Characterization of breakthrough hemolysis events observed in the phase III randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria

Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase III studies, ravulizumab was non-inferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor−naïve patients], 4.0% vs. 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs. 5.1%). In the current analysis, patientlevel data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase III PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 mg/mL); four (80%) were temporally associated with complement-amplifying conditions (CAC). Of the 22 events occurring in eculizumab-treated patients, 11 were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CAC only. Five events were unrelated to free C5 elevation or reported CAC. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. (Registered at clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.)