Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor that regulates hemoglobin (Hgb) levels in response to changes in the blood oxygen concentration. Erythropoiesis-stimulating agents (ESAs) are produced using recombinant DNA (deoxyribonucleic acid) technologies and have pharmacologic properties similar to endogenous EPO. The primary clinical use of ESAs is in patients with chronic anemia.
Endogenous erythropoietin (EPO) is a glycoprotein hematopoietic growth factor synthesized by cells near the renal tubules in response to changes in the blood oxygen concentration. When a patient is anemic, the ability of the blood to carry oxygen is decreased. An oxygen-sensing protein in the kidney detects the decrease in blood oxygen concentration and induces the production of EPO, which then acts upon the erythroid cell line in the bone marrow to stimulate hematopoiesis, thereby effectively increasing blood Hgb concentrations. Suppression of erythropoietin production or suppression of the bone marrow response to erythropoietin results in anemia in several disease processes, including chronic kidney disease (CKD), many types of cancer treatment, other chronic diseases, and use of certain drugs. The severity of anemia is defined by blood Hgb concentration. Normal ranges are 12–16 g/dL in women and 14–18 g/dL in men. Mild anemia is defined as Hgb from 10 g/dL to the lower limit of normal ranges, while moderate anemia is 8-10 g/dL. Severe anemia is defined as Hgb 8 g/dL or below.
ESAs are produced using recombinant DNA technologies. They were initially developed as replacement therapy to treat anemia due to endogenous erythropoietin deficiency that commonly occurs in individuals with chronic renal failure (CRF) secondary to CKD. Patients with CRF will become severely anemic, experience severe fatigue, and reduced exercise tolerance unless treated with blood transfusions or an ESA. Partial correction of anemia by ESA treatment of patients with CRF reduces the need for red blood cell transfusions and enhances physical functioning.
In cancer, anemia occurs with varying degrees of frequency and severity. It occurs most commonly in genitourinary, gynecologic, lung, and hematologic malignancies. Anemia may be directly related to cancer type or to its treatment. Oncologic anemia occurs by a variety of mechanisms. Poor oral intake or altered metabolism may reduce nutrients (folate, iron, vitamin B-12) essential for red cell production. Antibodies and/or immunoregulatory abnormalities associated with certain tumor types (most commonly, B-cell malignancies) may cause increased erythrocyte destruction (hemolysis). Tumors may cause blood loss via tissue invasion, for example gastrointestinal bleeding from colon cancer. Other neoplasms, particularly hematologic malignancies (leukemia, lymphoma, multiple myeloma) can invade the bone marrow and disrupt the erythropoietic microenvironment. In more advanced cases, there may be marrow replacement with tumor or amyloid. However, marrow dysfunction can occur even in the absence of frank invasion. Inflammatory proteins from interactions between the immune system and tumor cells are thought to cause inappropriately low erythropoietin production and poor iron utilization, as well as a direct suppression of red cell production. The treatment of cancer may also cause anemia. Radical cancer surgery can result in acute blood loss. Radiotherapy and many cytotoxic chemotherapeutic agents suppress marrow to varying degrees. Damage is due to a variety of mechanisms. For example, alkylating agents cause cumulative DNA damage, anti-metabolites damage DNA indirectly, and platinum-containing agents appear to damage erythropoietin-producing renal tubule cells.
Red blood cell (RBC) transfusion is the traditional approach to quickly ameliorate anemia symptoms. However, it carries risk for several potential adverse events. The highest adverse event risk (1 per 432 whole blood units transfused) is that for transfusion-related acute lung injury. Adverse events due to errors in transfusion (for example, type mismatch) are estimated to occur at a rate of 1 per 5,000–10,000 units of blood transfused. Current transfusion medicine and blood bank practices have significantly reduced the risk of transmissible infections, primarily due to better donor selection and screening for infectious diseases. Estimated risks per unit of blood transfused for transmission of hepatitis B virus (<1 in 400,000), hepatitis C virus (<1 in 1,000,000), human immunodeficiency virus (HIV) (<1 in 1,000,000), and bacterial contaminants (1 per 10,000-100,000) have fallen dramatically since the early 1990s. Therefore, while the initial impetus to commercialize erythropoietin replacement products was based on reduction in the risks associated with blood transfusion, current practices have mitigated many of those risks. Nonetheless, blood shortages, transfusion errors, and the risk for alloimmunization and transfusion-related acute lung injury provide sufficient rationale for use of ESA therapy in appropriately indicated patients.
Three ESA products have been licensed in the U.S. Epoetin alfa is manufactured, distributed, and marketed by Amgen, Inc. under the proprietary name, Epogen. The same epoetin alfa product manufactured by Amgen, Inc. is also marketed and distributed by Janssen Products, LP, a subsidiary of Johnson and Johnson, under the proprietary name, Procrit. Under a contractual agreement with Amgen, Janssen Products, LP has rights to development and marketing of Procrit for any indication other than for the treatment of anemia associated with chronic renal failure in patients on dialysis or use in diagnostic test kits. Epogen and Procrit have identical labeling information for all U.S. Food and Drug Administration (FDA) -approved indications. A second ESA, darbepoetin alfa, is marketed solely by Amgen, under the proprietary name, Aranesp. The third ESA product, peginesatide, was co-developed and commercialized by Affymax, Inc. and Takeda Pharmaceuticals, who market it under the proprietary name Omontys®.
The epoetin alfas have the same amino acid sequence as endogenous erythropoietin, while darbepoetin alfa has 2 additional oligosaccharide chains. In contrast, peginesatide lacks any amino acid sequence homology to erythropoietin. It is a synthetic dimer of identical 21-amino acid peptides bound to a linker and to polyethylene glycol, with a total molecular weight of approximately 45,000 daltons. However, the epoetins, darbepoetin, and peginesatide all have pharmacologic actions similar to those of the endogenous hormone. Each binds to and activates the human erythropoietin receptor and thus increases the number of red blood cells and the blood concentration of Hgb, when given to individuals with functioning erythropoiesis. All currently marketed ESAs are approved as treatment of anemia associated with CKD in adult patients on dialysis. The two epoetin alfas and darbepoetin are also approved to treat pediatric patients on dialysis with anemia from CKD, anemic patients with CKD not on dialysis, and for other indications.
The major regulatory timelines for approval actions pertaining to new indications is summarized below:
- Epoetin alfa (Epogen/Procrit):
- 1989: approved for use among anemic CRF [chronic renal failure] patients
- 1991: approved for use among zidovudine-treated HIV-infected patients
- 1993: approved for use for chemotherapy-induced anemia among patients with non-myeloid malignancies
- 1996: approved for presurgical use among certain patients undergoing surgery
- Darbepoetin alfa (Aranesp):
- 2001: approved for use among anemic CRF patients
- 2002: approved for use for chemotherapy-induced anemia among patients with non-myeloid malignancies
- Peginesatide (Omontys):
- 2012: approved for use among anemic adults with CKD on dialysis
ESAs must be prescribed and dispensed in accordance with a Risk Evaluation and Mitigation Strategy (REMS) drafted by the manufacturer and approved by the FDA (available online at: http://www.fda.gov/Drugs. The REMS for epoetin alfa and darbepoetin alfa each include a medication guide, a communication plan, elements to assure safe use, and an implementation system. ESA manufacturers must ensure that all hospitals and healthcare professionals who prescribe and/or dispense ESAs to patients with cancer have enrolled and completed training in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program. The ESA APPRISE program began on March 24, 2010 following the FDA’s initial approval of separate but similar REMS for epoetin alfa and darbepoetin alfa on February 16, 2010. Both REMS were subsequently modified on June 24, 2011 and then again on May 31, 2012. Healthcare providers and hospitals that prescribe and/or dispense an ESA for CKD must provide each patient with a copy of the REMS Medication Guide and ensure they are adequately informed of the risks associated with ESA treatment. However, they are not required to enroll in and complete the ESA APPRISE program. On March 27, 2012, FDA approved a REMS for peginesatide with a communication plan as its only component. The plan’s goal is to inform all healthcare professionals who might prescribe the drug that peginesatide is indicated only for adult patients with CKD on dialysis, and of potentially fatal risks associated with its use in CKD patients not on dialysis.
For all ESAs, effective March 27, 2013, the FDA approved a modification to the approved REMS to eliminate the requirement of prescriber and hospital re-enrollment every three years in the ESA APPRISE Oncology Program. (28)