First Drug From Transgenic Goats Nears Approval By Charles Q Choi

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TRANSGENIC GOATS made by GTC Biotherapeutics are ready to create a clot-inhibiting compound called ATryn for sale on the European market.

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Origen Therapeutics in Burlingame, Calif., and researchers at the University of California, Davis, developed a technique reported in the June 8 Nature that generates transgenic chickens by inserting genes into germ cells using electrical fields to open pores in the cells' membranes. After these modified cells are injected into normal chickens, they create transgenic progeny. Efforts to make drugs in eggs using retroviruses to carry genes into chicken embryos go back 20 years, notes Origen president and CEO Robert Kay.

This new technique can insert genetic sequences roughly 20 times as long as those possible with viruses, he explains, to help create more complex, larger protein drugs; moreover, it can create a greater abundance of the protein in desired tissues.

In the milk of 30 genetically modified goats on GTC Biotherapeutics's farm in Charlton, Mass., is a drug that can literally make your blood flow—the human protein antithrombin, which inhibits clotting. In a dramatic reversal, after European regulators rejected this drug (called ATryn), they now look ready to approve it later this year. The ruling would make ATryn the first human protein made by a transgen-ic animal for commercial production.

Perhaps more important, the judgment in favor of the goats paves the way for more drug-making transgenic farm animals. Origen Therapeutics in Burlingame, Calif., has developed a versatile, cost-effective method for genetically transforming chickens—one that is on par with creating transgenic mice, now common in the lab. In principle, the birds could produce a variety of different proteins in their eggs, including drugs.

Traditionally, the biotechnology industry has most commonly relied on mammalian cells grown in vats to generate protein drugs. A number of molecules, including proteins normally found in blood plasma, are hard to produce with these methods. Squeezing large amounts of drug from these cells is difficult as well, driving up their price. The capital costs for a mammalian cell fermentation system that generates 100 kilograms of drug a year reach hundreds of millions of dollars.

On the other hand, 150 of GTC's goats or 5,000 of Origen's chickens could produce roughly the same amount of drug and cost only tens of millions. A transgenic farm's operating costs would also be far cheaper, "at literally chicken feed with our chickens," says Origen Therapeutics's president and CEO Robert Kay.

GTC spent roughly 15 years developing the goats. When the firm was ready in January 2004, it turned to Europe, where the Eu- _

ropean Medicines Evaluation Agency Charles Q. Choi is a frequent contributor.

(EMEA) had guidelines for drugmakers seeking approval to treat patients with hereditary antithrombin deficiency (at the time the U.S. Food and Drug Administration had no comparable approval procedures). Afflicted individuals might suffer problems from clots during high-risk procedures such as surgery and childbirth. The disease is rare, occurring in one in 3,000 to 5,000 people, so few cases are available for study.

This past February an EMEA committee rejected ATryn, considering the five surgical cases that GTC offered insufficient. GTC appealed the decision even though the odds seemed slim. "The number of times companies have successfully appealed a decision against them from a regulatory agency are very few," remarks Philip Nadeau, biotechnology analyst at investment banking and research firm Cowen and Company. On June 1, after bringing in leading European blood specialists and reviewing the findings, the EMEA committee decided to accept data on nine childbirth patients they had excluded initially and "concluded that the benefits of ATryn outweigh its risks." Final authorization on ATryn for use in surgery is expected from the European Commission in September.

The market for patients with hereditary antithrombin deficiency is only about $50 million in Europe and the U.S. combined. ATryn, however, could also find therapeutic uses for burns, coronary artery bypass surgery, sepsis and bone marrow transplants, for up to a $700-million market worldwide.

GTC plans to enroll patients in a hereditary antithrombin deficiency study for the FDA by the end of the year, says Geoffrey Cox, GTC's chairman, president and CEO. Kay hopes the company's success will "lower the general reluctance to take on any new technology" and predicts "we'll see trans-genic animals becoming a commonplace manufacturing alternative." Nadeau agrees: "It won't take as long for the second and third transgenic drug to make it to the market as the first."

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