15/02/2026
Paroxysmal Nocturnal Haemoglobinuria (PNH): Evolving Complement Inhibition Strategies
Paroxysmal nocturnal haemoglobinuria remains a rare but high-impact complement-mediated disorder characterised by chronic intravascular haemolysis and a disproportionate risk of thrombosis in atypical sites. While anti-C5 therapy has transformed survival over the past 15 years, a significant proportion of patients continue to experience persistent anaemia due to residual extravascular haemolysis.
The biological rationale for therapeutic evolution is clear. C5 inhibition (eculizumab, ravulizumab) prevents membrane attack complex formation and controls intravascular haemolysis, but does not fully suppress upstream C3 activation. This has driven development of proximal complement inhibitors targeting C3 or the alternative pathway (factor B, factor D), with the aim of improving haemoglobin normalisation and transfusion independence.
Recent phase 3 data have expanded the evidence base:
• Eculizumab (TRIUMPH, SHEPHERD; phase 3) demonstrated marked LDH reduction, reduced transfusion need, and significant reduction in thrombotic events.
• Ravulizumab (Studies 301/302; phase 3) showed non-inferiority to eculizumab with extended 8-week dosing intervals.
• Pegcetacoplan (PEGASUS; phase 3) improved haemoglobin by approximately 3–4 g/dL in patients with persistent anaemia on C5 inhibition and increased transfusion avoidance.
• Iptacopan (APPLY-PNH; phase 3) demonstrated at least 2 g/dL haemoglobin increase in the majority of patients switched from C5 inhibitors, with high rates of transfusion independence.
• Danicopan (ALPHA; phase 3) improved haemoglobin when added to C5 blockade in patients with extravascular haemolysis.
International guidance, including ASH and European consensus statements, continues to recognise complement inhibition as the foundation of disease-modifying therapy, with treatment selection increasingly individualised according to haemolytic control, anaemia burden, thrombosis risk, route of administration, and patient preference.
For Malaysian practice, key considerations include vaccination protocols against Neisseria species, monitoring for breakthrough haemolysis, and the practical realities of treatment access. As proximal inhibition becomes more widely available, clinicians will need to consider whether persistent anaemia on C5 blockade warrants add-on therapy or switching strategy.
PNH has transitioned from a life-limiting haemolytic disorder to a chronic, biologically targetable condition. The current challenge is no longer whether to inhibit complement, but how best to sequence and individualise therapy for durable disease control with minimal treatment burden.
