Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Shortage could lead to more choices for patients sooner than expected.

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.

Genzyme’s plant shutdown may thus result in more therapeutic choices for Gaucher’s patients. Additionally, should Protalix’ prGCD and Shire’s velaglucerase win marketing approval, the newly competitive environment could focus attention on differences among these molecules as these similar yet different therapeutics become available.

Genzyme is currently the sole worldwide supplier of Cerezyme, a recombinant form of glucocerebrosidase (GCB) made in CHO cells. Until Genzyme pioneered ERT for Gaucher’s with its human placenta-derived Ceredase in 1991, no effective treatment existed for Gaucher’s. The firm sells more than $1.2 billion worth of Cerezyme annually. On June 25, however, due to the facility closure, the company said that it anticipate the period of constraint for two recombinant proteins (Fabrazyme for the treatment of Fabry disease and Cerezyme) to last approximately six to eight weeks, beginning in August for Cerezyme.

The only currently marketed alternative to ERTs is Actelion’s Zavesca®, which is indicated for the treatment of patients for whom enzyme replacement therapy is unsuitable. It works by slowing the buildup of glucocerebrosidase through inhibition of an enzyme needed to synthesize it.

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 vs. Shire

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 velaglucerase alfa is currently in three Phase III trials under fast-track protocol involving 100 patients in 24 countries. Suzanne L. Bruhn, Ph.D., svp of strategic planning and program management at Shire Human Genetic Therapies, believes that its human cell line production platform gives it the best, most authentic fully human protein. “We are now testing it in three Phase III studies at 24 sites in naive patients, in patients switching from Cerezyme to velaglucerase, and in head-to-head studies comparing it to Cerezyme.”

Dr. Bruhn also says that the company doesn’t anticipate a viral contaminant problem, since the virus discovered at the Genzyme plant, to date, does not appear to infect human cells.

In contrast, Protalix’ prGCD is produced in carrot cells that are engineered to express human proteins and grown on an industrial scale in a flexible bioreactor system. The enzyme is currently being tested in a Phase III study under an FDA special protocol assessment. The company says that its recombinant system, ProCellEx™, produces proteins that exhibit consistent enzymatic activity from batch to batch, resulting in a highly active product that may be more efficacious than proteins produced through mammalian cell-based systems. The company expects to file an NDA during the last quarter.

Both Protalix and Shire say that they would initially provide these recombinant enzymes free of charge to patients. As of July 24 Protalix had not filed a treatment protocol with the FDA.

Small Molecule Options

Both Genzyme and Shire are also developing small molecule alternatives to recombinant proteins. These orally available drugs don’t require the bi-weekly intravenous infusion and work by either preventing glucocerebroside buildup (substrate inhibition) or by fixing the dysfunctional enzyme. Genzyme’s substrate-inhibition candidate, GENZ-112638, is in Phase II and is expected to enter Phase III later this year.

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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