Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study

Abstract

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

Conflict of interest statement

Conflict-of-interest disclosure: A.G.K., A.H., R.W., F.A.G.-F., A.G., E.O.G., A.R., and S.N. have received honoraria and consulting fees from Alexion Pharmaceuticals, Inc. S.T.R., L.S., A.I.D., and S.O. are employees and stockholders of Alexion Pharmaceuticals, Inc. J.W.L. has received honoraria, consulting fees, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. E.B. is a former employee and stockholder of Alexion Pharmaceuticals, Inc. J.S. has received consultancies, honoraria, and advisory board membership for Alexion Pharmaceuticals, Inc. A.R. has received consultancies and honoraria from Alexion, Roche, and Novartis and research funding from Alexion and Roche. R.P.d.L. has received consultancies, honoraria, and research funding from Alexion, Novartis, and Pfizer and research funding from Amgen. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Treatment effect. (A) Primary end point. The red triangle indicates the noninferiority margin. [1] Difference (Diff) (95% CI) was based on estimated difference in percentage with 95% CI. [2] Treatment difference was estimated for eculizumab − ravulizumab. (B) Secondary end point. The red triangle indicates the noninferiority margin. [1] For the end points transfusion avoidance (TA), breakthrough hemolysis (BTH), and stabilized hemoglobin (HGB-S), Diff (95% CI) was based on estimated differences in percentage with 95% CI. For FACIT-Fatigue, Diff (95% CI) was based on estimated difference in change from baseline with 95% CI. [2] Treatment difference was estimated for ravulizumab − eculizumab, except for breakthrough hemolysis, where treatment difference was based on eculizumab − ravulizumab. PCHG, percentage change.

Figure 2.

Percentage of patients achieving LDH normalization over time in the ravulizumab and eculizumab treatment groups. LDH normalization is defined as proportion of patients who achieved LDH level ≤1× the ULN (246 U/L).

Figure 3.

Mean (95% CI) free C5 levels in the ravulizumab and eculizumab groups over time. (A-B) A gyros-based fluorescence assay was used for patients who received ravulizumab (A), and an electrochemiluminescence immunoassay was used for patients who received eculizumab (B). Baseline (BL) is defined as the last nonmissing value before first dose of study drug. Day 29, 43, 57, 85, 99, 113, 141, 155, and 169 data are from anytime for the ravulizumab group and predose for the eculizumab group. Horizontal line indicates free C5 level of 0.5 µg/mL. Free C5 levels <0.5 µg/mL are associated with complete inhibition of C5 activity.