Editorial: Is Transgenic Enzyme For Pompe’s Disease Really Dead?

In order to keep up with the growing demand for the production of protein substances biopharmaceutical companies have several options:

• Build a new facility to produce new compounds, which would entail a cost of $200M-$400M and take three to five years to complete.

• Reserve “production slots” at a contract manufacturing facility such as Boehringer Ingelheim in Germany (The CHO enzyme for Pompe’s disease was produced at this facility).

• Or pursue transgenic drug production (carrying genes transferred from another species or breed)

The article focused on GTC Biotherapeutics in Framingham, Massachusetts (formerly Genzyme Transgenic Corporation), and emphasized that manufacturing of proteins in animals is the wave of the future. The article states:

• “it takes about 18 months to make a transgenic goat (8 months for a transgenic rabbit) that produces a desired therapeutic protein in its milk….in a cow….. (it takes) about 3 years……”

• “….goats produce roughly 2 liters of milk a day, while cows produce about 20 liters a day.”

• “….creating a herd of transgenic goats costs about $100M….only a third the cost of building a protein production facility.”

• “The traditional method of production….which involves culturing large volumes of mammalian-derived cells and extracting their contents, costs about $150M a gram.” It is estimated that production of transgenic proteins will cost $1-2 a gram. (These costs contrast directly with what we have previously been told about transgenic enzyme production).

The future of transgenic therapy is also discussed in another article, which appeared in the San Antonio Express-News on September 11, 2002, entitled, “Cloning: Man Turns Creator” by Roy Bragg. Several biotech companies were mentioned including Infigen, Genzyme Transgenics, and Pharming (remember them). The article talks mainly about the production of transgenic cows which are so valuable that they are “kept under lock and key in a barn near De Forest, Wisconsin.” The article states.

“By splicing certain human genes into bovine embryo, the cloned offspring will produce specific human proteins in its milk. While a human might only produce a few grams of the protein, a cow could produce several hundred pounds of it in a year through twice-daily milking.”

“Genzyme Transgenics, a Framingham, Massachusetts based biotech company, has identified 60 proteins from the milk of genetically modified mice, rabbits, cows and goats that have pharmaceutical potential.”

This leads us to the search for a treatment for Pompe’s Disease. When scientists at Erasmus University Medical Center, Rotterdam, met a roadblock in their 25-year effort to develop a therapy for Pompe’s disease, they turned their approach to a new and novel way of producing the medicine – in animals rather than in the conventional reaction vessel. With the backing of an upstart Dutch pharmaceutical company, Pharming, a transgenic enzyme for Pompe’s disease was developed. Pharming entered into a joint venture with Genzyme Corporation, in October 1998, to develop and commercialize human alpha-glucosidase.

In July 2002, Genzyme Corporation abruptly halted production of the transgenic enzyme, although nine patients were still being treated with it. Catastrophes with improperly bottled enzyme and economic unfeasibility were cited by Genzyme as reasons for ceasing production. Genzyme wanted to focus on its new in-house produced CHO enzyme (Myozyme™) and the Novazyme product, which, at the time, was flaunted as being the second-generation treatment for Pompe’s disease. The Novazyme product has since disappeared from focus and what happened to the transgenic rabbit herd is anyone’s guess.

Of what interest is this to the patient who is anxiously awaiting treatment for Pompe’s disease? Perhaps it only gives us insight into the future of treatment for Pompe’s disease. The FDA under the Orphan Drug Act provides companies with incentives to develop a treatment for an orphan disease – a disease that affects a small number of people. The most notable incentive is the exclusive right to market the orphan product for seven years (ten years in Europe). If another production method is available at the end of this run, an additional seven years marketing exclusivity could be in the works.

What could this do? It would allow Genzyme to recover the initial investment cost of producing Myozyme™ while producing the next-generation drug at a reduced cost.

For example, in an article in May 2003 issue of Scientific American entitled, “The Orphan Drug Backlash”, the author Thomas Maeder states:

“A notable case of pricing and profit…(is) Genzyme’s Cerezyme. The drug, an enzyme replacement therapy for Gaucher disease, which afflicts 2,000 Americans, is the world’s most expensive medicine. Genzyme reportedly earns close to half a billion dollars a year from this treatment by charging patients between $100,000 and $400,00 a year for it, depending on whether the patient is a child or an adult. And the company did not lower the price when it switched from extracting the substance from human placentas to using the less expensive recombinant method of production. Patients, some of whom must spend their way into poverty to qualify for Medicaid to afford Cerezyme, are angry about the price but grateful for their lives.”

Will transgenic therapy be re-introduced as a treatment for Pompe’s disease? If so, will the introduction of a second, and possibly a third generation of enzyme therapy for Pompe’s disease, inhibit the development of gene therapy — “the cure.”Only time will tell.