OBJECTIVES

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of uncontrolled complement activation leading to platelet activation and red-blood-cell hemolysis. Since 2007, the only approved PNH treatment has been eculizumab (900 mg biweekly). Recently, the FDA approved ravulizumab for treating PNH (administered every 8 weeks). Although eculizumab has improved outcomes, some PNH patients receiving the approved eculizumab dosage experience breakthrough hemolysis (BTH). This study assessed the burden and cost associated with BTH in eculizumab-treated PNH patients.

METHODS

BTH was defined as ≥1 new or worsening symptoms/signs of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia, major adverse vascular event, dysphagia, or erectile dysfunction) in the presence of elevated serum lactate dehydrogenase (LDH) while on therapy. Known causes of BTH include insufficient C5 inhibition (<0.5 μg/ml), pregnancy, and complement-amplifying conditions (CAC). A systematic literature review (SLR) and survey of 10 PNH clinicians were implemented to understand the burden of BTH and develop a costing model to estimate the BTH direct medical cost.

RESULTS

The SLR identified 82 BTH patients across 23 publications; elevated LDH, hemoglobinuria, and transfusion needs were the most common clinical symptoms associated with BTH (reported in 52%, 26%, and 26% of publications, respectively). BTH management required eculizumab dose adjustment (eg, increase to 1200 mg or higher biweekly) and/or dosing interval reduction (eg, to 7 days), resulting in eculizumab use outside the regulatory approved dosage/dosing. Dosage/dosing adjustments were the main cost driver (especially during pregnancy), along with hospitalizations and blood transfusions. Annual costs associated with an initial BTH episode were $51,716 (due to CAC), $152,895 (insufficient C5 inhibition) and $186,107 (pregnancy).

CONCLUSIONS

BTH is burdensome to patients and society, requiring increases in dosing and frequency of treatment. The model showed the cost burden of BTH in eculizumab-treated PNH patients is substantial.