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 3 studies,
ravulizumab was noninferior to
eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with
ravulizumab versus
eculizumab in both studies (301 [
complement inhibitor-naive patients], 4.0% vs 10.7%; 302 [patients stabilized on
eculizumab at baseline], 0% vs 5.1%). In the current analysis, patient-level 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 3 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 μg/mL); four (80.0%) were temporally associated with
complement-amplifying conditions (CACs). Of the 22 events occurring in
eculizumab-treated patients, eleven were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant
infection. Six events were associated with CACs only. Five events were unrelated to free C5 elevation or reported CACs. 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. Clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.