A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria

Background/Objective: Breakthrough hemolysis (BTH) is the return of hemolytic disease activity during treatment with complement C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH). BTH may be associated with inadequate C5 inhibition or complement activating conditions (eg, infection). Despite reports that up to 19% of patients (pts) receiving eculizumab may experience BTH, there is no commonly accepted definition of BTH. The definition of BTH was derived from literature review and expert consensus. BTH was defined as ≥1 new or worsening symptom/sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of lactate dehydrogenase (LDH) ≥2 times the upper limit of normal (ULN). In the 2 largest pivotal studies in PNH pts to date, ravulizumab q8w was statistically significantly noninferior to eculizumab 900 mg q2w, with point estimates favoring ravulizumab for all primary (LDH normalization, transfusion avoidance [study 301], percent change in LDH [study 302]) and key secondary endpoints (including BTH). Ravulizumab reduced free C5 levels to <0.5 μg/mL in all pts at all times; eculizumab did not consistently achieve this level of complement inhibition, providing a mechanistic basis for consistency of the point estimates for all endpoints. In study 301, LDH levels had to be decreased to <1.5 xULN prior to a BTH episode. Here we report BTH prevalence and causality using a common definition in the setting of 2 well-controlled clinical studies.