current standard treatment for PNH centers on terminal complement inhibition with anti-C5 monoclonal antibodies such as eculizumab and ravulizumab, which substantially reduce hemolysis and thrombotic risk (Risitano et al., 2017). However, some patients experience breakthrough hemolysis or incomplete response due to residual proximal complement activation or C3-mediated extravascular hemolysis. This clinical gap has stimulated development of novel agents targeting earlier steps in the complement cascade or alternative pathways.
Recent advances include inhibitors of complement component C3, factor D, and factor B, which act upstream of C5 and may provide more comprehensive complement blockade (Apostolidou et al., 2025). For example, proximal inhibitors can potentially prevent both intravascular and extravascular hemolysis by blocking opsonization of PNH erythrocytes. Additionally, small molecules and subcutaneous agents are under investigation to improve convenience and reduce infusion-related burdens.
Animal models and molecular studies have elucidated the pathogenesis of PNH and informed these therapeutic strategies (Murakami et al., 2017; Kinoshita et al., 2003). Complement inhibition beyond C5 blockade is a rational approach to address residual hemolysis and improve quality of life. However, clinical trial data remain limited, and long-term safety, especially regarding infection risk and immune modulation, requires careful assessment.
Caveats and uncertainty
Despite promising mechanistic rationale, the clinical efficacy and safety of proximal complement inhibitors in relapsed/refractory PNH are not yet fully established. Most data derive from early-phase trials or preclinical models, with limited large-scale randomized controlled trials available. The risk of infections, particularly with encapsulated bacteria, may be heightened with broader complement inhibition, necessitating vigilant prophylaxis and monitoring.
Heterogeneity in patient response and disease phenotype complicates treatment selection. Some patients may benefit from combination approaches or sequential therapies, but optimal regimens remain undefined. Additionally, cost and access considerations may impact real-world implementation.
The evolving landscape of PNH therapeutics underscores the need for ongoing research to clarify which patients derive the greatest benefit from novel agents and how to integrate them with existing standards of care (Risitano et al., 2017; Apostolidou et al., 2025).
How this may change practice
Clinicians managing relapsed or refractory PNH should remain informed about emerging complement inhibitors targeting proximal components and alternative pathways. These agents represent a potential paradigm shift by addressing limitations of current C5 blockade, particularly breakthrough hemolysis and extravascular hemolysis.
Pending further validation, incorporation of proximal complement inhibitors may offer improved disease control and patient convenience. Personalized treatment strategies considering disease severity, prior therapy response, and infection risk will be essential.
Multidisciplinary collaboration with hematology, infectious disease, and pharmacy specialists will be important to optimize prophylaxis and monitor for adverse effects. Participation in clinical trials should be encouraged to advance evidence generation.
Ultimately, these advancements hold promise to expand therapeutic options for a challenging patient population, but cautious interpretation and individualized clinical judgment remain paramount.