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| |  Phase 3 Trial Looks at Safety and Efficacy of Eculizumab in Paroxysmal Nocturnal Haemoglobinuria: Presented at EHA By Chris Berrie AMSTERDAM, THE NETHERLANDS -- June 21, 2006 -- Eculizumab is the first safe and effective targeted therapy for patients with paroxysmal nocturnal haemoglobinuria (PNH), according to research presented here at the 11th Congress of the European Hematology Association (EHA). Principal investigator Peter Hillmen, PhD, MBCHR, consultant in haematology, department of haematology, Leeds General Infirmary, Leeds, United Kingdom, presented the multicenter, randomised, double-blind, placebo-controlled, phase 3 trial on June 17th during the EHA's Presidential Symposium. Paroxysmal nocturnal haemoglobinuria is a rare form of haemolytic anemia that is characterised by destruction of red blood cells by the body's complement system. It is characterised by a triad of clinical features: haemoglobulinuria, with intravascular haemolysis that causes disabling symptoms of abdominal pain, dysphagia, erectile failure, and severe lethargy; Budd-Chiari syndrome, the most feared PNH complication that can cause fatal thrombosis; and aplastic anaemia, which results from bone marrow failure. According to Dr. Hillmen, the complement cascade described by 3 main activation pathways converge at the cleavage of the C5 terminal complement, which thus provided a pivotal target for therapy in patients with PNH. "Eculizumab is a humanised monoclonal antibody specific to the C5 complement cascade -- that has no effector function at all, and purely blocks the cleavage of C5," Dr. Hillmen detailed. A pilot study previously showed that eculizumab is safe and well tolerated, and promotes significant decreases in intravascular haemolysis, transfusion requirements, and haemoglobulinuria. For the patient, eculizumab was shown to promote improved quality of life, including decreased fatigue, which was maintained for more than 3 years. As a result of the pilot study, the researchers designed the Transfusion Reduction Efficacy and Safety Clinical Investigation, Randomised, Multicentre, Double-blind, Placebo-controlled, Using Eculizumab in Paroxysmal Nocturnal Hemoglobulinuria (TRIUMPH) Study. Key entry criteria were for adult patients with the following characteristics: 4 or more episodes of transfusions in the previous 12 months; a PNH type 3 erythrocyte population of 10% or more; platelets 100,000/mm3 or greater; lactate dehydrogenase (LDH) 1.5 or more times the upper limit of normal. Exclusion criteria included transfusion with haemoglobin > 10.5 g/dL in the previous year, known complement deficiency, an active bacterial infection or prior meningococcal disease, and pregnancy. The study design had an initial observation period of up to 3 months for the qualifying transfusion, followed by randomisation to placebo or eculizumab for a 6-month treatment period, and then a 24-month extension study. Following the assessment of 115 patients for trial eligibility, 87 reached randomisation to placebo (n = 44) and eculizumab (n = 43). Eculizumab 600 mg was initially administered as IV infusions over 30 minutes, every week for 4 doses. This was followed by the maintenance period of eculizumab 900 mg both 1 week later and then every 2 weeks for 26 weeks. Concomitant medication was allowed, providing there were no changes in immunosuppressives, steroids, anticlotting agents, or haematinics. All patients were vaccinated against Neisseria meningitides infection. The first coprimary study endpoint was stabilisation of haemoglobin levels, without the need for transfusions for the entire trial period. The second was the units of packed red blood cells (PRBCs) transfused. The secondary endpoints were haemolysis and fatigue, with exploratory endpoints of quality of life including fatigue, and thrombosis. Safety monitoring was also predefined. In the haemolytic assay for the ability of a patient's serum to haemolyse red blood cells, the first dose of eculizumab caused a dramatic decrease in the mean trough haemolytic activity to below the 20% baseline, which was maintained throughout the 26-week duration of the study. Similarly, haemolysis was dramatically decreased to just above normal lactate dehydrogenase levels, which remained low throughout the duration of the study. The effects of eculizumab on transfusions were also dramatic, with the first coprimary endpoint of median transfusions showing a highly significant, almost complete removal of the need for transfusion (P < 10-9). Similarly, as the second coprimary endpoint, there was a highly significant stabilisation of haemoglobin levels in over half of the eculizumab-treated patients (P < 10-7). For the time to first transfusion during eculizumab treatment, there was a highly significant increased avoidance of transfusions with eculizumab treatment (P < 10-6) that led to a 44% reduction in the PRBC units transfused. According to the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scale, where a 3-point change is considered to be clinically meaningful, eculizumab treatment resulted in a highly significant 10-point increase in score by the end of the treatment period (week 26; P = .00001). Quality-of-life scores (a 5-10 point change is considered clinically meaningful), eculizumab promoted significant changes of up to 25 points across all of the functional characteristics, and for most of the symptoms range. The total serious adverse events were higher in the placebo group (20.5% vs 9.3% for eculizumab), while adverse events were generally similar and light for both treatment groups. The eculizumab group did experience higher levels of headache (44.2% vs 27.3% for placebo), which were more apparent in the first 2 weeks of treatment. Evaluation of immunogenicity in terms of production of human antihuman antibodies saw 2 weak positive responses, 1 in each of the placebo and eculizumab groups. "So, in conclusion, the coprimary endpoints of this trial were both hit in a very strong statistical way, all the secondary endpoints were also achieved, as a reduction in intravascular haemolysis and a very meaningful reduction in fatigue, and [eculizumab] was safe and well tolerated," Dr. Hillmen said. Sponsored by Alexion and Schering.
[Presentation title: Safety and Efficacy of the Terminal Complement Inhibitor Eculizumab in a Phase 3 Trial in Patients With Paroxysmal Nocturnal Hemoglobinuria. Abstract 0535]
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