Proteins are essential components of the human body. They perform specific biological functions within a cell and each type of protein has a unique function. For example, enzymes are proteins that help biochemical reactions to occur within the body. But before they can carry out these important functions, proteins must assemble into precise three-dimensional shapes through a process called protein folding. This process is critical and fundamental to virtually all of biology, but in many ways remains a mystery.
Genetic mutations may alter the instructions for making proteins. Some mutations are very severe and prevent the production of a specific protein, while other mutations can lead to the production of faulty proteins in cells that do not achieve their correct three-dimensional shape and are generally referred to as “misfolded” proteins. Many well known diseases, including neurodegenerative diseases such as Parkinson’s, Alzheimers, and Huntington’s, in addition to many cancers, arise when misfolded proteins are unable to perform their intended biological function or when they are not recognized as defective and eliminated by the cell’s own internal processes.
Protein misfolding can also result in rare diseases, such as lysosomal storage disorders [Gaucher disease, Fabry disease, Pompe disease, and Mucopolysaccharidosis Type I and Type II]. Historically, these disorders have been described as being caused by a missing protein, with each one involving a different lysosomal enzyme. However, recent evidence reveals that many individuals who have lysosomal storage disorders actually do make lysosomal enzymes – they are just misfolded and unable to perform their intended biological function.
Despite the fact that lysosomal storage disorders are less common [defined as affecting fewer than 200,000 people], companies have found the markets extremely profitable. In addition, the Orphan Drug Act [ODA] of 1983 provides incentives for sponsors to develop products for rare diseases, such as seven years of marketing exclusivity upon regulatory approval, as well as the opportunity to apply for grant funding from the U.S. government to defray costs of clinical trial expenses, tax credits for clinical research expenses and potential waiver of the FDA’s application user fee. The ODA has been very successful – more than 200 drugs and biological products for rare diseases have been brought to market since 1983. In contrast, the decade prior to 1983 saw fewer than ten such products come to market.
To date, the primary therapeutic strategy for lysosomal storage disorders has been enzyme replacement therapy [ERT], which involves the administration of exogenous recombinant human enzymes into the patient. For example, people with Gaucher disease are deficient in the enzyme glucocerebrosidase, which is responsible for breaking down a certain fat molecule called glucocerebroside. This causes a buildup of glucocerebroside in certain cells, called Gaucher cells. Clinical manifestations of the disease are the simultaneous enlargement of both the liver and the spleen [hepatosplenomegaly], skeletal disorders, and, in some instances, lung, kidney, and central nervous system impairment with the progression sometimes ending in death. It is estimated that Gaucher disease affects approximately 8,000 to 10,000 people worldwide.
Genzyme Corporation (GENZ) markets Cerezyme® [imiglucerase for injection] to replace the missing enzyme in Type 1 Gaucher disease. Cerezyme is a a mammalian cell expressed version of glucocerebrosidase that is created using recombinant DNA technology. It has been used since 1994 in thousands of patients around the world with reported annual sales of $1.24 billion in 2008.
On June 16, 2009, Genzyme announced the disruption of Cerezyme manufacturing due to a viral bioreactor contamination and that current product inventories would not be sufficient to meet projected global demand. Genzyme indicated that the period of constraint for Cerezyme should last approximately 6-8 weeks beginning in August, but that the manufacturing plant should be fully operational again by the end of July 2009. Production of Fabrazyme® (agalsidase beta) at the plant was also interrupted. While the news resulted in a significant decline in Genzyme’s common stock, several other companies have benefited.
For example, the FDA requested treatment protocols from Shire plc (SHPGY) and Protalix Biotherapeutics, Inc. (PLX) for their competitive ERT products. If approved by the FDA, the treatment protocols would allow physicians to treat Gaucher patients ahead of commercial availability in the US. Shire is currently developing velaglucerase alfa, a version of glucocerebrosidase made from a human cell line that has the exact human amino acid sequence and carries a human glycosylation pattern. Shire reported filing a treatment protocol with the FDA on July 6, 2009 with plans to file a New Drug Application [NDA] as early as possible. Protalix only indicated that the company “expects to submit” a treatment protocol to the FDA for its prGCD product candidate, a plant-cell expressed recombinant form of glucocerebrosidase that is currently the subject of a pivotal Phase 3 clinical trial being conducted under the FDA’s Special Protocol Assessment [SPA]. However, shares of Protalix have risen more than 40% since Genzyme’s announcement.
Shares of Amicus Therapeutics, Inc. (FOLD) also gained more than 40% following news of the Genzyme manufacturing disruption. Amicus Therapeutics is currently conducting a Phase 2 study of Plicera™ [afegostat tartrate] for Gaucher disease as part of a strategic collaboration with partner Shire to develop novel, oral therapeutics known as pharmacological chaperones for the treatment of a range of human genetic diseases. Amicus Therapeutics’ pharmacological chaperone technology involves the use of small molecules that selectively bind to and stabilize proteins in cells, leading to improved protein folding and trafficking, and increased activity. Amicus previously reported that enrollment has been completed for the Phase 2 Gaucher study with results to be available in the third quarter of 2009. Amicus has also commenced the U.S. registration Phase 3 trial for Amigal™ [migalastat hydrochloride] for the treatment of Fabry disease and is studying AT2220 [deoxynojirimycin] in a Phase 2 clinical trial for the treatment of Pompe disease, although this particular study was placed on clinical hold by the FDA in February 2009.
While not working in the area of lysosomal storage disorders, shares of CytRx Corporation (CYTR) have also risen dramatically since Genzyme’s manufacturing disruption announcement. CytRx is developing novel compounds that amplify the production of endogenous molecular chaperones. In January of 2008, CytRx announced that a Phase 2b study with the company’s drug candidate arimoclomol for the treatment of amyotrophic lateral sclerosis [ALS, or Lou Gehrig’s disease] was placed on clinical hold by the FDA pending additional data and preclinical toxicology studies.
Amicus and CytRx are taking different approaches to small molecule chaperone technology. One potential advantage for Amicus is that their pharmacological chaperones directly stabilize the misfolded proteins, while CytRx’s molecule will indirectly stabilize a misfolded protein through upregulation of endogenous molecular chaperones, possibly leading to cellular desensitization with chronic drug intervention.
Lysosomal storage diseases are rare and debilitating diseases, but with the advancement of ERT are becoming more manageable. However, as the pharmacoeconomic landscape changes, difficult decisions need to be made about the costs for some of these therapies. In fact, several insurance companies refuse to pay for ERT for adults (click here for reference).
Amicus Therapeutics and others have several small molecule compounds in development that may offer improved patient outcomes at a significant reduction in cost. Upcoming clinical trial results will be critical for the evaluation of improved efficacy in these patient populations.
In addition, there is the possibility for combination therapy with ERT and pharmacological chaperones leading to improved patient outcomes.
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