FDA Report: Eculizumab (Soliris®) for the Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria

Oncologist - Tập 13 Số 9 - Trang 993-1000 - 2008
Andrew Dmytrijuk1, Kathy Robie‐Suh1, Martin H. Cohen1, Dwaine Rieves1, K Weiss1, Richard Pazdur1
1Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

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Abstract Learning Objectives After completing this course, the reader will be able to: Describe the mechanism of action of eculizumab in PNH.Discuss the efficacy findings upon which the approval of eculizumab was based.Manage the safety concerns surrounding the use of eculizumab for the treatment of patients with PNH.Discuss the efficacy and side effect profile of eculizumab. CME This article is available for continuing medical education credit at CME.TheOncologist.com On March 16, 2007, eculizumab (Soliris®; Alexion Pharmaceuticals, Inc. Cheshire, CT), a humanized monoclonal antibody that binds to the human C5 complement protein, received accelerated approval by the U.S. Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Eculizumab was studied in a randomized, double-blind, placebo-controlled clinical trial in 87 RBC transfusion–dependent adult PNH patients and in a supportive single-arm study in 96 patients. The eculizumab dose was 600 mg as a 35-minute i.v. infusion administered weekly for the first 4 weeks followed by 900 mg (week 5) then 900 mg every 14 days thereafter. Hemoglobin stabilized in 21 of 43 (48.8%) eculizumab-treated patients, compared with none of 44 placebo-treated patients. Eculizumab-treated patients required significantly fewer RBC transfusions than placebo-treated patients (median, 0 versus 10 units). There was also a significant reduction in the serum lactate dehydrogenase area under the curve with eculizumab compared with placebo treatment. Results of the phase II supportive study were similar to those of the phase III study. The safety database included 196 adult patients with PNH. Significant findings included the development of human anti-human antibody responses in three patients and serious meningococcal infections in three patients. Patients should undergo meningococcal vaccination at least 2 weeks prior to receiving the first eculizumab treatment and have revaccination according to current medical guidelines. Patients must be monitored and evaluated immediately for early signs of meningococcal infections and treated with antibiotics as indicated.

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Tài liệu tham khảo

Schwartz, 2004, Black mornings, yellow sunsets—a day with paroxysmal nocturnal hemoglobinuria, N Engl J Med, 350, 537, 10.1056/NEJMp038223

Hill, 2007, Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria, Br J Haematol, 137, 181, 10.1111/j.1365-2141.2007.06554.x

Rother, 2005, The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: A novel mechanism of human disease, JAMA, 293, 1653, 10.1001/jama.293.13.1653

Schechter, 2003, Hemoglobin and the paracrine and endocrine functions of nitric oxide, N Engl J Med, 348, 1483, 10.1056/NEJMcibr023045

Hillmen, 1995, Natural history of paroxysmal nocturnal hemoglobinuria, N Engl J Med, 333, 1253, 10.1056/NEJM199511093331904

Parker, 2005, Diagnosis and management of paroxysmal nocturnal hemoglobinuria, Blood, 106, 3699, 10.1182/blood-2005-04-1717

Brodsky, New insights into paroxysmal nocturnal hemoglobinuria, Hematology Am Soc Hematol Educ Program, 2006, 24, 10.1182/asheducation-2006.1.24

Socié, 1996, Paroxysmal nocturnal haemoglobinuria: Long-term follow-up and prognostic factors. French Society of Haematology, Lancet, 348, 573, 10.1016/S0140-6736(95)12360-1

Rother, 2007, Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria, Nat Biotechnol, 25, 1256, 10.1038/nbt1344

Hillmen, 2006, The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria, N Engl J Med, 355, 1233, 10.1056/NEJMoa061648

Hill, 2005, Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria, Blood, 106, 2559, 10.1182/blood-2005-02-0564

Hillmen, 2004, Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria, N Engl J Med, 350, 552, 10.1056/NEJMoa031688

Overturf, 2003, Indications for the immunological evaluation of patients with meningitis, Clin Infect Dis, 36, 189, 10.1086/345527

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Oncologist

Tập 13 Số 9

993-1000

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