Summary of the Book
The book is a story of a couple’s unrelenting search for a cure for a rare genetic disorder, the Pompe’s disease. It covers the struggles (and successes) of John and Aileen Crowley in their quest for a cure for this rare genetic disorder. The young family had a perfect family life. John had graduated from Harvard Business School, secured a well-paying job and bought a nice home for his family. The couple and their three children were living happily until the mother, Aileen, discovered that their fifteen-month-old daughter’s motor skills were deteriorating. Later, a diagnosis revealed that, the daughter, Megan, and her five-month-old brother, Patrick, had the Pompe’s disease, a rare genetic condition for which there was no effective cure. It was further revealed that the degenerative condition would affect the children’s muscles and lead to reduced ability to walk, talk or even eat. They were told that their two children would succumb to this disease before reaching puberty.
In an attempt to save his children, John set out to search for a cure for the Pompe’s disease. He quit his job and launched a Biotech company, Priozyme Pharmaceuticals, which undertook research to identify a novel enzyme that would substitute the non-functional enzyme in the Pompe’s disease. However, the race for a causal treatment was a long and tedious one especially with regard to the clinical trials and the FDA approval process. Furthermore, competition among research scientists and pharmaceutical companies threatened to derail John’s search for the cure. In the final experiment, the top four drug compounds that had shown promising results were compared in a double-blind clinical trial and a potent compound was identified (Anand 67). A subsequent five-year drug development process yielded the cure, which was given to the children. The book essentially brings into light the lengthy drug development and approval process, and the competition among research teams, care providers, and pharmaceutical companies in the development of new drugs.
Genetic and Clinical Aspects of the Pompe’s Disease
Pompe’s Disease is an inherited rare genetic disorder that is estimated to affect one in every 40,000 children (Joppi, Bertele and Garattini 355). This degenerative disorder affects the skeletal and heart muscles, hence, a fatal condition. It has been found that mutations involving a gene that codes for alpha-glucosidase (GAA) enzyme cause the Pompe’s disease. The function of GAA in the body is to hydrolyze glycogen (sugar stored in cellular lysosomes) to release energy for use by the muscle cells. However, in the Pompe’s Disease, the GAA gene mutation encodes a defective GAA enzyme that lacks the ability to break down glycogen (Joppi, Bertele and Garattini 358). Consequently, the level of glycogen in the muscle cells increases leading to muscle degeneration.
Alpha-glucosidase enzyme converts blood glucose into glycogen, which is reserve energy for muscle cells (Joppi, Bertele and Garattini 357). Glycogen degradation by alpha-glucosidase occurs in the lysosomes while the conversion of glucose to glycogen occurs in the cytoplasm, whereby insulin converts excess glucose into glycogen for lysosomal storage. The glycogen formed is then transported through a mechanism called ‘autophagy’ into the lysosomal cavity (Joppi, Bertele and Garattini 359). Upon reaching the lysosome, the alpha-glucosidase enzyme breaks down the glycogen to glucose for use by body cells. However, if alpha-glucosidase is lacking, the glycogen accumulates to critical levels in the lysosome leading to muscle wasting. The lysosomal glycogen accumulation in Pompe’s disease primarily affects the muscle cells. Muscle wasting occurs when the lysosomal glycogen accumulation causes lysosomes to rupture releasing autolytic enzymes, which then break down muscle tissues (Joppi, Bertele and Garattini 358). Muscle wasting also arises from glycogen accumulation, which affects the integrity of the myofibrils.
Over 70 GAA gene mutations associated with different symptoms of the disease have been identified. The symptoms vary widely with regard to the severity of the disease and the onset period, which, in turn, depend on the patient’s level of enzyme deficiency. “Carriers” of this disease have one mutated (recessive) allele and one normal (dominant) gene copy (Joppi, Bertele and Garattini 356). Thus, though the “carriers” are not affected by the disease, they transmit the defective gene to their children, which predisposes them to the disease. In Anand’s book, John and his wife were both carriers; their two children inherited the mutated genes for the Pompe’s disease from their parents. It is only when two mutant GAA genes occur in a person that the individual develops the Pompe’s disease.
The Concept of Orphan Drugs
An orphan drug refers to a medication used in the treatment of a rare disease. A rare disease (an orphan disease) describes illnesses usually neglected by physicians and research scientists (Joppi, Bertele and Garattini 356). Common examples include conditions such as high myopia, alveolar echinococcosis and endometrial cancer among others. The definition of an orphan disease varies from one country to another. For instance, in the US, an orphan disease affects less than 200,000 people. In contrast, W.H.O. defines an orphan disease as one affecting fewer than 10 individuals in a population of 10,000 people (Joppi, Bertele and Garattini 359). Some genetic disorders such as the Pompe’s disease and Zuska’s disease meet this threshold because of their rarity.
Common orphan drugs include haem arginate, which is used in the treatment of intermittent porphyria and myozyme, which is used to treat Pompe’s disease (Joppi Bertele and Garattini 356). There are many obstacles to the development of orphan drugs both in the clinical trial stage and the marketing stage. In particular, efficacy trials of orphan drugs are relatively uncommon, which makes it difficult to determine their efficacy in the treatment of rare conditions. In the recent past, there have been incentives to encourage pharmaceutical companies to invest in orphan drug development including tax exemptions and simplification of the approval process. In the US, a drug is classified as an orphan drug based on the rarity of the condition, its therapeutic benefits and its mechanism of action (Joppi, Bertele and Garattini 357). Given that an orphan disease is a rare disease, it should be cost-effective to treat it. Thus, based on cost-effective analysis, research and clinical trials for most orphan drugs may not be justified. This implies that, though people with rare diseases need treatment, the development of such drugs should not come at a cost for those with common illnesses. Therefore, an orphan drug should be cost-effective to develop so that the treatment of common diseases is not compromised.
Roles of Pharmaceutical Companies and FDA in Drug Development
Drug development is often a lengthy and complicated process. It brings together professionals from interrelated fields of biochemistry, toxicology, molecular biology, statistics, computer science and pharmacology. Drug development spans 10-12 years from the laboratory research stage to the clinical trial stage. Only a few drugs from the preclinical testing stage make it to the clinical testing stage involving human subjects and only one or two of these drugs are approved for use.
The Food and Drug Administration (FDA) is mandated with the role of overseeing clinical trials of drugs by pharmaceutical companies. At the initial stage of drug development (preclinical stage), FDA has a limited role as the drug testing normally involves lab animals. After successful animal testing, the process proceeds to clinical trials involving healthy volunteers. It is at this point that FDA monitors the clinical trials and approves the drug for use if it is found that the drug has positive therapeutic effects on humans. The agency also requires drug manufacturers to provide user instructions before approving the drug.
Drug discovery and development entails four main steps. The first step is the preclinical research stage, whereby research scientists identify the causative agent of the disease, the infection process, the lead compound and the new drug for the disease (Joppi, Bertele and Garattini 355). Drug testing at this stage only involves lab animals and can last for up to three years. The second step is the testing of the new drug, which comprises of three clinical trials (phases) involving human subjects. The clinical trials help in the determination of drug toxicity levels, efficacy, safety and dosage of the new drug. New Drug Application (NDA) is the third step. After successful clinical trials, the pharmaceutical company serves the FDA with an NDA containing the scientific data about the drug’s safety and effectiveness. The fourth step is the approval step. At this stage, the FDA examines the information provided before approving the drug for patient use on a prescription basis. Even after approval, the FDA requires pharmaceutical companies to carry out further tests on the drug that has already been released into the market.
References
Anand, Geeta. The Cure: How a Father Raised $100 Million – and Bucked the Medical Establishment – In a Quest to Save His Children. New York: Harper Collins Publishers, 2006. Print.
Joppi Roberta, Bertele, Vittorio and Garattini, Silvio. “Orphan drug development is progressing too slowly”. British Journal of Clinical Pharmacology 61.3 (2006): 355–360. Print.