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Biotechnology Update
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BIOTECHNOLOGY U P D ATE of epoetin alfa, which is marketed under two trade names (Epogen-Amgen and Procrit-Ortho), have expanded from one therapeutic use in 1989 to three approved uses in 1995 (fable 1). The flfSt approved use was for anemia associated with chronic renal failure ; this indication was followed by anemia in patients infected with human immunodeficiency virus (HIV) who are receiving zidovudine (Retrovir-Burroughs Wellcome). Most recently, epoetin alfa has been indicated for use in chemotherapy-induced anemia in patients with nonmyeloid malignancies. In addition, several investigational uses for epoetin alfa have been suggested. These include autologous blood transfusion, anemia of prematurity, and sickle cell anemia. Neupogen (filgrastim; Amgen) was originally approved in 1991 for neutropenia associated with chemotherapy and in 1994 for neutropenia associated
Expanding Indications for Biotechnology Agents by Peggy Piascik, PhD
Most of the approximately 20 biotechnology products that have been marketed as therapeutic agents since 1982 were flfst approved for relatively narrow indications. Many of these agents, like Betaseron (beta interferon; Berlex), approved in 1993 for relapsing-remitting multiple sclerosis; Epogen (epoetin alfa), initially approved in 1989 for chronic renal failure; and Cerezyme (imiglucerase; Genzyme), approved in 1994 as an enzyme replacement product for treatment of Gaucher disease, received orphan drug status because the patient population for the drug, when used only for these particular indications, is fewer than 200,000 patients.
Companies developing and marketing biotechnology agents have sometimes been criticized for investing large amounts of money to develop agents with high price tags for limited indications and small patient populations. However, in the 14 years since recombinant insulin became the first approved therapeutic biotechnology agent, many of these drugs have been approved for other indications. Approved indications for existing biotechnology drugs have expanded greatly in the last five years. This is particularly true of the hematopoietic growth factors and interferon alfa. Hematopoietic Growth Factors. Indications for use
Table 1
Approved Uses of Hematopoietic Growth Factors Epogen-Atngen (epoetin alfa)
Procrit-Ortho (epoetin alfa)
Neupogen-Atngen (filgrastilTl)
Anemia associated with chronic renal failure (1989)
Anemia associated with chronic renal failure (1989)
Chemotherapy-induced neutropenia (1991)
Anemia in patients with HIV infection who are treated with zidovudine (RetrovirBurroughs Wellcome) (1989)
Anemia in patients with HIV infection who are treated with zidovudine (1990)
Neutropenia associated with bone marrow transplant (1994)
Anemia caused by chemotherapy in patients with nonmyeloid malignancies (1993)
Anemia caused by chemotherapy in patients with nonmyeloid malignancies (1993)
Chronic severe neutropenia (1994)
HIV = human immunodeficiency virus.
AMERICAN PHARMACY
II
with bone marrow transplant. In December 1994, ftlgrastim received approval for its third indication, severe chronic neutropenia. Interferon a1fa. Perhaps the best example of a biotechnology drug whose uses have greatly broadened since its initial approval is interferon alfa. Intron A (interferon alfa-2b; ScheringPlough) was flfSt approved inJune 1986 for hairy-cell leukemia, a relatively rare form of cancer with fewer than 1,000 new cases each year in the United States. Since 1988, Intron A has been approved for four additional indications (fable 2). The second approved indication - treatment of condylomata acuminata, or genital warts-provided a new patient population for the drug of approximately 1 million people. In November 1988, Intron A was approved for treatment of Kaposi's sarcoma related to acquired immunodeficiency syndrome (AIDS), which occurs at a rate of 4,500 new cases each year. Intron A was approved for treatment of hepatitis C and Bin 1991 and 1992, respectively. Approximately 2 million patients in the United States currently have hepatitis C, and 170,000 new cases are added annually. Fifty percent of patients with newly diagnosed hepatitis C will become chronically infected. Hepatitis B now affects 1 million U.S. patients, with 300,000 new cases diagnosed yearly. Six to ten percent of patients with April1995
Vol. NS35, No.4
hepatitis B become chronically infected. Clinical trials have been completed and a product license application flIed with the Food and Drug Administration (FDA) for two new indications for interferon alfa-2b: malignant melanoma and non-Hodgkin's lymphoma. Intron A is also in clinical trials for treatment of a variety of cancers, including bladder cancer, chronic myelogenous leukemia, head and neck cancer, multiple myeloma, and renal cell carcinoma. By mid-1996, which will mark Intron A's 10th year as an approved agent, it will have expanded the number of its approved indications from one (for fewer than 1,000 patients yearly) to as many as seven (for millions of patients). Roferon-A (interferon alfa2a; Roche) was approved in June 1986 for hairy cell leukemia and in 1988 for AIDS-related Kaposi's sarcoma. Roferon-A is an investigational agent for treatment of chronic myelogenous leukemia and hepatitis C. Additionally, a product called consensus interferon, a second-generation recombinant protein that combines the properties of several naturally occurring alpha interferons, is in clinical trials for treatment of hepatitis C. An attractive feature of consensus interferon is that it has approximately five times the therapeutic activity of naturally occurring products, with a reduction in toxicity. Vol. NS35, No.4
Apri11995
Other ExalT1ples Some additional examples of biotechnology products with expanded uses are given below. Alteplase. Tissue plasminogen activator, or alteplase (Activase-Genentech), lyses blood clots. It was ftrst approved in November 1987 for acute myocardial infarction. In June 1990, it was also approved for treatment of acute pulmonary embolism. Current investigational uses of alteplase include peripheral arterial occlusion and unstable angina. Muromonab-CD3. The monoclonal antibody product muromonab-CD3 (Orthoclone OKT3-0rtho) can reverse transplant rejection by binding to blood cells (T lymphocytes), which mediate the rejection of transplanted tissue . It was ftrst approved in June 1986 for reversal of acute kidney transplant rejection and, seven years later, for reversal of heart and liver transplant rejection. An application has been submitted to FDA for approval of muromonabCD3 for prevention of kidney transplant rejection. Two recently approved products-beta interferon and dornase alfa-are being investigated for additional indications. Beta interferon (Betaseron) was approved in August 1993 for treatment of the most commonly occurring form of multiple sclerosis (MS), relapsing-remitting MS. It is currently investiga-
Table 2
Approved Uses of Alpha Interferons Intron A-Schering-Plough (interferon alfa-2b)
Roferon-A-Roche (interferon alfa-2a)
Hairy-cell leukemia (1986) Genital warts (1988)
Hairy-cell leukemia (1986)
AIDS-related Kaposi's sarcoma (1988)
AIDS-related Kaposi's sarcoma (1988)
Hepatitis C (1991) Hepatitis B (1992) AIDS
= acquired immunodeficiency syndrome.
tional for other forms of MS, such as chronic progressive MS. In addition, beta interferon is being investigated for viral and neoplastic diseases such as basal cell carcinoma, cervical dysplasia, and hepatitis Band C. Dornase alfa (Pulmozyme) was approved in 1993 for treatment of cystic ftbrosis. Pulmozyme is an enzyme, DNase, which dissolves the strands of deoxyribonucleic acid (DNA) that cause thick mucous secretions in cystic fibrosis patients. These secretions can obstruct glands and ducts in a number of organs, particularly the lungs. The product is administered by nebulizer. It is currently an investigational agent for treatment of chronic bronchitis.
Summary Many biotechnology products currently on the market were initially approved for indications affecting only a small number of patients. However, pharmaceutical manufacturers have contin-
ued to study these agents for potential new therapeutic uses. The result is that several of these products are now approved for multiple uses involving large patient populations. In many cases, the biotechnology agents are being used in patients for whom no effective therapy was previously available. Peggy Piascik, PhD, is assistant professor ofpharmacology and experimental therapeutics, the University of Kentucky College of Pharmacy, Lexington.
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 of Amgen.
AttGEN® AMERICAN PHARMACY
BIOTECHNOLOGY U P D ATE of epoetin alfa, which is marketed under two trade names (Epogen-Amgen and Procrit-Ortho), have expanded from one therapeutic use in 1989 to three approved uses in 1995 (fable 1). The flfSt approved use was for anemia associated with chronic renal failure ; this indication was followed by anemia in patients infected with human immunodeficiency virus (HIV) who are receiving zidovudine (Retrovir-Burroughs Wellcome). Most recently, epoetin alfa has been indicated for use in chemotherapy-induced anemia in patients with nonmyeloid malignancies. In addition, several investigational uses for epoetin alfa have been suggested. These include autologous blood transfusion, anemia of prematurity, and sickle cell anemia. Neupogen (filgrastim; Amgen) was originally approved in 1991 for neutropenia associated with chemotherapy and in 1994 for neutropenia associated
Expanding Indications for Biotechnology Agents by Peggy Piascik, PhD
Most of the approximately 20 biotechnology products that have been marketed as therapeutic agents since 1982 were flfst approved for relatively narrow indications. Many of these agents, like Betaseron (beta interferon; Berlex), approved in 1993 for relapsing-remitting multiple sclerosis; Epogen (epoetin alfa), initially approved in 1989 for chronic renal failure; and Cerezyme (imiglucerase; Genzyme), approved in 1994 as an enzyme replacement product for treatment of Gaucher disease, received orphan drug status because the patient population for the drug, when used only for these particular indications, is fewer than 200,000 patients.
Companies developing and marketing biotechnology agents have sometimes been criticized for investing large amounts of money to develop agents with high price tags for limited indications and small patient populations. However, in the 14 years since recombinant insulin became the first approved therapeutic biotechnology agent, many of these drugs have been approved for other indications. Approved indications for existing biotechnology drugs have expanded greatly in the last five years. This is particularly true of the hematopoietic growth factors and interferon alfa. Hematopoietic Growth Factors. Indications for use
Table 1
Approved Uses of Hematopoietic Growth Factors Epogen-Atngen (epoetin alfa)
Procrit-Ortho (epoetin alfa)
Neupogen-Atngen (filgrastilTl)
Anemia associated with chronic renal failure (1989)
Anemia associated with chronic renal failure (1989)
Chemotherapy-induced neutropenia (1991)
Anemia in patients with HIV infection who are treated with zidovudine (RetrovirBurroughs Wellcome) (1989)
Anemia in patients with HIV infection who are treated with zidovudine (1990)
Neutropenia associated with bone marrow transplant (1994)
Anemia caused by chemotherapy in patients with nonmyeloid malignancies (1993)
Anemia caused by chemotherapy in patients with nonmyeloid malignancies (1993)
Chronic severe neutropenia (1994)
HIV = human immunodeficiency virus.
AMERICAN PHARMACY
II
with bone marrow transplant. In December 1994, ftlgrastim received approval for its third indication, severe chronic neutropenia. Interferon a1fa. Perhaps the best example of a biotechnology drug whose uses have greatly broadened since its initial approval is interferon alfa. Intron A (interferon alfa-2b; ScheringPlough) was flfSt approved inJune 1986 for hairy-cell leukemia, a relatively rare form of cancer with fewer than 1,000 new cases each year in the United States. Since 1988, Intron A has been approved for four additional indications (fable 2). The second approved indication - treatment of condylomata acuminata, or genital warts-provided a new patient population for the drug of approximately 1 million people. In November 1988, Intron A was approved for treatment of Kaposi's sarcoma related to acquired immunodeficiency syndrome (AIDS), which occurs at a rate of 4,500 new cases each year. Intron A was approved for treatment of hepatitis C and Bin 1991 and 1992, respectively. Approximately 2 million patients in the United States currently have hepatitis C, and 170,000 new cases are added annually. Fifty percent of patients with newly diagnosed hepatitis C will become chronically infected. Hepatitis B now affects 1 million U.S. patients, with 300,000 new cases diagnosed yearly. Six to ten percent of patients with April1995
Vol. NS35, No.4
hepatitis B become chronically infected. Clinical trials have been completed and a product license application flIed with the Food and Drug Administration (FDA) for two new indications for interferon alfa-2b: malignant melanoma and non-Hodgkin's lymphoma. Intron A is also in clinical trials for treatment of a variety of cancers, including bladder cancer, chronic myelogenous leukemia, head and neck cancer, multiple myeloma, and renal cell carcinoma. By mid-1996, which will mark Intron A's 10th year as an approved agent, it will have expanded the number of its approved indications from one (for fewer than 1,000 patients yearly) to as many as seven (for millions of patients). Roferon-A (interferon alfa2a; Roche) was approved in June 1986 for hairy cell leukemia and in 1988 for AIDS-related Kaposi's sarcoma. Roferon-A is an investigational agent for treatment of chronic myelogenous leukemia and hepatitis C. Additionally, a product called consensus interferon, a second-generation recombinant protein that combines the properties of several naturally occurring alpha interferons, is in clinical trials for treatment of hepatitis C. An attractive feature of consensus interferon is that it has approximately five times the therapeutic activity of naturally occurring products, with a reduction in toxicity. Vol. NS35, No.4
Apri11995
Other ExalT1ples Some additional examples of biotechnology products with expanded uses are given below. Alteplase. Tissue plasminogen activator, or alteplase (Activase-Genentech), lyses blood clots. It was ftrst approved in November 1987 for acute myocardial infarction. In June 1990, it was also approved for treatment of acute pulmonary embolism. Current investigational uses of alteplase include peripheral arterial occlusion and unstable angina. Muromonab-CD3. The monoclonal antibody product muromonab-CD3 (Orthoclone OKT3-0rtho) can reverse transplant rejection by binding to blood cells (T lymphocytes), which mediate the rejection of transplanted tissue . It was ftrst approved in June 1986 for reversal of acute kidney transplant rejection and, seven years later, for reversal of heart and liver transplant rejection. An application has been submitted to FDA for approval of muromonabCD3 for prevention of kidney transplant rejection. Two recently approved products-beta interferon and dornase alfa-are being investigated for additional indications. Beta interferon (Betaseron) was approved in August 1993 for treatment of the most commonly occurring form of multiple sclerosis (MS), relapsing-remitting MS. It is currently investiga-
Table 2
Approved Uses of Alpha Interferons Intron A-Schering-Plough (interferon alfa-2b)
Roferon-A-Roche (interferon alfa-2a)
Hairy-cell leukemia (1986) Genital warts (1988)
Hairy-cell leukemia (1986)
AIDS-related Kaposi's sarcoma (1988)
AIDS-related Kaposi's sarcoma (1988)
Hepatitis C (1991) Hepatitis B (1992) AIDS
= acquired immunodeficiency syndrome.
tional for other forms of MS, such as chronic progressive MS. In addition, beta interferon is being investigated for viral and neoplastic diseases such as basal cell carcinoma, cervical dysplasia, and hepatitis Band C. Dornase alfa (Pulmozyme) was approved in 1993 for treatment of cystic ftbrosis. Pulmozyme is an enzyme, DNase, which dissolves the strands of deoxyribonucleic acid (DNA) that cause thick mucous secretions in cystic fibrosis patients. These secretions can obstruct glands and ducts in a number of organs, particularly the lungs. The product is administered by nebulizer. It is currently an investigational agent for treatment of chronic bronchitis.
Summary Many biotechnology products currently on the market were initially approved for indications affecting only a small number of patients. However, pharmaceutical manufacturers have contin-
ued to study these agents for potential new therapeutic uses. The result is that several of these products are now approved for multiple uses involving large patient populations. In many cases, the biotechnology agents are being used in patients for whom no effective therapy was previously available. Peggy Piascik, PhD, is assistant professor ofpharmacology and experimental therapeutics, the University of Kentucky College of Pharmacy, Lexington.
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 of Amgen.
AttGEN® AMERICAN PHARMACY