Abstract
Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.
Highlights
This manuscript reports on the long-term safety and efficacy of eculizumab in 195 patients with haemolytic Paroxysmal nocturnal haemoglobinuria (PNH) who had participated in one of three prospective parent trials: the Phase II pilot study (Hillmen et al, 2004; Hill et al, 2005b) and its extensions, the Phase III TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation, a Randomized, Multicenter, Double-Blind, Placebo-Controlled, Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study (NCT00122330) (Hillmen et al, 2006), or the Phase III SHEPHERD (Safety in Hemolytic PNH Patients Treated With Eculizumab: A Multi-Center Open-Label Research Design) study (NCT00130000) (Hillmen et al, 2007; Brodsky et al, 2008)
Twenty-nine percent of patients had a history of aplastic anaemia and 1Á5% had a history of myelodysplastic syndrome
The entire period of eculizumab administration across the parent and extension trials was 66 months, a 36-month cut-off was used for safety and efficacy assessments to ensure that there were a sufficient number of patients for robust statistical analysis
Summary
Study design and patientsThis manuscript reports on the long-term safety and efficacy of eculizumab in 195 patients with haemolytic PNH who had participated in one of three prospective parent trials: the Phase II pilot study (Hillmen et al, 2004; Hill et al, 2005b) and its extensions, the Phase III TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation, a Randomized, Multicenter, Double-Blind, Placebo-Controlled, Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study (NCT00122330) (Hillmen et al, 2006), or the Phase III SHEPHERD (Safety in Hemolytic PNH Patients Treated With Eculizumab: A Multi-Center Open-Label Research Design) study (NCT00130000) (Hillmen et al, 2007; Brodsky et al, 2008). At the end of these initial studies, 187 of the 195 patients (95Á9%) enrolled in an openlabel extension study (Fig 1). All patients had a minimum of 10% PNH red blood cells at enrolment in the parent trials and were vaccinated with a meningococcal vaccine at least 14 d before the first eculizumab infusion in the parent studies. It was recommended that all patients be revaccinated at intervals of between 2Á5 and 3 years, with meningococcal vaccine titre assays collected prior to and within 1–2 months of the revaccination. All three parent trials employed the same dosing regimen: 600-mg infusions of eculizumab every week for 4 weeks, followed 1 week later by a single 900-mg dose, and a maintenance dose of 900 mg every 14 (Æ2) days until the end of the study. In the extension study patients continued to receive the maintenance dose of eculizumab
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