Eculizumab Solution for Intravenous Infusion (Soliris™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
The FDA has approved a humanized monoclonal antibody for the treatment of paroxymal nocturnal hemoglobinuria (PNH). Eculizumab, a complement inhibitor, is the first drug to be approved for reducing hemolysis associated with this condition. It is marketed by Alexion Pharmaceutical, Inc as Soliris.
Eculizumab is indicated for the patients with PNH to reduce hemolysis.1
The recommended dose is 600 mg every 7 days (±2 days) for the first 4 weeks, 900 mg for the fifth dose 7 days later (±2 days), and 900 mg every 14 days (±2 days) thereafter. The drug is given by intravenous infusion over 35 minutes. If adverse reactions due to infusion occur, the infusion rate may be slowed or stopped. If the rate is slowed it should not exceed 2 hours. Patients should be monitored for one hour after infusion in case of infusion-related reactions. All patients must receive meningococcal vaccine at least 2 weeks prior to initiation of therapy.1
Eculizumab is supplied as 300 mg vials (10 mg/ml, 30 ml).
Eculizumab reduces hemolysis, hemoglobinuria, need for transfusions, and fatigue, and improves the quality of life.1,2,3
There is an increased risk of serious menogococcal infections and possibly infections caused by encapsulated bacteria such as Streptococcus pneumoniae and Hemophilus influenzae. Serious meningitis was reported in 2 of 196 subjects in clinical trials even with vaccination. The most common adverse events (10% or higher) include headache, nasopharyngitis, back pain, and nausea.1
PNH is a rare acquired clonal disorder characterized by intravascular hemolysis, anemia, hemoglobinuria, and venous thrombosis.4,5 The presence of blood in the urine and plasma is evident after sleeping. Hemolysis leads to recurrent abdominal pain, dysphagia, severe lethargy and erectile dysfunction. Thrombosis is the leading cause of premature mortality. A mutation in the phosphatidylinositol glycan complementation class A gene (PIG-A) leads to defective proteins essential to protect the red blood cells (RBC) from destruction by complement. Eculizumab blocks the activation of complement resulting in inhibition of hemolytic activity. Efficacy was based on one randomized, double-blind, placebo-controlled study, a single arm study, and a long-term extension study.
In the randomized study (n = 87), patients who had at least 4 transfusions in the previous 12 months, PNH type III erythrocyte proportion of 10% or more, platelet counts of at least 100,000/mm3, and lactate dehydrogenase levels at least 1.5 the upper limit of normal were randomized to eculizumab or placebo for 26 weeks.3 The primary endpoints were stabilization of hemoglobin and units of transfusion. Secondary endpoints include transfusion independence, hemolysis (area under the curve for lactate dehydrogenase value), fatigue, and assessment of quality of life (Functional Assessment of Chronic Illness Therapy-Fatigue Instrument and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire). Eculizumab stabilized hemoglobin levels in 49% of patients without transfusion vs 0% for placebo. The median units of RBC transfusion were 0 and 10 units respectively. Transfusion independence was achieved in 51% of and 0% respectively, and intravascular hemolysis was reduced.
Significant improvements in fatigue and quality of life were also observed. The single-arm study enrolled patients (n = 97) who had at least one transfusion in the past 24 months with at least 30,000 platelets/microliter and received eculizumab for 52 weeks. Similar results were achieved as in the first study.1 In an extension study (n = 187), reduction in hemolysis was sustained over the duration of drug exposure (10 - 54 months). Thrombotic events appear to be reduced compared to the same period prior to therapy although 63% were on antithrombotic therapy and this outcome was not studied in a controlled setting. Alexion has agreed to conduct a randomized, controlled clinical study to assess the effect of discontinuation of antithrombotic therapy while on eculizumab. A global registry of PNH is being developed to follow the natural history of the disease. Patients and providers must enroll with the Soliris OneSource (1-888-765-4747) prior to initiation of treatment.
The cost of eculizumab was not available at the time
of this review.
PNH is a rare disease with no cure except for bone marrow transplantation. The condition is managed with supportive therapy including antithrombotic therapy. Eculizumab represents a promising treatment for this condition. While eculizumab reduces hemolysis and the need for transfusion and improves quality of life, it has not yet been shown to reduce thrombotic events and improve survival.
1. Soliris Product Information. Alexion Pharmaceuticals, Inc. March 2007.
2. Hillmen P, et al. N Engl J Med. 2004;350:552-559.
3. Hillmen P, et al. N Engl J Med. 2006;355:1233-1243.
4. Hill A et al. Blood. 205;106:2559-2565.
5. Hill A et al. Br J Haematol. 2007;137(3):181-192.