History of Biopharmaceuticals (Genetics & Inherited Conditions)
Drugs have been used by humans for thousands of years. More than three thousand years ago, the Sumerians were the first culture to compile written medical information that outlined symptoms and treatments for disease. Most ancient cultures used medicines derived from plants and animals. These drugs were different from modern biopharmaceuticals in many ways, but the most significant difference is that the drugs were not engineered to treat a particular disease. Since there was no real understanding of the underlying problem, a rational approach to drug selection and design was difficult, if not impossible. One philosophy of medicine that developed to address this problem was called the doctrine of similitudes, in which treatments were based on similarities of structure with disease manifestation. For example, the leaves of St. John’s wort looked similar to damaged skin, so it was thought this plant extract could effectively treat cuts and burns.
It was not until the twentieth century that the underlying genetic basis for disease was discovered. The discovery that DNA is the genetic material that provides instructions to make proteins was revolutionary. In the mid-1900’s, sickle-cell disease was shown to be caused by a single nucleotide mutation from an A (adenine) to a T (thymine) in the hemoglobin beta-chain gene. This small change alters the shape of a red blood cell from a biconcave disc to a...
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Design of Biopharmaceuticals (Genetics & Inherited Conditions)
A popular method for the identification of disease-related genes is called genomics. Gene chip analysis is used to screen thousands of genes in a single experiment. This approach is drastically faster and more efficient than traditional methods and can be used for any disease, even those that are not hereditary.
Once the genomic information is obtained, it is used to build a broad understanding of how a disease gene functions and what role the gene plays in the cell. This information is gathered through the use of experimental models, genetic analysis, biochemical analysis, and structural analysis. Experimental models can range from cell culture to transgenic mice and can provide physiological information about the disease. Genetic analysis can provide information about where and when the gene is expressed. Biochemical analysis can provide information about protein-protein interactions, post-translational modifications of the protein, and its enzymatic activity. Structural analysis can yield extremely detailed information about the physical arrangement of the atoms that make up the protein. All these approaches can identify important potential targets for treatment of the disease. A better understanding of the disease at the genetic and molecular levels facilitates the design of a biopharmaceutical.
Once a disease is better understood, it becomes possible to target a key pathway or protein for...
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Clinical Trials (Genetics & Inherited Conditions)
Before a biopharmaceutical can be used to treat disease, it must undergo rigorous clinical trials that test its safety and effectiveness in humans. There are four phases of clinical trials. Phase I trials involve studies on a small number of patients (fewer than one hundred) in order to determine drug safety and dosage. Phase II trials involve more patients (up to five hundred) in order to determine effectiveness and additional safety information, such as side effects. Phase III trials are the most extensive and involve large numbers of people (between one thousand and three thousand). These trials establish risk-benefit information and are compared with other currently used treatments. Phase IV trials determine the drug’s optimal use in a clinical setting.
In 2003, the entire process of drug design—from discovery to clinical trials—cost approximately $802 million and took an average of twelve years. By 2006, there were 111 biopharmaceuticals in late-stage development that targeted thirty-eight different disease categories, the majority of which was cancer. Many years of research and millions of dollars are expended in an extraordinary effort that yields little success—only one in five thousand drugs makes it to market. By 2008, 64 therapeutic biological products were under review in the Center for Drug Evaluation and Research at the FDA.
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Biopharmaceuticals Today (Genetics & Inherited Conditions)
Biopharmaceuticals are classified into several categories, including blood factors, thrombolytic agents, hormones, hematopoietic growth factors, interferons, interleukin-based products, vaccines, monoclonal antibodies, and other products. Some FDA-approved biopharmaceuticals of particular interest include Aralast, Campath, Gardasil, and ATryn. Aralast is marketed by Baxter and was approved for use by the FDA in 2003. Aralast is the trade name for the recombinant human protein known as alpha-1 proteinase inhibitor (A1PI). A1PI deficiency, also called alpha-1-antitrypsin deficiency, results in the destruction of lung tissue, which can lead to emphysema. Aralast is given to patients intravenously each week, protecting against future lung damage.
Campath is marketed by Millennium Pharmaceuticals and was approved by the FDA in 2001. Campath is the trade name for a humanized antibody against the CD52 antigen found on lymphocytes. The antibody is used to treat chronic lymphocytic leukemia and works by destroying lymphocytes through agglutination and complement activation.
While many biopharmaceuticals are designed to target a specific disease, the popular vaccine Gardasil was designed to prevent genital human papillomavirus (HPV) infection. Gardasil is marketed by Merck & Company and was approved by the FDA for use in young women in 2006. HPV is the most commonly sexually transmitted disease in the United States...
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Further Reading (Genetics & Inherited Conditions)
Barr, E., and H. L. Sings. “Prophylactic HPV Vaccines: New Interventions for Cancer Control.” Vaccine 26, no. 49 (2008): 6244-6257. Overviews the clinical trials evaluating the long-term safety and efficacy of the quadrivalent HPV vaccine.
Collins, F., and V. McKusick. “Implications of the Human Genome Project for Medical Science.” JAMA 285, no. 5 (2001): 540-541. Overviews the significant impact of the Human Genome Project on medical research, including specific examples of drug design.
Nagle, P. C., C. A. Nicita, L. A. Gerdes, and C. J. Schmeichel. “Characteristics of and Trends in the Late-Stage Biopharmaceutical Pipeline.” American Journal of Managed Care 14, no. 4 (2008): 226-229. Provides a review of the drug development databases and analyzes the biopharmaceuticals in late-stage development in the United States.
Niemann, H., and W. A. Kues. “Transgenic Farm Animals: An Update.” Reproduction, Fertility, and Development 19, no. 6 (2007): 762-770. A review of the history of genetic engineering in farm animals to date.
Wu-Pong, S., and Y. Rojanasakul. Biopharmaceutical Drug Design and Development. Totowa, N.J.: Humana Press, 1999. Outlines the process of biopharmaceutical design, including basic molecular biology, major classes of biopharmaceuticals, and clinical trials.
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Web Sites of Interest (Genetics & Inherited Conditions)
American Chemical Society, The Pharmaceutical Century. http://pubs.acs.org/journals/pharmcent. Posts articles about the science of biopharmaceuticals, including the role played by genetics and the Human Genome Project in the development of new drugs.
Clinical Today.com. http://www.clinicaltoday.com. Articles about the most recent developments in clinical trials.
ClinicalTrials.gov. http://www.clinicaltrials.gov. Search ongoing and completed FDA clinical trials using a variety of search criteria.
Food and Drug Administration (FDA). http://www.fda.gov/cder/index.html. Information regarding all drugs regulated by the FDA.
International Biopharmaceutical Association-Alliance. http://www.ibpaalliance.org. Wikipedia-powered glossary of commonly encountered biopharmaceutical terms and common pharmaceutical companies that produce biopharmaceuticals.
Pharma Industry Today. http://www.pharmaindustrytoday.com. Up-to-date news from the pharmaceutical and biotechnology industries.
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