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

Jong Wook Lee, Flore Sicre de Fontbrune, Lily Wong Lee Lee, Viviani Pessoa, Sandra Gualandro, Wolfgang Füreder, Vadim Ptushkin, Scott T. Rottinghaus, Lori Volles, Lori Shafner, Rasha Aguzzi, Rajendra Pradhan, Hubert Schrezenmeier and Anita Hill

Data supplements

Article Figures & Data

Figures

  • 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).

Tables

  • Table 1.

    Demographics and baseline clinical characteristics

    CharacteristicRavulizumab (N = 125)Eculizumab (N = 121)Total (N = 246)
    Sex, n (%)
     Male65 (52.0)69 (57.0)134 (54.5)
     Female60 (48.0)52 (43.0)112 (45.5)
    Age at first infusion of study drug, mean (SD), y44.8 (15.2)46.2 (16.2)45.5 (15.7)
    Race, n (%)
     Asian72 (57.6)57 (47.1)129 (52.4)
      Japanese19 (15.2)15 (12.4)34 (13.8)
     White43 (34.4)51 (42.1)94 (38.2)
     Black or African American2 (1.6)4 (3.3)6 (2.4)
     American Indian or Alaska Native1 (0.8)1 (0.8)2 (0.8)
     Other4 (3.2)4 (3.3)8 (3.3)
     Not reported3 (2.4)4 (3.3)7 (2.8)
    Weight, mean (SD), kg68.2 (15.6)69.2 (14.9)68.7 (15.2)
    Height, mean (SD), cm166.3 (9.0)166.2 (10.7)166.2 (9.8)
    LDH ratio, n (%)
     1.5 to <3× ULN*18 (14.4)16 (13.2)34 (13.8)
     ≥3× ULN107 (85.6)105 (86.8)212 (86.2)
    Packed RBC units received within 1 y before study entry, randomization strata, n (%)
     0 U23 (18.4)21 (17.4)44 (17.9)
     1-14 U79 (63.2)78 (64.5)157 (63.8)
     >14 U23 (18.4)22 (18.2)45 (18.3)
    Age at PNH diagnosis, mean (SD), y37.9 (14.9)39.6 (16.7)38.7 (15.8)§
    Number of years from PNH diagnosis to consent, median (minimum, maximum), y3.8 (0, 41)3.9 (0, 34)3.9 (0, 41)§
    LDH, mean (SD), U/L1633.5 (778.8)1578.3 (727.1)1606.4 (752.7)
    PNH clone size, mean (SD), %
     Type II RBCs12.4 (20.5)||13.7 (17.7)13.0 (19.2)#
     Type III RBCs26.3 (17.2)||25.2 (16.9)25.8 (17.1)#
     Total RBCs38.4 (23.7)38.7 (23.2)38.6 (23.4)
     Granulocytes84.2 (21.0)85.3 (19.0)84.7 (20.0)
     Monocytes86.9 (18.1)89.2 (15.2)88.0 (16.7)
    History of major adverse vascular events, n (%)17 (13.6)25 (20.7)42 (17.1)
    • PNH, paroxysmal nocturnal hemoglobinuria; RBC, red blood cell; SD, standard deviation.

    • * The ULN for LDH is 246 U/L.

    • n = 123.

    • n = 118.

    • § n = 241.

    • || n = 124.

    • n = 120.

    • # n = 244.

  • Table 2.

    Coprimary and key secondary efficacy outcomes at day 183

    Ravulizumab (N = 125)Eculizumab (N = 121)Statistic for comparisonTreatment effectNoninferiority marginConclusion
    Coprimary end points
     Transfusion avoidance rate, % (95% CI)73.6 (65.87, 81.33)66.1 (57.68, 74.55)Difference in rate6.8 (−4.66, 18.14)−20%Noninferior
     LDH normalization, % (95% CI)53.6 (45.9, 61.2)49.4 (41.7, 57.0)OR1.19 (0.80, 1.77)0.39Noninferior
    Key secondary efficacy end points
     LDH, least squares mean % change (95% CI)−76.84 (−79.96, −73.73)−76.02 (−79.20, −72.83)Difference in % change from baseline−0.83 (−5.21, 3.56)20%Noninferior
     FACIT-Fatigue score, least squares mean change (95% CI)7.07 (5.55, 8.60)6.40 (4.85, 7.96)Difference in change from baseline0.67 (−1.21, 2.55)−5.0Noninferior
     Breakthrough hemolysis rate, % (95% CI)4.0 (0.56, 7.44)10.7 (5.23, 16.26)Difference in rate−6.7 (−14.21, 0.18)20%Noninferior
     Hemoglobin stabilization rate, % (95% CI)68.0 (59.82, 76.18)64.5 (55.93, 72.99)Difference in rate2.9 (−8.80, 14.64)−20%Noninferior
    • For the transfusion avoidance end point, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. For the LDH-N end point, the adjusted prevalence within each treatment is displayed. Testing of the noninferiority hypothesis is assessed by comparing the bolded limit of the 95% CI to the noninferiority margin.

  • Table 3.

    Other secondary efficacy outcomes at day 183

    Ravulizumab (N = 125)Eculizumab (N = 121)*
    Patients who received packed RBC transfusions, n (%)32 (25.6)40 (33.1)
    Total number of packed RBC units transfused, mean (SD)4.8 (5.1)5.6 (5.9)
    Patients with major adverse vascular events, n (%)2 (1.6)1 (0.8)
    Clinical manifestations of paroxysmal nocturnal hemoglobinuria, n (%)BaselineDay 183BaselineDay 183
     Fatigue80 (64.0)36 (28.8)76 (63.9)36 (30.3)
     Abdominal pain17 (13.6)6 (4.8)15 (12.6)6 (5.0)
     Dyspnea42 (33.6)18 (14.4)38 (31.9)17 (14.3)
     Dysphagia13 (10.4)3 (2.4)16 (13.4)1 (0.8)
     Chest pain5 (4.0)3 (2.4)17 (14.3)7 (5.9)
     Hemoglobinuria§71 (56.8)13 (10.4)56 (47.5)11 (9.3)
     Erectile dysfunction||16 (12.8)10 (8.0)21 (17.6)5 (4.2)
    • * n = 119 patients were included in the analysis of clinical manifestations of PNH.

    • One patient, who was taking concomitant oral contraceptive medication, experienced an event of lower leg deep vein thrombosis. The other patient had history of lower leg pain and edema and was taking an oral anticoagulant, which was discontinued after initiation of study drug.

    • This event of mesenteric venous thrombosis with concurrent neutropenic colitis occurred in a patient who had history of aplastic anemia.

    • § n = 118 patients with evaluable data in the eculizumab group.

    • || n = 65 male patients in the ravulizumab group and n = 68 male patients in the eculizumab group.

  • Table 4.

    Adverse events

    VariableRavulizumab (N = 125)Eculizumab (N = 121)
    Patients with AEs, n (%)110 (88.0)105 (86.8)
    Most common AEs (≥5% of patients in either treatment group), n (%)
     Headache45 (36.0)40 (33.1)
     Nasopharyngitis11 (8.8)18 (14.9)
     Nausea11 (8.8)10 (8.3)
     Upper respiratory tract infection13 (10.4)7 (5.8)
     Pyrexia6 (4.8)13 (10.7)
     Viral upper respiratory tract infection9 (7.2)10 (8.3)
     Arthralgia8 (6.4)8 (6.6)
     Dizziness9 (7.2)7 (5.8)
     Pain in extremity9 (7.2)7 (5.8)
     Diarrhea10 (8.0)5 (4.1)
     Myalgia7 (5.6)9 (7.4)
     Abdominal pain7 (5.6)7 (5.8)
     Oropharyngeal pain8 (6.4)6 (5.0)
     Back pain7 (5.6)6 (5.0)
     Cough4 (3.2)8 (6.6)
     Hypokalemia6 (4.8)6 (5.0)
     Dyspepsia4 (3.2)6 (5.0)
     Insomnia2 (1.6)6 (5.0)
    Patients with serious AEs, n (%)*11 (8.8)9 (7.4)
    Meningococcal infections, n (%)00
    Death, n (%)01 (0.8)
    Patients with AEs leading to withdrawal of study drug, n (%)01 (0.8)
    Patients with serious AEs leading to withdrawal of study drug, n (%)01 (0.8)
    • * Serious AEs in the ravulizumab group included: anemia, aplastic anemia, neutropenia, thrombocytopenia, left ventricular failure, myocardial ischemia, pyrexia, leptospirosis, systemic infection, laceration, uterine leiomyoma, renal colic, and deep vein thrombosis (n = 1 patient each). Serious AEs in the eculizumab group included: pyrexia (n = 2 patients), ileus, neutropenic colitis, limb abscess, cellulitis, infection, pneumonia, viral upper respiratory tract infection, adenocarcinoma of colon, lung adenocarcinoma, and paroxysmal nocturnal hemoglobinuria (n = 1 patient each).

    • One patient in the eculizumab arm died of lung cancer (unrelated to treatment) during the extension phase of the study.