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Insight & Intelligence : Jul 24, 2009
Companies Step In to Fill Gap in Enzyme Replacement Therapy for Gaucher’s
Shortage could lead to more choices for patients sooner than expected.!--h2>
As Genzyme shut down its Allston Landing, MA, plant due to viral contamination, the FDA tapped two potential competitors, Protalix Biotherapeutics and Shire, to help avert supply shortages of Cerezyme®, the enzyme replacement therapy (ERT) for Gaucher’s disease patients. The agency requested that these companies submit treatment protocols for use of their Phase III ERT candidates.
Gaucher’s disease results from a hereditary deficiency of GCB, required to break down a normal, fatty body substance, glucocereobroside. Absent functional GCB, glucocerebroside accumulates within macrophages leading to cellular engorgement, organ enlargement, and organ system dysfunction. Gaucher’s reportedly afflicts about 8–10,000 people worldwide and is the most common genetic disease among people of Ashkenazi Jewish descent in North America.
Protalix’ prGCD is produced in a plant recombinant system while Shire’s velaglucerase alfa is produced in a human cell line. Each recombinant type of producer cell churns out slightly different variations on a protein theme. These include changes in post-translational modifications such as glycosylation, which can impact the enzyme’s performance including its half-life in the body. Genzyme, for example, modifies the carbohydrate structures on Cerezyme to terminate mannose sugars that help facilitate macrophage uptake where its substrate accumulates.
Shire’s candidate Plicera is licensed from and is being developed by Amicus Therapeutics. It is currently in Phase II and works by allowing the mutated Gaucher’s enzyme to become functional. It binds to and stabilizes the misfolded enzyme resulting from Gaucher mutations, allowing its transport to the lysozome where it is active. Amicus expects to report Phase II data from testing the drug in Gaucher’s patients who are naive to ERT at the end of this quarter.
“Substrate inhibition doesn’t stabilize the enzyme that’s inherently deficient and doesn’t fix the problem at its source,” according to John Crowley, president and CEO of Amicus. Thus, Crowley says, Amicus’ approach “changes the thermodynamic stability of the mutated enzyme, enhancing its folding and allowing it to reach the cellular target, the lysozome. Once in the lysozome the drug dissociates from the enzyme, but at that point the enzyme, even with the mutation in it, remains catalytically competent. The trick is getting it where it needs to go.”
Amicus notes that new entrants into the ERT market and completely novel drug approaches will offer Gaucher's patients and their physicians a range of therapeutic choices best suited to their needs.
Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.
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