Efficacy and Safety of Eculizumab in Children and Adolescents with Paroxysmal Nocturnal Hemoglobinuria
Authors: Reiss Ulrike M. , Schwartz Jeffrey , Sakamoto Kathleen M , Puthenveetil Geetha , Ogawa Masayo , Ware Russell E. 
Published: October 2019

Abstract
Abstract 1034

Background:
Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive, life-threatening disease characterized by chronic intravascular hemolysis caused by uncontrolled complement activation. The cellular abnormality in PNH originates from a somatic mutation in the PIG-A gene resulting in a deficiency of the glycosylphosphatidyl-inositol (GPI) anchored complement regulatory proteins, CD55 and CD59. Featuring a complex pathophysiology, PNH is associated with hemolysis, cytopenia, thromboembolism (TE), multi-organ damage, bone marrow failure, and death. Patients with PNH also experience a range of debilitating symptoms including fatigue, shortness of breath, erectile dysfunction, and abdominal pain that significantly reduce quality of life (QoL). The terminal complement inhibitor eculizumab has been shown to provide a rapid and sustained reduction in intravascular hemolysis, leading to significant reductions in TE events, pulmonary hypertension and improvements in renal disease, QoL and anemia. In a single center study of long term eculizumab treatment (up to 8 years), eculizumab was shown to normalize the survival of adult PNH patients compared to age and sex-matched controls. In contrast, systematic research focused on pediatric PNH patients has been limited, largely due to small patient numbers. However, pediatric PNH patients experience many of the same clinical features and life-threatening complications as adult patients. The current study assessed the safety, pharmacokinetics, and efficacy of short-term eculizumab treatment in children and adolescents with PNH.

Methods:
The study began in May 2009, and is no longer recruiting as the enrollment targets have been met. In this 12-week, open-label, multicenter study, children and adolescents (aged 2 to 17 years) were eligible with a diagnosis of PNH, ≥5% GPI-deficient red blood cells (RBC) or granulocytes, and serum lactate dehydrogenase (LDH) levels > upper limit of normal (ULN) or those who had received ≥1 transfusion during the previous 2 years for anemia or anemia-related symptoms. Eculizumab was administered using weight-based dosing (300–900 mg IV) at pre-determined regular 7–14 day intervals throughout the treatment period. In addition to pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and efficacy parameters included adverse events (AEs), LDH and hemoglobin levels, platelet counts, and granulocyte and RBC type III clone size.

Results:
Seven pediatric patients with PNH ranging in age from 11 to 17 years participated in this study (4 females, 3 males). One patient also had aplastic anemia at study enrollment. At baseline, patients had elevated LDH (normal range 100–275 U/L), thrombocytopenia and anemia, and a median PNH granulocyte clone size of 79%. Eculizumab was well-tolerated; common AE's included headache, fever, and nasal congestion, all mild to moderate in severity. All 7 patients completed the 12-week trial and are currently alive; the safety and AE profile of eculizumab was consistent with that previously reported in adults participating in Phase III PNH clinical trials. Eculizumab treatment led to a rapid and sustained reduction in LDH levels, from a mean of 1,020 U/L at baseline to 256 U/L at 12 weeks (Table 1). PK-PD analysis is ongoing.

Conclusions:
Consistent with results in adults, pediatric patients with PNH tolerate short-term eculizumab infusions well and have reduced intravascular hemolysis. These results highlight the potential of eculizumab for the treatment of children and adolescents with PNH.

Disclosures:
Sakamoto: Abbott: Research Funding; Genentech: Research Funding. Puthenveetil:Novartis Pharmaceuticals Corporation: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau. Ogawa:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership.