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

Austin G. Kulasekararaj, Anita Hill, Scott T. Rottinghaus, Saskia Langemeijer, Richard Wells, F. Ataulfo Gonzalez-Fernandez, Anna Gaya, Jong Wook Lee, Emilio Ojeda Gutierrez, Caroline I. Piatek, Jeff Szer, Antonio Risitano, Shinji Nakao, Eric Bachman, Lori Shafner, Andrew I. Damokosh, Stephan Ortiz, Alexander Röth and Regis Peffault de Latour

Data supplements

Article Figures & Data

Figures

  • 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.

Tables

  • Table 1.

    Demographic and baseline clinical characteristics

    CharacteristicRavulizumab (n = 97)Eculizumab (n = 98)Total (N = 195)
    Sex, no. (%)
     Male50 (51.5)48 (49.0)98 (50.3)
     Female47 (48.5)50 (51.0)97 (49.7)
    Age at first infusion of study drug, mean (SD), y46.6 (14.4)48.8 (14.0)47.7 (14.2)
    Race, no. (%)
     White50 (51.5)61 (62.2)111 (56.9)
     Asian23 (23.7)19 (19.4)42 (21.5)
     Japanese5 (5.2)7 (7.1)12 (6.2)
     African American5 (5.2)3 (3.1)8 (4.1)
     Other/multiple3 (3.1)1 (1.0)4 (2.1)
     Not reported/unknown16 (16.5)14 (14.3)30 (15.4)
    Weight, mean (SD), kg72.4 (16.8)73.4 (14.6)72.9 (15.7)
    Height, mean (SD), cm168.3 (10.1)168.8 (9.9)168.5 (10.0)
    Years on eculizumab before first study infusion6.0 (3.5)5.6 (3.5)5.8 (3.5)
    Patients with packed red blood cells/whole blood transfusions received within 1 y before first dose, no. (%)13 (13.4)12 (12.2)25 (12.8)
    Age at PNH diagnosis, mean (SD), y34.1 (14.4)36.8 (14.1)35.5 (14.3)
    Time from PNH diagnosis to consent, mean (SD), y12.4 (8.4)11.9 (9.4)12.2 (8.9)
    LDH, mean (SD),* U/L228.0 (48.7)235.2 (49.7)231.6 (49.2)
    PNH clone size, mean (SD), %
     Type II red blood cells14.9 (19.6)16.3 (23.6)15.6 (21.6)
     Type III red blood cells44.6 (30.5)43.5 (29.7)44.0 (30.0)
     Total red blood cells60.6 (32.5)59.5 (31.4)60.1 (31.9)
     Granulocyte82.6 (23.6)84.0 (21.4)83.3 (22.5)
     Monocyte85.6 (20.5)86.1 (19.7)85.9 (20.0)
    Hemoglobin, g/L, mean (SD)110.8 (18.4)109.1 (18.4)Not available
    Haptoglobin, g/L, mean (SD)§0.283 (0.235)0.255 (0.174)Not available
    History of major adverse vascular events, no. (%)28 (28.9)22 (22.4)50 (25.6)
    History of aplastic anemia, no. (%)34 (35.1)39 (39.8)73 (37.4)
    • * Normal range, 120 to 246 U/L.

    • Erythrocytes with complete deficiency in glycosylphosphatidylinositol-anchored proteins, including complement regulatory proteins CD59 and CD55.30

    • Normal range, 11.5 to 16.0 g/dL (women) and 13.0 to 17.5 g/dL (men).

    • § Normal range, 0.4 to 2.4 g/dL.

  • Table 2.

    Primary and key secondary efficacy outcomes at day 183

    Ravulizumab (n = 97)Eculizumab (n = 98)Statistic for comparisonTreatment effectNoninferiority marginConclusion*
    Primary end point
     LDH, least squares mean % change (95% CI)−0.82 (−7.8, 6.1)8.4 (1.5, 15.3)Difference in percentage change from baseline9.2 (−0.42 to 18.8)−15%Noninferior
    Key secondary efficacy end points
     Breakthrough hemolysis rate, % (95% CI)0 (0 to 3.7)5.1 (1.7 to 11.5)Difference in rate5.1 (−8.9 to 19.0)−20%Noninferior
     FACIT-Fatigue score, least squares mean change (95% CI)2.0 (0.6 to 3.4)0.54 (−0.8 to 1.9)Difference in change from baseline1.5 (−0.2 to 3.2)−3.0Noninferior
     Transfusion avoidance rate, % (95% CI)87.6 (81.1 to 94.2)82.7 (75.2 to 90.2)Difference in rate5.5 (−4.3 to 15.7)−20%Noninferior
     Stabilized hemoglobin rate, % (95% CI)76.3 (67.8 to 84.8)75.5 (67.0 to 84.0)Difference in rate1.4 (−10.4 to 13.3)−20%Noninferior
    • Testing of the noninferiority hypothesis is assessed by comparing the bolded limit of the 95% CI to the noninferiority margin.

    • * A conclusion of noninferiority indicates that the noninferiority margin is larger or smaller than the lower or upper bound of the 95% CI indicated in boldface.

  • Table 3.

    Other secondary efficacy outcomes at day 183

    Ravulizumab (n = 96)Eculizumab (n = 95)
    Total number of packed red blood cell units transfused, mean (SD)4.3 (4.76)3.4 (3.01)
    Patients with major adverse vascular events, n (%)0 (0)0 (0)
    Baseline*Day 183Baseline*Day 183
    Clinical manifestations of PNH, n (%)
     Fatigue29 (30.2)42 (43.8)38 (40)36 (37.9)
     Abdominal pain5 (5.2)5 (5.2)6 (6.3)12 (12.6)
     Dyspnea6 (6.3)6 (6.3)10 (10.5)17 (17.9)
     Dysphagia2 (2.1)5 (5.2)2 (2.1)5 (5.2)
     Chest pain0 (0)2 (2.1)1 (1.1)5 (5.2)
     Hemoglobinuria4 (4.2)8 (8.3)7 (7.4)9 (9.5)
     Erectile dysfunction§5 (10.0)6 (12.0)7 (14.6)6 (12.5)
    • * Baseline was defined as the last nonmissing value before the first dose of study drug.

    • n = 97.

    • n = 98.

    • § n = 50 male patients in the ravulizumab group and n = 48 male patients in the eculizumab group.

  • Table 4.

    Adverse events

    VariableRavulizumab (n = 97)Eculizumab (n = 98)
    Patients with adverse events85 (87.6)86 (87.8)
    Most common adverse events (≥5% of patients in either treatment group)
     Headache26 (26.8)17 (17.3)
     Nasopharyngitis21 (21.6)20 (20.4)
     Upper respiratory tract infection18 (18.6)10 (10.2)
     Diarrhea9 (9.3)7 (7.1)
     Pyrexia9 (9.3)5 (5.1)
     Nausea8 (8.2)9 (9.2)
     Constipation7 (7.2)5 (5.1)
     Influenza-like illness7 (7.2)8 (8.2)
     Abdominal pain6 (6.2)9 (9.2)
     Anemia6 (6.2)3 (3.1)
     Fatigue6 (6.2)6 (6.1)
     Vomiting6 (6.2)4 (4.1)
     Cough5 (5.2)10 (10.2)
     Pain in extremity5 (5.2)4 (4.1)
     Rhinitis5 (5.2)4 (4.1)
     Oropharyngeal pain4 (4.1)9 (9.2)
     Chest pain3 (3.1)9 (9.2)
     Dizziness3 (3.1)7 (7.1)
     Musculoskeletal pain2 (2.1)5 (5.1)
     Dyspnea0 (0.0)6 (6.1)
    Patients with serious adverse events4 (4.1)8 (8.2)
    Meningococcal infections00
    Death00
    Patients with adverse events leading to withdrawal of study drug00
    Patients with serious adverse events leading to withdrawal of study drug00
    • Values are reported as n (%) of patients.