by Anita Hill, Peter Hillmen, Stephen J

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Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria by Anita Hill, Peter Hillmen, Stephen J. Richards, Dupe Elebute, Judith C. Marsh, Jason Chan, Christopher F. Mojcik, and Russell P. Rother Blood Volume 106(7):2559-2565 October 1, 2005 ©2005 by American Society of Hematology

PK and PD analyses of eculizumab in patients with PNH PK and PD analyses of eculizumab in patients with PNH. Initiation of eculizumab dosing is indicated at time 0 on the x axis. PK and PD analyses of eculizumab in patients with PNH. Initiation of eculizumab dosing is indicated at time 0 on the x axis. (A) Serum levels of eculizumab in 11 patients with PNH during the 64 weeks of treatment. The dashed line indicates the level of eculizumab required to completely block complement activity (≥ 35 μg/mL). Time 0 shows levels of eculizumab before (encircled) and 1 hour after dosing, whereas all other time points represent trough values. Two patients with trough levels of eculizumab below 35 μg/mL during the maintenance dosing are identified (patients 1 and 2). (B) Serum hemolytic activity (PD) during the 64-week treatment period, as determined by the ability of serum to lyse antibody-presensitized chicken erythrocytes. The dashed line indicates the percentage of hemolytic activity at which complement is considered effectively inhibited (≤ 20%). Time 0 shows serum hemolytic activity before (encircled) and 1 hour after dosing, whereas all other time points represent trough values. Two patients with trough serum hemolytic activity values above 20% are identified (patients 1 and 2). Anita Hill et al. Blood 2005;106:2559-2565 ©2005 by American Society of Hematology

LDH levels in patients with PNH before and during eculizumab treatment. LDH levels in patients with PNH before and during eculizumab treatment. Initiation of eculizumab dosing is indicated at time 0 on the x axis. LDH values are shown for 11 patients with PNH for 25 weeks before and 64 weeks during eculizumab treatment. (Normal) Upper limit of normal of the LDH range at the Leeds Teaching Hospital. The dashed line indicates off-scale points from one patient with a peak value of 12 100 IU/L. Two patients who experienced a return of serum hemolytic activity during treatment are identified (patients 1 and 2). Anita Hill et al. Blood 2005;106:2559-2565 ©2005 by American Society of Hematology

Paroxysm rate in patients with PNH before and during eculizumab treatment. Paroxysm rate in patients with PNH before and during eculizumab treatment. A urine color scale2 was used to assess the incidence of paroxysms in 8 patients with PNH before and during treatment with eculizumab. Paroxysm was prospectively defined by a urine colorimetric score of 6 or more. Bars represent the paroxysm rates (number of paroxysms per patient per month) during the screening period, during the first 12 weeks, and over the total 64 weeks of eculizumab treatment. Three patients were not included in the analysis either because their pretreatment urine scores were inadvertently not collected (2 patients) or because an iron-chelating agent that resulted in artificially colored urine was administered during the extension study (1 patient). Anita Hill et al. Blood 2005;106:2559-2565 ©2005 by American Society of Hematology

Relationship between complement inhibition with eculizumab and various hemolytic parameters and symptoms during a transient breakthrough in serum-complement activity. Relationship between complement inhibition with eculizumab and various hemolytic parameters and symptoms during a transient breakthrough in serum-complement activity. Urine color, symptoms, biochemical parameters of hemolysis, PK, and PD were assessed during a 14-day eculizumab-dosing interval in a patient with a transient breakthrough in serum hemolytic activity. Eculizumab was administered on day 0 after assay samples were collected. A urine colorimetric score of 6 or greater was considered abnormal (hemoglobinuria). Levels of the hemolytic markers LDH and AST are shown (IU/L). Eculizumab serum concentrations (PK, μg/mL) of ≥ 35 μg/mL were sufficient to maintain a serum hemolytic activity (PD, % serum hemolytic activity) of ≤ 20%, a value known to represent complete complement blockade. The eculizumab-dosing interval was reduced to 12 days between visits 5 and 9. Urine row presents colorimetric scores. — indicates not determined. *Dose of eculizumab. Anita Hill et al. Blood 2005;106:2559-2565 ©2005 by American Society of Hematology