vrn products have been availBIOTECHNOLOGY UPDA TE
Recent Biotechnology Approvals Peggy Piascik
The Food and Drug Administration (FDA) recently approved one new biotechnology agent, approved a second indication for an existing product, and recommended approval of a third product. On March 6, recombinant factor vm (ReFacto-WyethAyerst Laboratories) was approved for treatment of hemophilia A. On March 20, gemtuzumab ozogamicin (Mylotarg-Wyeth-Ayerst Laboratories), a monoclonal antibody, was recommended for approval for treatment of acute myelogenous leukemia (AML) by FDA's Oncologic Drugs Advisory Committee. A previously approved product, interferon gamma-1 b (Actimmune--InterMune Pharmaceuticals), was approved in February for a new indication, treatment of osteopetrosis in children.
ReFacto Approval ReFacto is approved for the control and prevention of bleeding episodes and surgical prophylaxis in patients ~ith hemophilia A. It is also approved for short-term routine prophylaxis to reduce the frequency of spontaneous bleeding episodes. ReFacto is the only factor vm product indicated for short-term rou-
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tine prophylaxis. Hemophilia A is the most common form of hemophilia, a genetically inherited blood clotting disorder. This form of the disease is the result of deficiency in the blood clotting protein, factor Vill. Currently, more than 17,000 American patients have a hemophilia A diagnosis. In clinical trials, ReF acto was administered to 218 patients who received more than 60,000 infusions. l Adverse reactions during the trials included headache, fever, chills, flushing, nausea, vomiting, lethargy, and allergic reactions. These adverse reactions are commonly reported with intravenous administration of recombinant protein products. Older, nonrecombinant factor VIII products to treat hemophilia A are prepared from pooled human blood. Recombinant technology allows preparation of clotting factors without the addition of human blood or plasma products. This eliminates the risk of blood-borne viral contamination, a matter of grave concern to the hemophiliac population. The combined market for factor vrn products in the United States and Europe is more than $1 billion annually. Recombinant clotting factor
able in the United States since 1993. Previously approved products include Bioclate (Centeon), Kogenate (Bayer), and Recombinate (Baxter). In addition, there are seven nonrecombinant factor VIII products currently on the market. ReFacto, developed by the Genetics Institute of WyethAyerst Laboratories, does not contain human serum albumin in the final formulation. All of the previously approved recombinant products add albumin while the cells are growing during the cell culture phase and during the final product formulation. This poses at least a theoretical possibility of viral contamination. According to WyethAyerst, ReFacto will be launched during the third quarter of 2000. The delayed launch is for manufacturing purposes, to ensure that sufficient quantities of the product are available. Another biotech treatment for hemophilia A is currently in gene therapy trials at the University of Pennsylvania and other sites. Gene therapy trials were halted in February after the death of a patient during treatment for ornithine transcarbamylase deficiency. Trials have since been resumed.
Recommendation for Mylotarg Approval Mylotarg is indicated for treatment of patients who are older than 60 years of age and who have CD-33 positive relapsed AML. The most common type of adult leukemia, AML is characterized by a
rapid rise in white blood cell count in blood and bone marrow followed by severe anemia with or without infection. Hemorrhage is also characteristic of the disease. The American Cancer Society estimates that 9,700 new cases of AML will be diagnosed in the United States this year. Patients with untreated AML deteriorate rapidly. Even with treatment, only 20% of AML patients survive 5 years or longer. 2 Traditional treatment for AML consists of two phases of chemotherapy: remission induction and post-remission therapy using an aggressive combination of chemotherapeutic agents. This regimen is rigorous and patients experience many adverse effects. Some patients are treated with high-dose chemotherapy to destroy the bone marrow in preparation for a stem cell transplant. Relapsed AML patients, who would be candidates for Mylotarg therapy, usually require prolonged hospitalization and have a poor prognosis. Mylotarg is a humanized recombinant antibody linked with an antitumor antibiotic called calicheamicin. The antibiotic is isolated from a bacterium in caliche clay, a soil found in Texas. The antibody part of the molecule binds to the CD-33 glycoprotein antigen commonly found on the myeloid leukemia cell membrane. The calicheamicin portion of the molecule that has been directed to the tumor cell by antibody binding attacks the leukemia celis, but does not attack normal cells. This makes the therapeutic antibody more specific than
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traditional chemotherapy. The result is that patients experience fewer adverse effects, such as hair loss and mouth sores, than they experience from traditional chemotherapy. In clinical trials, patients who were treated with the antibody were in fIrst relapse from AML. Typically, they received treatment during a I-day hospital visit consisting of a 2-hour infusion followed by 6 to 8 hours of observation. Mylotarg was administered every 2 weeks for two doses. Mylotarg results were reported from 11 leukemia centers. In recommending approval of Mylotarg, the Oncologic Drugs Advisory Committee noted that Mylotarg induced remission of disease in about 34% of patients with relapsed AML. 3 This is statistically equivalent to the results with standard chemotherapy. However, patients experienced signifIcantly fewer adverse effects. Mylotarg is currently undergoing priority review by the FDA. Currently, there are no approved agents for treatment of relapsed AML patients. If approved, Mylotarg would be the fIrst chemotherapeutic monoclonal antibody targeted to cancer cells. The previously approved therapeutic antibody, rituximab (Rituxan), targets a receptor called the CD20 antigen on the surface of mature B cells and B-cell tumors marking the cells for destruction by the immune system. It does not contain a chemotherapeutic portion to the molecule. Rituxan is used to treat patients with low-grade non-Hodgkin's lymphoma who have failed conventional therapy. Several other antibodies are
in clinical trials to treat other cancers. Tositumomab (Bexxar) is in development by Coulter Pharmaceutical and SmithKline Beecham. Bexxar is a radioimmunotherapy. The antibody, targeted to the surface of B cells, is conjugated to iodine 131, allowing a concentration of radiation at the site of the B cell. Bexxar is proposed as a treatment for relapsed or refractory lowgrade or transfonned lowgrade B-cell non-Hodgkin's lymphoma. The manufacturers are seeking approval under the FDA's fast-track approval process.
Nevv Approval for Actirnmune Actimmune injection, previously approved to treat acute granulomatous disease, recent1y received approval to delay disease progression of severe, malignant osteopetrosis. In this congenital disorder, there is an overgrowth of bony structures leading to blindness, deafness, and increased susceptibility to infection. Patients usually die before the age of 10. The most seriously ill children die before age two. Phase III clinical trial data
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measured the time to disease progression. This was defIned as death, signifIcantly decreased hemoglobin or platelet counts, serious bacterial infection requiring antibiotics, a 50-decibel decrease in hearing, or progressive optic atrophy. Fifteen trial patients were randomized to receive either Actimmune or calcitri01, a vitamin D analogue, used as a control drug. The median time to disease progression in control patients was 65 days. Actimmune patients' median time to disease progression was at least 165 days. Adverse effects seen during clinical trials included flu-like symptoms that were alleviated by acetaminophen taken 1 hour before the injection. 4 Actimmune received a fasttrack review because of its treatment potential. Orphan drug status was also granted due to the rare nature of the disease. Among the advantages that orphan drug status provides to the drug's manufacturer is exclusive approval for a particular indication and its marketing for 7 years. Clinical trial data indicate that Actimmune may have additional uses in several other diseases, including lung dis-
ease and systemic infection. InterMune Pharmaceuticals, a biotechnology company, owns exclusive rights in the United States to Actimmune for several diseases, including infectious diseases. InterMune is aggressively pursuing additional indications for use in the areas of fungal and tuberculosis infections. Peggy Piascik, PhD, is associ· ate professor ofpharmacology & experimental therapeutics and pharmacy practice & science, College of Pharmacy, University of Kentucky, Lexington.
References 1. ReFacto [package label!. Available at: www.fda.gov. Accessed March 8,2000. 2. FDA committee recommends approval of Mylotarg (gem· tuzumab ozogam icin) for AML [press releasel. Wyeth· Ayerst Laboratories. March
20,2000. 3. The Leukemia & Lymphoma Society. Antibody Conjugate Represents New Way to Treat AML. Available at: www. leukemia.org. Research Updates section . Accessed March 20, 2000. 4. InterMune Pharmaceuticals, Inc. FDA approval of Actim· mune provides hope for chil· dren with fatal disease [press releasel. February 11,2000. Available at: www.actimmune. com. Accessed March 3D,
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