One-Year Efficacy and Safety from a Phase 3 Trial of Ravulizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Receiving Prior Eculizumab Treatment

INTRODUCTION Ravulizumab, an innovative long-acting C5 complement inhibitor, was recently approved in the United States, Europe, and Japan for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). In the largest phase 3 study (ALXN1210-PNH-302; NCT03056040) in eculizumab-experienced PNH patients (pts), ravulizumab (q8w) was shown to be noninferior to eculizumab (q2w) after 26 wks for all primary and key secondary endpoints. At the end of the 26-wk treatment period, all pts had the option to receive weight-based dosing of ravulizumab in an extension for up to 2 y. We report on the efficacy and safety of ravulizumab through 52 wks of treatment. METHODS This was an extension of the open-label, phase 3, multicenter study described above. Adult PNH pts who were stable on eculizumab for ≥6 mo and with lactate dehydrogenase (LDH) of ≤1.5xULN at screening were randomly assigned 1:1 to switch to ravulizumab or continue receiving eculizumab for 26 wks. After 26 wks, pts in the ravulizumab arm continued ravulizumab maintenance therapy (R-R arm), and pts in the eculizumab arm were switched to ravulizumab (E-R arm). For the 52-wk data, the primary efficacy endpoint was percent change in LDH from baseline (BL), and key secondary endpoints included the proportion of pts with breakthrough hemolysis (BTH), transfusion avoidance, improvement in FACIT-Fatigue total score, and stabilized hemoglobin (HGB-S) levels. Additional endpoints included change in plasma free C5 levels from BL and safety evaluations. RESULTS Of the 192 pts who received ravulizumab during the study, 191 entered the extension period (R-R arm: n=96; E-R arm: n=95). Pts in both groups showed a durable response for percentage change in LDH up to 52 wks, similar to what was observed during the first 26 wks (Figure A). At 52 wks, pts in the R-R arm had an 8.8% increase in LDH from baseline (standard deviation [SD], 29%), while pts in the E-R arm had 5.8% (SD, 27%) change in LDH from baseline. Mean LDH levels in both groups were maintained at 1.0xULN (<246 U/L). The proportion of pts who experienced BTH was low and stable over the 52-wk treatment with ravulizumab (Table). During wks 0-26, no pts in the R-R arm experienced BTH vs 3 during wks 27-52. In the E-R arm, 5 pts experienced BTH during wks 0-26 vs 1 in wks 27-52 after switching to ravulizumab. During wks 27-52, no BTH events were associated with free C5 of ≥0.5 μg/mL (threshold for complete C5 inhibition). The percentage of pts avoiding transfusion remained stable in the extension period (Table). During wks 0-26, 88% of pts in the R-R arm avoided transfusion vs 87% in wks 27-52; in the E-R arm, 83% (0-26 wks) vs 83% (27-52 wks) avoided transfusion. FACIT-Fatigue scores were maintained in both treatment groups through 52 wks. The proportion of pts with HGB-S was 76% in each arm during wks 0-26, and 81% in each arm during wks 27-52. All pts in the R-R arm continued to maintain free C5 of <0.5 μg/mL at all time points through 52 wks (n=96; Figure B). All pts in the ravulizumab treatment group continued to maintain free C5 of <0.5 μg/mL at all time points through 52 wks (n=96). In pts initially randomized to eculizumab, the switch to ravulizumab showed improved free C5 control, and no pts had free C5 of ≥0.5 µg/mL after the switch. During the extension, 79% in the R-R arm experienced a treatment-emergent adverse event (TEAE) vs 75% in the E-R arm. The most frequently reported TEAEs in the R-R arm were upper respiratory tract infection (URTI; 9 pts [9%]), and headache and nasopharyngitis (6 pts [6%] each). The most common TEAEs in the E-R arm were headache (10 pts [10%]), URTI (8 pts [8%]), and nasopharyngitis (7 pts [7%]). Eight pts (8%) in the R-R arm and 5 pts (5%) in the E-R arm experienced serious AEs; none led to discontinuation or death. No new treatment-emergent antidrug antibody-positive responses were reported during wks 27-52. There were no meningococcal infections, deaths, or discontinuations due to AEs. CONCLUSIONS Adult PNH pts receiving stable eculizumab therapy who received ravulizumab over 52 wks experienced durable efficacy; pts who received eculizumab for 26 wks and then switched to ravulizumab had an efficacy response consistent with pts in the R-R arm. All pts who had suboptimal free C5 control receiving eculizumab achieved complete free C5 inhibition after the switch to ravulizumab; no BTH events were associated with free C5 levels of ≥0.5 μg/mL. Ravulizumab continues to be well tolerated through wk 52 with no new safety concerns. Disclosures Kulasekararaj: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Novartis: 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; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hill:Akari: Honoraria; Alexion: Honoraria; Bioverativ: Honoraria; Apellis: Honoraria; Novartis: Honoraria; Regeneron: Honoraria; Roche: Honoraria; Ra Pharma: Honoraria. Wells:Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gonzalez-Fernandez:Alexion: Research Funding, Speakers Bureau. Gaya:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria; Novartis: 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. Mitchell:Novartis: Honoraria; Alexion: Honoraria. Usuki:Alexion: Honoraria, Speakers Bureau. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding. Ogawa:Alexion Pharmaceuticals: Employment, Equity Ownership. Ortiz:Alexion: Employment. Röth:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Consultancy, Honoraria; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Achillion: Research Funding. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

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