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INTRODUCTION In patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) receiving eculizumab, approximately 11%-27% may experience breakthrough hemolysis (BTH)-the return of hemolytic disease activity. BTH may be associated with inadequate C5 inhibition or complement-activating conditions (CACs; eg, infection). Although there is no broad consensus regarding the definition of BTH, this study defined BTH based on literature review and expert consensus: ≥1 new or worsening sign or symptom 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 elevated lactate dehydrogenase (LDH) (≥2 × ULN) after prior LDH reduction to <1.5 × ULN on therapy. Ravulizumab, an innovative long-acting C5 complement inhibitor, was recently approved in the United States, Japan, and Europe for the treatment of PNH. In two phase 3 trials, ALXN1210-PNH-301 (301; NCT02946463) and ALXN1210-PNH-302 (302; NCT03056040), ravulizumab (q8w) was shown to be noninferior to eculizumab 900 mg (q2w) for all primary and key secondary endpoints (including BTH). Each study had a 26-wk randomized primary evaluation period, followed by an extension period during which pts could receive ravulizumab for up to 2 y. In the current analysis, pt-level data were evaluated to assess causes and clinical parameters associated with BTH incidences reported up to 1 y in the two phase 3 trials. METHODS The trials were phase 3, randomized, open-label, noninferiority, multicenter studies. Eligible pts were ≥18 y with confirmed PNH diagnosis. Pts in study 301 were naive to C5 inhibitor therapy, with LDH of ≥1.5 × ULN and ≥1 sign/symptom of PNH at screening. Pts in study 302 were stable receiving eculizumab treatment for ≥6 mo, with LDH of ≤1.5 × ULN at screening. Pts received weight-based dosing of ravulizumab q8w or the approved eculizumab dose (900 mg q2w) for 183 d; in the extension, eligible pts continued (R-R arm) or switched to ravulizumab (E-R arm). The outcome of interest was the proportion of pts with BTH during the extensions of 301 and 302 (wks 27-52), causes, and clinical parameters associated with BTH incidents. BTH causation was determined by clinical review and categorized as related to inadequate C5 inhibition (free C5 ≥0.5 μg/mL), CAC due to an inciting event (eg, infection, trauma, surgery), or unrelated to either event. RESULTS Study 301: 243 pts entered the extension period (R-R arm: n=124; E-R arm: n=119). In both groups, 99% of pts who had no BTH during wks 0-26 experienced no BTH incidents during wks 27-52. Four pts in the R-R arm experienced BTH during wks 27-52, of which 3 pts had experienced BTH during wks 0-26. In the E-R arm, there were fewer BTH events during wks 27-52 compared with wks 0-26 (Table A). Two pts experienced BTH after switching to ravulizumab in the E-R arm, of which 1 had experienced BTH during wks 0-26. During wks 27-52, 2 BTH events (1 in each arm) were associated with infection and 4 BTH events in the R-R arm and 1 in the E-R arm were unrelated to free C5 elevation or reported infection. Study 302: 191 pts entered the extension period (R-R arm: n=96; E-R arm: n=95). Of these pts, 97% in the R-R arm and 100% in the E-R arm who had no BTH during wks 0-26 had no BTH incidents during wks 27-52. Three pts in the R-R arm experienced BTH during wks 27-52. In the E-R arm, there were fewer BTH events during wks 27-52 compared with wks 0-26 (Table B). One pt experienced BTH after switching to ravulizumab; this pt previously experienced BTH during wks 0-26. During wks 27-52, 2 BTH events in the R-R arm and 1 event in the E-R arm were associated with infection, and 1 BTH event in the R-R arm was unrelated to free C5 elevation or reported infection. In both studies, no BTH incidents were associated with free C5 of >0.5 μg/mL (the threshold associated with complete inhibition of C5) during wks 27-52 while on ravulizumab treatment. CONCLUSIONS During wks 27-52, in both studies, the number of pts who experienced BTH events was similar to that in wks 0-26 in the R-R group, and fewer pts experienced BTH events after switching from eculizumab to ravulizumab. No BTH events were associated with elevations in free C5 to >0.5 μg/mL in pts taking ravulizumab. Similar numbers of pts initially receiving ravulizumab or eculizumab experienced infection-related BTH events, possibly due to proximal complement activation. Hill: Bioverativ: Honoraria; Alexion: Honoraria; Regeneron: Honoraria; Novartis: Honoraria; Roche: Honoraria; Apellis: Honoraria; Akari: Honoraria; Ra Pharma: Honoraria. Piatek:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Wells:Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding. Nishimura:Alexion: Honoraria, Research Funding; Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Pavani:Alexion: Employment. Liu:Alexion: Employment. Ortiz:Alexion: Employment. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kulasekararaj:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.