Eculizumab Shows Efficacy and Tolerability in Pediatric Patients with PNH

SAN DIEGO, CA—An open-label study of seven pediatric patients with paroxysmal nocturnal hemoglobinuria (PNH) found short-term infusions of eculizumab to be well tolerated, with reduced intravascular hemolysis. These results, reported during the 53rd American Society of Hematology Annual Meeting and Exposition, were consistent with those found in adults with this disease and suggest the potential for this treatment in children and adolescents with PNH.

PNH is a progressive, life-threatening disease characterized by chronic intravascular hemolysis. Eculizumab, a terminal complement inhibitor, provides rapid and sustained reduction in intravascular hemolysis, which results in significant reductions in thromboembolic events and pulmonary hypertension as well as improvements in renal disease, quality of life, and anemia. Results from a single-center study of up to eight years of treatment with eculizumab have demonstrated normalized survival of adults with PNH compared with age- and sex-matched controls. However, despite the fact that pediatric patients with PNH experience many of the same clinical features and life-threatening complications as adults, systematic research in the pediatric population has been limited, primarily due to small patient numbers.

Patients aged 2–17 years with a diagnosis of PNH were eligible for this Phase 1/2, 12-week, multicenter trial if they had ≥5% GPI-deficient red blood cells (RBC) or granulocytes and serum lactate dehydrogenase (LDH) levels that exceeded the upper limit of normal (ULN). Also eligible were children who had received one or more transfusions during the previous two years for anemia or anemia-related symptoms, said Ulrike M. Reiss, MD, of the Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.

The study sought to assess the safety and efficacy of short-term eculizumab treatment in children and adolescents with PNH, as well as determine appropriate dosing regimens. Safety and efficacy parameters included pharmacokinetic and pharmacodynamic parameters, adverse events (AEs), LDH and hemoglobin levels, platelet counts, and granulocyte and RBC type III clone size. In this study, four females and three males 10–17 years of age, three with a history of aplastic anemia, received eculizumab and completed the 12-week study. Eculizumab 600mg was given during the induction phase every 7±2 days for four weeks and increased to 900mg at Week 5. Patients continued on the 900mg dose for 14±2 days during the maintenance phase. Eculizumab was administered as an intravenous infusion at a dose of 5mg/mL at a rate of 5–10mL/kg/hr over at least 25 minutes.

At baseline, patients had elevated LDH (mean 1,020 ± 366U/L; normal range 100–275 U/L), thrombocytopenia, and anemia, and a median PNH granulocyte clone size of 74% (range 42–96). Study investigators reported that treatment with eculizumab was found to lead to a rapid reduction in LDH levels to 256U/L that was achieved by the second week of treatment (See Table). Using a repeated measures approach, investigators noted that the average reduction in LDH from baseline was significant throughout the entire 12-week study (P=0.0182). Plasma-free hemoglobin (Hb) levels were reduced by 27% from baseline (17.7mg/dL) during the first four weeks (12.91mg/dL) and by 58% (7.44mg/dL) by the end of the study.

Among these seven patients, eculizumab was found to be well-tolerated. The most commonly observed AEs were mild-to-moderate headache (42.9%), cough (28.6%), upper respiratory infection (28.6%), fever (14.3%), and upper abdominal pain (14.3%), a safety profile consistent with that previously reported in adults participating in phase III trials of PNH and eculizumab.

Prior to receiving therapy, hemolysis was in excess of 90% in all patients. An increase in plasma eculizumab concentrations was associated with a corresponding reduction in hemolysis; this reduction was evident following the first infusion and reached a maximum when steady-state eculizumab levels were achieved. No breakthrough hemolysis was observed. All seven patients completed the trial and remain alive. Pharmacokinetic and pharmacodynamic analysis is ongoing.

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