Breakthrough hemolysis in adult patients with paroxysmal nocturnal hemoglobinuria treated with Ravulizumab: Results of a 52-week extension from two phase 3 studies
Schrezenmeier H, Hill A, Piatek CI, de la Tour RP, Lee LWL, Wells R, Brodsky R, Kim JS, Nishimura J, Kuriakose P, Pavani R, Liu P, Ortiz S, Lee JW, and Kulasekararaj A. Breakthrough hemolysis in adult patients with paroxysmal nocturnal hemoglobinuria treated with Ravulizumab: Results of a 52-week extension from two phase 3 studies. British Journal of Haematology 2019; 134(SUPPL 1): 952.
British Journal of Haematology
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/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 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.