Results from a Phase 3, Multicenter, Non-Inferiority Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Currently Treated with Eculizumab
Authors: Kulasekararaj Austin G. , Hill Anita , Rottinghaus Scott T. , Langemeijer Saskia , Wells Richard A. , Gonzalez-Fernandez F. Ataulfo , Gaya Anna , Lee Jong-Wook , Ojeda Gutierrez Emilio , Piatek Caroline I. , Szer Jeffrey , Risitano Antonio M. , Nakao Shinji , Bachman Eric , Shafner Lori , Damokosh Andrew I. , Ortiz Stephan , Röth Alexander , Peffault De Latour Regis 
Published: October 2019

Abstract

Introduction
Ravulizumab, an innovative complement C5 inhibitor given every 8 weeks (q8w), was recently demonstrated in a large phase 3 study of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) and naïve to complement inhibitor therapy to be non-inferior to eculizumab given every 2 weeks (q2w) across all endpoints that measured different aspects of PNH disease (transfusion avoidance [TA], lactate dehydrogenase normalization [LDH-N], percent LDH reduction, breakthrough hemolysis [BTH], Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, and hemoglobin stabilization [HGB-S]) (Lee JW et al. EHA Learning Center, Jun 17, 2018; LB2603). PNH pts currently receiving eculizumab may experience treatment burden associated with the q2w dosing regimen. With the development of ravulizumab, PNH pts on prior eculizumab therapy can potentially switch to ravulizumab without interruption of treatment. The primary objective of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult PNH pts who were clinically stable after having been treated with eculizumab for at least 6 months.
Methods
In this phase 3, open-label, multicenter study (NCT03056040), adult pts with a documented diagnosis of PNH who were treated with labelled-dose eculizumab for >6 months having LDH levels ≤1.5 times the upper limit of normal at screening were randomly assigned 1:1 to continue eculizumab or switch to ravulizumab. Pts randomized to ravulizumab received weight-based loading [day 1]/maintenance doses [day 15 and q8w thereafter]: ≥40 to <60 kg body weight [2400/3000mg]; ≥60 to <100 kg [2700/3300mg]; ≥100 kg [3000/3600mg]) through day 183 (primary completion date). Pts randomized to eculizumab received 900mg q2w. All pts must have received vaccination against N. meningitidis. Primary efficacy endpoint was hemolysis, as measured by percentage change in LDH levels from baseline (BL) to day 183. Non-inferiority was declared if the upper bound of the 95% confidence interval (CI) for the difference in change of LDH from BL (ravulizumab-eculizumab) was <15%. Key secondary efficacy endpoints tested in a hierarchal manner were proportion of patients with BTH, change in quality of life assessed by FACIT-Fatigue score, TA (percentage of pts remaining transfusion-free), and proportion of pts with HGB-S from BL to day 183. Change from BL in free C5 level over time was also assessed.
Results
Of 208 pts screened, 197 pts were randomized (1:1) to ravulizumab or eculizumab, 195 received treatment (ravulizumab, n=97; eculizumab, n=98), and 191 pts completed 183 days of treatment. Pt demographics and baseline clinical characteristics were similar between treatment groups. On average, pts had received prior eculizumab therapy for 5.8 years. All pts received all planned infusions of study medication. Ravulizumab was statistically significantly noninferior to eculizumab for the primary and all key secondary endpoints, with all point estimates favoring ravulizumab: percentage change in LDH levels (difference of -9.21% [95% CI: -18.84, 0.42]), BTH (difference of -5.1 [95% CI -18.89, 8.89]), change in FACIT-Fatigue score (difference of 1.47 [-0.21, 3.15]), TA (difference of 5.5 [95% CI -4.27, 15.68]), and HGB-S (difference of 1.4 [-10.41, 13.31]) (Fig A, Fig B). Superiority testing of the primary endpoint (percentage change in LDH) did not reach statistical significance (P=0.0583 vs P<0.05 required). Complete inhibition of serum C5 (mean free C5 serum of <0.5 µg/mL) was observed by the end of the first ravulizumab infusion and was sustained throughout the treatment period (Fig C). The most frequently reported adverse event was headache (26.8% versus 17.3% for ravulizumab and eculizumab, respectively). There were no meningococcal infections or discontinuations due to adverse events.
Conclusion
Results of this large phase 3 study show that ravulizumab achieved noninferiority compared with eculizumab in pts with PNH on stable eculizumab therapy. Pts can be safely and effectively switched from eculizumab given q2w to ravulizumab given q8w. In pts previously stable on eculizumab, no pts switched to ravulizumab experienced BTH vs 5 pts on eculizumab during the 26-week treatment period. This may be related to optimized ravulizumab dosing compared to eculizumab, resulting in complete and sustained C5 inhibition for all pts.
Figure. Figure.

Disclosures
Kulasekararaj: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Hill:Apellis: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Akari: Consultancy, Honoraria; Ra Pharma: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Wells:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support , Research Funding. Gonzalez-Fernandez:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Gaya:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Ojeda Gutierrez:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Nakao:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Novartis: Honoraria. Bachman:Alexion Pharmaceuticals, Inc.: Equity Ownership, Other: Former employee. Shafner:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Damokosh:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Ortiz:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Röth:Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria; Amgen: Research Funding. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding.