Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study

Abstract

Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (-76.8% vs -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Conflict of interest statement

Conflict-of-interest disclosure: J.W.L. has received honoraria, consulting fees, and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. F.S.d.F. has received honoraria and research support (to St. Louis Hospital) from Alexion Pharmaceuticals, Inc. V. Pessoa and S.G. have received research support from Alexion Pharmaceuticals, Inc. W.F. has received honoraria from Alexion Pharmaceuticals, Inc, and Novartis. V. Ptushkin has received honoraria from Alexion Pharmaceuticals, Inc. S.T.R., L.V., L.S., R.A., and R.P. are employees and stockholders of Alexion Pharmaceuticals, Inc. H.S. has received honoraria and research support (all to University of Ulm) from Alexion Pharmaceuticals, Inc. A.H. has received honoraria and consulting fees from Alexion Pharmaceuticals, Inc. L.W.L.L. declares no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Treatment effect for the coprimary and key secondary efficacy end points. (A) Treatment difference is estimated for ravulizumab-eculizumab. For the TA end point, treatment differences (Diff) (95% CI) are based on estimated differences in percent with 95% CI. For the LDH normalization (LDH-N) end point, adjusted prevalence within each treatment is displayed. *Red triangle indicates the noninferiority margin. (B) For key secondary end points LDH-PCHG (percent change), breakthrough hemolysis (BTH), and hemoglobin stabilization (HGB-S), Diff (95% CI) is based on estimated differences in percent with 95% CI. For FACIT-Fatigue, Diff (95% CI) is based on estimated differences in change from baseline with 95% CI. *Red triangle indicates the noninferiority margin. †Treatment difference is estimated for ravulizumab-eculizumab except for LDH-PCHG and BTH, where treatment difference is based on eculizumab-ravulizumab. ‡P < .06 for the lower bound of the 95% CI.

Figure 2.

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

Figure 3.

Mean (95% CI) free C5 concentrations in the ravulizumab and eculizumab groups over time. Free C5 levels were assessed using a Gyros-based fluorescence assay in patients who received ravulizumab and an electrochemiluminescent immunoassay in patients who received eculizumab; 3 patients in the ravulizumab group and 8 in the eculizumab group had day 1 samples excluded because the samples were considered biologically implausible. Free C5 levels <0.5 µg/mL are associated with complete inhibition of C5 activity. Data from days 1, 15, 71, and 127 are from predose and end of infusion for both treatment groups, whereas at days 8, 22, 29, 43, 57, 85, 99, 113, 141, 155, and 169, the data are from any time for the ravulizumab group and predose for the eculizumab group; and at day 183, data are from end of the randomized treatment period for both treatment groups. BL, baseline (the last nonmissing assessment value before first dose of study drug).