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1994 Biotechnology Drug Approvals
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BIOTECHNOLOGY U P D ATE
1994 Biotechnology Drug Approvals by S. Machelle Manuel
111is column will focus on two biotechnology products approved in 1994. In February, Enzon, Inc., gained approval from the Food and Drug Administration (FDA) for Oncaspar (pegaspargase) to be used for treatment of acute lymphoblastic leukemia (ALL), with i-asparaginase. In May, FDA approved Genzyme Corporation's Cerezyme (imiglucerase) for use in Type 1 Gaucher disease. Both drugs are used to treat enzyme deficiencies. Oncaspar replaces two nonrecombinant products that are difficult to manufacture and available to only a limited number of patients. Cerezyme is designed to meet the needs of patients with hypersensitivity reactions to the nonrecombinant product.
L-asparaginase and ALL i-asparaginase is the enzyme responsible for catalyzing the conversion of the amino acid i-asparagine to aspartic acid and ammonia. For normal cells, i-asparagine is a nonessential amino acid that is synthesized intracellularly. Some leukemic cells, however, lack the ability to synthesize L-asparagine and so are dependent on extracellular AMERICAN PHARMACY
sources for this amino acid, which is required for protein synthesis. When administered intravenously or intramuscularly as part of a chemotherapeutic regimen, L-asparaginase degrades all circulating i-asparagine, thereby depleting the extracellular source of the amino acid for leukemic cells. In this way, i-asparaginase can be used as a fairly specific chemotherapeutic agent to kill leukemic cells while preserving normal cells. ALi, the most common pediatric cancer, is characterized by an increased lymphoblast count, enlarged lymph nodes, and increased spleen size. All of these symptoms are rapidly decreased in patients who respond to i-asparaginase treatment. The goal in ALi treatment is to induce remission, which often requires multiple drug therapy. Lasparaginase is ideal for use in induction therapy because it causes little myelosuppression, a common side effect of many chemotherapeutic agents, and has been shown to prolong remission. Before the approval of Oncaspar, only two sources of native i-asparaginase for use as a chemotherapeutic agent were available. Elspar
(L-asparaginase-Merck & Co., Inc.) is derived from Escherichia coli. Erwinia carotovora i-asparaginase is
available as a class C agent from the National Cancer Institute for patients allergic to E. coli L-asparaginase. An unfortunate consequence of prolonged administration of E. coli L-asparaginase is development of dose-limiting hypersensitivity reactions in up to 78% of patients. Previously, hypersensitive patients were switched to Erwinia L-asparaginase because no cross-reactivity occurs between antibodies against the two proteins. However, Erwinia i-asparaginase has a shorter half-life and requires more frequent dosing. Even though little cross-reactivity with E. coli L-asparaginase occurs, most hypersensitive patients will eventually develop hypersensitivity reactions specific to this form of i-asparaginase.
Oncaspar To address the issue of immunogenicity, Genzyme covalently linked E. coli L-asparaginase to units of monomethoxypolyethylene glycol (pEG) to form PEGL-asparaginase, Oncaspar's active ingredient. Oncaspar was well tolerated in clinical trials by patients with known previous hypersensitivity to native L-asparaginases, which indicates that conjugation with PEG decreased the immunogenicity of L-asparaginase. The addition of PEG to sites distant from the
enzyme's active site resulted in a half-life for Oncaspar of about 5 days, compared with 1 day for E. coli L-asparaginase and 0.7 days for Erwinia L-asparaginase. Product labeling suggests that Oncaspar be administered in a dosage of 2,500 ill/m2 every 14 days, either intramuscularly or intravenously, as a component of selected multipleagent regimens. Because of its potential to inhibit protein synthesis with subsequent effects on the pancreas, liver, and coagulation system, Oncaspar, like native L-asparaginases, is contraindicated in patients with pancreatitis or a history of pancreatitis and in patients with a history of severe hemorrhagic events. Use of Oncaspar is also contraindicated in patients who have experienced hypersensitivity reactions to native i-asparaginase resulting in generalized urticaria, bronchospasm, laryngeal edema, or hypotension, because these patients are most likely to have a lifethreatening reaction to Oncaspar. Patients on anticoagulant therapy should be Biotechnology Update is developed by the American Pharmaceutical Association, edited by Peggy Piascik, PhD, University of Kentucky COllege of Pharmacy, and supported by an educational grant from Amgen Inc. The views expressed are not necessarily those ofAmgen.
AMCHN. March 1995
Vol. NS35, No.3
administered Oncaspar with caution because L-asparaginase may interfere with the synthesis of coagulant proteins. Patients should be informed of the possibility of severe hypersensitivity reactions to Oncaspar, including anaphylaxis, bleeding problems, liver dysfunction, and interactions with other medications.
Gaucher Disease Glucocerebroside is a lipid found primarily in cell membranes. Gaucher disease is characterized by the accumulation of glucocerebroside in tissue macrophages caused by a lack of beta-glucocerebrosidase, the enzyme responsible for the breakdown of glucocerebroside to ceramide and glucose. The cells affected by this enzyme deficiency are the bone marrow -derived tissue macrophages, important components of the immune system. Affected cells, called Gaucher cells, have a characteristic appearance caused by lipid engorgement and are found in the liver and spleen of affected patients. Three types of Gaucher disease can occur. Type 1 Gaucher disease is the most common, occurring in about 1 of every 50,000 live births in the general population and in about 1 of every 500 live births in Ashkenazi Jews, making it the most prevalent Jewish genetic disease. Age of onset and severity of symptoms can vary Vol. NS35, No.3
March 1995
greatly for patients with Type 1 Gaucher disease. Onset of Type 1 Gaucher disease may occur in early childhood or late adulthood, with survival being anywhere from 6 to 80 years. Early onset has been linked to more severe manifestations and earlier death. Patients with Type 1 Gaucher disease often have a grossly enlarged spleen that sometimes requires surgical removal. The liver may also become enlarged because of the increased size and numbers of tissue macrophages. Thrombocytopenia and anemia may also occur because of splenic sequestration of platelets and red blood cells in nonsplenectomized patients or because of replacement of bone marrow cells by Gaucher cells in splenectomized patients. Gaucher cells can also cause totally debilitating skeletal manifestations by fonning bony lesions that lead to easily broken bones and necrosis of bone tissue. Lung involvement is rare but nearly always fatal. Until the initiation of enzyme replacement therapy, treatment of Type 1 Gaucher disease was symptomatic, using iron and vitamin supplements, total or partial splenectomy, and androgen therapy to intervene in hematologic symptoms. Most cases involving skeletal manifestations were treated by pain management. Bone marrow transplant can be wholly curative because destroying the
patient's bone marrow and replacing it with new, unaffected bone marrow can eliminate Gaucher-cell development. However, the cost and risk involved in treating a usually nonlethal disease, coupled with the difficulty in securing matched sibling donors, have prevented widespread use of bone marrow transplant in Type 1 Gaucher disease. In 1991, Type 1 Gaucher disease became the first lysosomal storage disease to be treated successfully by enzyme therapy. Ceredase (alglucerase-Genzyme) is purifled human placental beta-glucocerebrosidase modified by removing outer sugars. This removal exposes additional mannose residues to enhance binding to mannose receptors located on macrophages, or, in this case, Gaucher cells. This alteration increases the efficiency of enzyme transportation into the Gaucher cell. This enzyme replacement therapy is very expensive, costing up to $150,000 per patient each year.
Cerezyme Cerezyme (imiglucerase) is a recombinant deoxyribonucleic acid (DNA) product that is manufactured using the protein-synthesizing machinery of cultured Chinese hamster ovary cells, to produce the enzyme in large quantities. Imiglucerase, a monomeric glycoprotein differing from human placental betaglucocerebrosidase by one
amino acid, terminates in mannose sugars, to ensure targeting to macrophages. Clinical trials show that Cerezyme improves anemia and thrombocytopenia and decreases spleen and liver size in a manner similar to that of Ceredase. Cerezyme is administered by intravenous infusion. The dosage should be individualized for each patient, depending on the severity of symptoms. Recommended dosing ranges from 2.5 units/ kg three times weekly, up to as much as 60 units!kg as often as once weekly or as infrequently as every four weeks. After therapy is initiated, progressive reductions in dose, titrated carefully to patient response, can be made at intervals of three to six months, to establish maintenance dosing. Adverse reactions during clinical trials with Cerezyme included headache, nausea, abdominal discomfort, dizziness, pnuitus, rash, mild decrease in blood pressure, and decrease in urinary frequency. However, no patients required discontinuation of therapy because of these events. A number of patients receiving Ceredase experienced symptoms of allergic hypersensitivity, but only one patient experienced signs of hypersensitivity after being switched to Cerezyme. S. Machelle Manuel, a community pharmacist, is a PhD candidate at the University of Kentucky College of Pharmacy, Lex ington.
AMERICA N PHARMACY
BIOTECHNOLOGY U P D ATE
1994 Biotechnology Drug Approvals by S. Machelle Manuel
111is column will focus on two biotechnology products approved in 1994. In February, Enzon, Inc., gained approval from the Food and Drug Administration (FDA) for Oncaspar (pegaspargase) to be used for treatment of acute lymphoblastic leukemia (ALL), with i-asparaginase. In May, FDA approved Genzyme Corporation's Cerezyme (imiglucerase) for use in Type 1 Gaucher disease. Both drugs are used to treat enzyme deficiencies. Oncaspar replaces two nonrecombinant products that are difficult to manufacture and available to only a limited number of patients. Cerezyme is designed to meet the needs of patients with hypersensitivity reactions to the nonrecombinant product.
L-asparaginase and ALL i-asparaginase is the enzyme responsible for catalyzing the conversion of the amino acid i-asparagine to aspartic acid and ammonia. For normal cells, i-asparagine is a nonessential amino acid that is synthesized intracellularly. Some leukemic cells, however, lack the ability to synthesize L-asparagine and so are dependent on extracellular AMERICAN PHARMACY
sources for this amino acid, which is required for protein synthesis. When administered intravenously or intramuscularly as part of a chemotherapeutic regimen, L-asparaginase degrades all circulating i-asparagine, thereby depleting the extracellular source of the amino acid for leukemic cells. In this way, i-asparaginase can be used as a fairly specific chemotherapeutic agent to kill leukemic cells while preserving normal cells. ALi, the most common pediatric cancer, is characterized by an increased lymphoblast count, enlarged lymph nodes, and increased spleen size. All of these symptoms are rapidly decreased in patients who respond to i-asparaginase treatment. The goal in ALi treatment is to induce remission, which often requires multiple drug therapy. Lasparaginase is ideal for use in induction therapy because it causes little myelosuppression, a common side effect of many chemotherapeutic agents, and has been shown to prolong remission. Before the approval of Oncaspar, only two sources of native i-asparaginase for use as a chemotherapeutic agent were available. Elspar
(L-asparaginase-Merck & Co., Inc.) is derived from Escherichia coli. Erwinia carotovora i-asparaginase is
available as a class C agent from the National Cancer Institute for patients allergic to E. coli L-asparaginase. An unfortunate consequence of prolonged administration of E. coli L-asparaginase is development of dose-limiting hypersensitivity reactions in up to 78% of patients. Previously, hypersensitive patients were switched to Erwinia L-asparaginase because no cross-reactivity occurs between antibodies against the two proteins. However, Erwinia i-asparaginase has a shorter half-life and requires more frequent dosing. Even though little cross-reactivity with E. coli L-asparaginase occurs, most hypersensitive patients will eventually develop hypersensitivity reactions specific to this form of i-asparaginase.
Oncaspar To address the issue of immunogenicity, Genzyme covalently linked E. coli L-asparaginase to units of monomethoxypolyethylene glycol (pEG) to form PEGL-asparaginase, Oncaspar's active ingredient. Oncaspar was well tolerated in clinical trials by patients with known previous hypersensitivity to native L-asparaginases, which indicates that conjugation with PEG decreased the immunogenicity of L-asparaginase. The addition of PEG to sites distant from the
enzyme's active site resulted in a half-life for Oncaspar of about 5 days, compared with 1 day for E. coli L-asparaginase and 0.7 days for Erwinia L-asparaginase. Product labeling suggests that Oncaspar be administered in a dosage of 2,500 ill/m2 every 14 days, either intramuscularly or intravenously, as a component of selected multipleagent regimens. Because of its potential to inhibit protein synthesis with subsequent effects on the pancreas, liver, and coagulation system, Oncaspar, like native L-asparaginases, is contraindicated in patients with pancreatitis or a history of pancreatitis and in patients with a history of severe hemorrhagic events. Use of Oncaspar is also contraindicated in patients who have experienced hypersensitivity reactions to native i-asparaginase resulting in generalized urticaria, bronchospasm, laryngeal edema, or hypotension, because these patients are most likely to have a lifethreatening reaction to Oncaspar. Patients on anticoagulant therapy should be Biotechnology Update is developed by the American Pharmaceutical Association, edited by Peggy Piascik, PhD, University of Kentucky COllege of Pharmacy, and supported by an educational grant from Amgen Inc. The views expressed are not necessarily those ofAmgen.
AMCHN. March 1995
Vol. NS35, No.3
administered Oncaspar with caution because L-asparaginase may interfere with the synthesis of coagulant proteins. Patients should be informed of the possibility of severe hypersensitivity reactions to Oncaspar, including anaphylaxis, bleeding problems, liver dysfunction, and interactions with other medications.
Gaucher Disease Glucocerebroside is a lipid found primarily in cell membranes. Gaucher disease is characterized by the accumulation of glucocerebroside in tissue macrophages caused by a lack of beta-glucocerebrosidase, the enzyme responsible for the breakdown of glucocerebroside to ceramide and glucose. The cells affected by this enzyme deficiency are the bone marrow -derived tissue macrophages, important components of the immune system. Affected cells, called Gaucher cells, have a characteristic appearance caused by lipid engorgement and are found in the liver and spleen of affected patients. Three types of Gaucher disease can occur. Type 1 Gaucher disease is the most common, occurring in about 1 of every 50,000 live births in the general population and in about 1 of every 500 live births in Ashkenazi Jews, making it the most prevalent Jewish genetic disease. Age of onset and severity of symptoms can vary Vol. NS35, No.3
March 1995
greatly for patients with Type 1 Gaucher disease. Onset of Type 1 Gaucher disease may occur in early childhood or late adulthood, with survival being anywhere from 6 to 80 years. Early onset has been linked to more severe manifestations and earlier death. Patients with Type 1 Gaucher disease often have a grossly enlarged spleen that sometimes requires surgical removal. The liver may also become enlarged because of the increased size and numbers of tissue macrophages. Thrombocytopenia and anemia may also occur because of splenic sequestration of platelets and red blood cells in nonsplenectomized patients or because of replacement of bone marrow cells by Gaucher cells in splenectomized patients. Gaucher cells can also cause totally debilitating skeletal manifestations by fonning bony lesions that lead to easily broken bones and necrosis of bone tissue. Lung involvement is rare but nearly always fatal. Until the initiation of enzyme replacement therapy, treatment of Type 1 Gaucher disease was symptomatic, using iron and vitamin supplements, total or partial splenectomy, and androgen therapy to intervene in hematologic symptoms. Most cases involving skeletal manifestations were treated by pain management. Bone marrow transplant can be wholly curative because destroying the
patient's bone marrow and replacing it with new, unaffected bone marrow can eliminate Gaucher-cell development. However, the cost and risk involved in treating a usually nonlethal disease, coupled with the difficulty in securing matched sibling donors, have prevented widespread use of bone marrow transplant in Type 1 Gaucher disease. In 1991, Type 1 Gaucher disease became the first lysosomal storage disease to be treated successfully by enzyme therapy. Ceredase (alglucerase-Genzyme) is purifled human placental beta-glucocerebrosidase modified by removing outer sugars. This removal exposes additional mannose residues to enhance binding to mannose receptors located on macrophages, or, in this case, Gaucher cells. This alteration increases the efficiency of enzyme transportation into the Gaucher cell. This enzyme replacement therapy is very expensive, costing up to $150,000 per patient each year.
Cerezyme Cerezyme (imiglucerase) is a recombinant deoxyribonucleic acid (DNA) product that is manufactured using the protein-synthesizing machinery of cultured Chinese hamster ovary cells, to produce the enzyme in large quantities. Imiglucerase, a monomeric glycoprotein differing from human placental betaglucocerebrosidase by one
amino acid, terminates in mannose sugars, to ensure targeting to macrophages. Clinical trials show that Cerezyme improves anemia and thrombocytopenia and decreases spleen and liver size in a manner similar to that of Ceredase. Cerezyme is administered by intravenous infusion. The dosage should be individualized for each patient, depending on the severity of symptoms. Recommended dosing ranges from 2.5 units/ kg three times weekly, up to as much as 60 units!kg as often as once weekly or as infrequently as every four weeks. After therapy is initiated, progressive reductions in dose, titrated carefully to patient response, can be made at intervals of three to six months, to establish maintenance dosing. Adverse reactions during clinical trials with Cerezyme included headache, nausea, abdominal discomfort, dizziness, pnuitus, rash, mild decrease in blood pressure, and decrease in urinary frequency. However, no patients required discontinuation of therapy because of these events. A number of patients receiving Ceredase experienced symptoms of allergic hypersensitivity, but only one patient experienced signs of hypersensitivity after being switched to Cerezyme. S. Machelle Manuel, a community pharmacist, is a PhD candidate at the University of Kentucky College of Pharmacy, Lex ington.
AMERICA N PHARMACY