Specialty Pharmaceuticals: Therapy Class Review: Blood Modifiers
Author: Todd Cooperman, PharmD, RPh, PAHM, and Russel Allinson, RPh, MS
The blood modifier category of drugs works stimulating bone marrow to produce more cells and they affect certain diseases such as cancer and chronic kidney failure.
In reviewing the therapeutic category of blood modifiers, there are 3 areas of focus: red blood cells (erythropoiesis growth factors, ie, Procrit, Epogen); white blood cells (myeloid growth factors, ie, Neupogen, Leukine, Neulasta); and platelets (thrombopoietic growth factors, ie, Neumega). All of these products work by stimulating bone marrow to produce more cells.
Anemia is a condition that occurs when the blood does not contain enough red blood cells that carry oxygen from the lungs to the body’s tissues. In a healthy person, the body sends signals to the bone marrow to create more red blood cells whenever it needs more oxygen. Erythropoietin, which is produced in the kidney, is the signal that stimulates the bone marrow to produce red blood cells. When the body does not produce enough erythropoietin, fewer red blood cells are produced and therefore less oxygen is delivered to the body.1
Certain diseases, such as cancer and chronic kidney failure, are related to anemia. Cancer patients undergoing chemotherapy often suffer from anemia because chemotherapy attacks not only cancerous cells but also other cells in the body including red blood cells. Because erythropoietin is produced in the kidneys, in patients who have kidney disease and whose kidney function is reduced, less erythropoietin is produced, which leads to reduced production of red blood cells.2
Neutropenia is a condition defined by an abnormally low number of neutrophils. Neutrophils serve as the major defense of the body against acute bacterial and certain fungal infections. Neutrophils usually constitute about 45% to 75% of all white blood cells in the bloodstream. When the neutrophil count falls below 1000 cells per microliter of blood, the risk of infection increases somewhat; when it falls below 500 cells per microliter, the risk of infection increases greatly. Without the key defense provided by neutrophils, an individual has problems controlling infections and could be at risk of dying from an infection. Neutropenia can be caused by many things—radiation therapy, chemotherapy, autoimmune disorders, viral infections, leukemia, and aplastic anemia, to name a few.3
Thrombocytopenia is the term for a reduced platelet (thrombocyte) count. It happens when platelets are lost from the circulation faster than they can be replaced from the bone marrow. Platelets play a very important role in stopping bleeding and beginning the repair of injured blood vessels.
Normally, a person has anywhere from 150,000 to 450,000 platelets per microliter of circulating blood. Because each platelet lives for only about 10 days, the platelet supply is continually renewed by production of new platelets. Typically, thrombocytopenia can result from 2 causes: a failure of platelet production and/or an increased rate of removal from the blood.
Idiopathic thrombocytopenic purpura (ITP) is a disease where the patient produces antibodies that destroy platelets, which results in thrombocytopenia. ITP is an autoimmune disease that has an incidence rate of 50 to 100 new cases per million per year, with children accounting for half of that number.4
In clinical trials, initiating the use of white blood cell (granulocyte colony-stimulating factor) 24 hours after myelosuppressive chemotherapy resulted in 50% fewer occurrences of febrile neutropenia and fewer days of intravenous antibiotic usage and hospitalization.6 In 1 economic impact study of cancer patients receiving chemotherapy, data were examined from a large US health plan with 10 million covered lives. According to this study, the cost of febrile neutropenia hospitalization was $27,000; the cost for the subsequent febrile neutropenia-related care was $9900; and the cost for all care related to febrile neutropenia was $37,000. Overall, febrile neutropenia-related charges were more than 10-fold higher among cases than among controls ($40,928 vs $3933).7 The majority of patients with certain tumors who develop neutropenia–will either have their chemotherapy postponed or will have their dose decreased, both of which can reduce survival rates.8,9
• Mortality rate associated with febrile neutropenia is 5% to 10%.10
• The initial episode of febrile neutropenia is most likely to occur during the first cycle of chemotherapy across all major tumor types.11
• Fatigue exists in 14% to 96% of individuals with cancer, particularly in individuals actively undergoing treatment.12
• Administration of colony-stimulating factors results in a 50% risk reduction of developing febrile neutropenia.13
• The incidence of ITP is approximately 50 to 100 cases per 1,000,000 per year.14
• Median diagnosis age of ITP in adults is 56 to 60 years.15
• A broad review of clinical trials noted that mild anemia after chemotherapy can occur in 100% of patients and the incidence of more severe anemia can reach 80%.16
Current Market Observations17
In March 2007, the FDA published an alert regarding erythropoiesis stimulating agents (ESAs), more commonly known as red blood cell stimulating agents. The FDA warning advised the following:
Patients with Cancer
• ESAs may shorten survival time or may cause tumors to grow faster.
• ESAs should only be used to treat anemia caused by chemotherapy and not other anemia from other causes in patients with cancer.
• ESAs should not be used to treat the symptoms of anemia, such as fatigue, or improve the quality of life in patients with cancer. The goal of treatment with ESAs is to avoid blood transfusions.
• Treatment with an ESA should be stopped following completion of the course of chemotherapy.
Patients with Chronic Kidney Failure
This includes both patients on dialysis and those not on dialysis:
• Patient’s hemoglobin level should be checked regularly to make sure it stays between 10 and 12 g/dL.
• ESAs can increase the chance of heart attack, stroke, blood clots, heart failure, and death when they are given to maintain higher hemoglobin levels.
• If a patient is not responding to treatment with an ESA (the patient’s hemoglobin level is not increasing), the patient should be checked for other causes of anemia.
• If a patient is taking Zidovudine for HIV and is being treated with an ESA for anemia, the patient should be informed that there is no evidence that ESAs lessen the symptoms of anemia, such as fatigue.
In light of the FDA warnings, overall worldwide sales of all the erythropoiesis growth factors have fallen as physicians have become more cautious in prescribing them.
Another area of intense interest to the class of blood modifiers is biogenerics, also known as biosimilars or follow-on protein products. This area is set to become the focus of the generics industry. On March 30, 2010, President Barack Obama signed into law the Patient Protection and Affordable Care Act. The Act creates a regulatory pathway for the approval of follow-on biologics (FOBs). The relevant statutory text is subtitled “Biologics Price Competition and Innovation Act” and a concise summary can be found at http:// dpc.senate.gov/healthreformbill/health bill70.pdf.
The blood modifier segment will be affected by the approval and marketing of biogenerics. Epogen/Procrit is scheduled to come off patent in 2013 and a biogeneric of Neupogen is already being sold in the EU. Biogenerics would seem to be a win–win situation for health plans since the products are expected to cost less than their branded counterparts; how the branded products will compete with them remains to be seen. But with future drug costs being driven largely by biologics, biogenerics offer the promise of greater competition and potential cost reductions. PT
2. Anemia. Amgen, Inc Web site. Last modified in 2008. Available at: http://www.amgen.ca/english/science/research_areas_anemia.html. Accessed TK.
3. Territo M. Neutropenia (agranulocytosis; granulocytopenia). The Merck Manuals: Online Medical Library for Healthcare Professionals. Last modified June 2008. Available at: http://www.merck.com/mmpe/sec11/ch132/ch132b.html?qt=neutropenia&alt=sh. Accessed TK.
4. Idiopathic thrombocytopenic purpura. Wikipedia, The Free Encyclopedia. Wikimedia Foundation, Inc. Last modified June 3, 2010. Available at: http://en.wikipedia.org/wiki/Idiopathic_thrombocytopenic_purpura. Accessed June 20, 2008.
5. Caggiano V, Weiss R, et al. Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer. 2005 May 1;103(9):1916-1924.
6. Montoya L. Managing hematological toxicities in the oncology patient. Journal of Infusion Nursing. 2007;30(3):168-172.
7. Weycker D, Malin, J, Glass A, Oster G. Economic burden of chemotherapy-related febrile neutropenia. J Support Oncol. 2007;5(4 suppl 2):44-45.
8. Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332:901-906.
9. Budman D, Berry D, Cirrincione C, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. Natl Cancer Inst. 1998;90:1205-1211.
10. Montoya L. Managing hematological toxicities in the oncology patient. Journal of Infusion Nursing. 2007;30(3):168-172.
11. Crawford J, Wolff D, Culakova E, et al. First-cycle risk of severe and febrile neutropenia in cancer patients receiving systemic chemotherapy: results from a prospective nationwide registry. Blood. 2004;104(11):607a. Abstract 2210.
12. National Cancer Institute. Fatigue – overview. Last modified April 29, 2010. Available at: www.cancer.gov/cancertopics/pdq/supportivecare/fatigue/Patient/page2. Accessed June 17, 2008.
13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Myeloid Growth Factors v.1.2008. Available at: http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf. Accessed TK.
4, 15. Idiopathic thrombocytopenic purpura. Wikipedia, The Free Encyclopedia. Wikimedia Foundation, Inc. Last modified June 3, 2010. Available at: http://en.wikipedia.org/wiki/Idiopathic_thrombocytopenic_purpura. Accessed June 20, 2008.
16. Groopman J, Itri L. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst. 1999;91:1616-1634.
17. FDA Public Health Advisory. Erythropoiesis-stimulating agents (ESAs): epoetin alfa (marketed as Procrit, Epogen), darbepoetin alfa (marketed as Aranesp). November 8, 2007. Available at: www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm054716.htm. Accessed TK.
Dr. Cooper is director of research and development and Mr. Allinson is chief executive officer and chief clinical officer of Therigy, LLC.