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GTCB interview in RedHerring:

http://tinyurl.com/exzvk

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Q&A: GTC’s Geoffrey F. Cox

The CEO of GTC Biotherapeutics says his firm is rearing transgenic goats that will lead to a drug to treat blood-clotting problems.

January 12, 2006

Geoffrey Cox knows all about “pharming.” Since 2001, he has been CEO, president, and chairman of GTC Biotherapeutics, a company that rears transgenic goats to produce human therapeutics in their milk. These animals have genes from animals other than goats, including from humans.

If all goes as planned, the milk from Mr. Cox’s goats will be purified and the first result will be a drug to treat blood-clotting problems. His company is expecting approval in the European Union this year and by 2008 in the United States.

Before joining GTC, Mr. Cox had a long history working in biotechnology. With a PhD in biochemistry at the University of East Anglia, in England, Dr. Cox joined Genzyme during 1984, becoming executive vice president of operations. He stayed at Genzyme until 1997 and then moved to Aronex Pharmaceuticals, as CEO.

Upon the company’s merger with New York City-based cancer vaccine company Antigenics, he heard that GTC—a 1991 Genzyme spinout—was looking for a CEO. The company, which has been public since 1993, had spent much of the mid-to-late 1990s making antibodies for Centocor, Abbott, and Bristol-Myers Squibb.

“When I joined, it wasn't really a unique thought, but I felt we needed to take responsibility for the regulatory process ourselves,” he says. This he has done, and GTC anticipates its first regulatory agency opinion in February.

RedHerring.com recently chatted with Dr. Cox at a JP Morgan healthcare conference in San Francisco about GTC’s goats and the process of getting approval for human drugs extracted from milk.

Q: Why goats?

A: Goats are a good animal to go for because they have a six-month gestation period. They're fertile after the kid is born in about 6 months so you produce a herd of lactating animals very quickly.

They produce about one or two liters of milk a day; only a tenth of what a cow produces, but a cow has very long gestation. We have one program in cattle too.

Q: Tell me about your goat farm.

A: We have about 1,500 animals at our farm in Massachusetts, of which about 400 are transgenic.

They're animals that were brought in from New Zealand. We only breed within the herd. We have an eight-foot fence around a 300-acre site in central Massachusetts, of which we use about 150 acres at this moment.

The barns have very specifically been designed, where they stay in pens. We provide these little platforms for them to climb on because they always want to be king of the mountain. They roam outside, not in grass but in pens.

We’re very careful about access to the site so that nobody brings infections onto it. If you came you’d be required to put your shoes through a footbath. If you’d been to a farm in the last two or three weeks, you wouldn’t be allowed to come.

Q: How do you get the goats to produce human proteins?

A: There are two ways. One is through microinjection. You have a construct of DNA which codes for the human protein you want to produce, and it’s linked to a promoter for casein—a protein found in significant quantities in milk.

By linking it to the promoter, you end up with a situation where the protein is only produced when the animal lactates. But when you do this by microinjection, it’s a bit random whether the DNA actually gets incorporated into the genome.

So we also developed nuclear transfer technology, which we tend to use because it has a certainty about whether you have a transgenic animal.

Q: Cloned animals tend to have health problems. Do your cloned goats?

A: No. We’ve seen no evidence of unhealthy animals in the cloning work we’ve done. You do find that not all of them come to full term, but the animals that live are healthy animals.

We’re very careful and ethical about what we do.

Q: Why did you feel you had to handle the approval process yourselves?

A: This is the first transgenically derived therapeutic protein that a regulatory agency has ever reviewed anywhere in the world, so we’re literally writing the road map for the way in which these proteins will be approved.

In 2001, when I joined, the EMEA [European Medicines Evaluation Agency] had just published a scientific guidance document which said that if you want to develop antithrombin in the European Union, then this is the study that you need to do.

Antithrombin is an essential part of the control of the coagulation cycle in the blood stream. We had already done quite a bit of work with a recombinant version of human antithrombin. We already had all the transgenic animals and all the other things that you need to produce the product, and we’ve been conducting those studies since that time.

We filed that program in January 2004, and we’re just at this moment, waiting with fingers crossed and bated breath, for what we hope will be a positive opinion in February.

This is a major moment for us. It’s not just about a product—it validates the technology platform as a new production system for these proteins and unlocks the value of everything that comes out of it.

Q: Antithrombin is currently made by purifying it from blood people donate. What sort of proof of safety did you have to show in the trial?

A: The EMEA trial was what’s called an open-label study. It required a minimum of 12 patients in a genetic disorder called hereditary antithrombin deficiency. It’s a very unusual trial—a non-inferiority study.

Patients with hereditary antithrombin deficiency have low levels of antithrombin in their bloodstream, and as a result they have a high propensity to developing thromboses [blood clots]. Very often people don't know they have it until they have their first event. There's probably about 60,000 to 70,000 people in the U.S. who have this disorder, and a similar amount in Europe.

You can treat these patients using a blood thinner such as warfarin. But you can’t keep women who are about to give birth or patients who want to go into surgery on blood thinners because they'll bleed excessively during the course of the procedure. So you take their antithrombin levels up to a normal level to take them through the procedure, and then return them to their blood thinners after that.

It's also probably the most rigorous study that has ever been required for antithrombin because many of the plasma proteins which exist in the market today were approved way back, some of them on fairly limited data.

Q: How efficiently can you make proteins using goats?

A: You can produce several hundred kilos in tonnage quantities with quite a modest herd of goats. One of the little pictures I paint to demonstrate this is, in the case of antithrombin, if you took a number of people that need treatment for acquired deficiency, you'd need about five or six hundred kilos of product.

If you collect plasma from all the donated blood in the U.S., you could make about 100 kilos of antithrombin. We can make this from about 150 goats. So, in very round terms, if you say a goat can produce a kilo of purified protein a year, this is equivalent to 90,000 blood donations.

Being able to produce large volumes of therapeutic proteins at very modest cost is one of the valuable characteristics of the technology.

But what’s also important is to produce proteins that are very difficult to make in other manufacturing systems. We don't know of any process, other than plasma fractionation, that can produce antithrombin in viable and economic quantities.

Q: When do you expect the first goat-produced therapeutic to hit the market?

A: If it’s a positive opinion in February, it goes to the European Commission, which takes around two to three months before it issues a marketing authorization. From then on we go to each of the individual countries to negotiate reimbursement. We expect to introduce the product to the marketplace at the end of this year.

In the U.S. we expect to complete enrollment in our study somewhere around the end of the third quarter of this year. We’ll hopefully get U.S. approval in 2008.

Our intention is to do a broader clinical development in what’s called an acquired deficiency indication, where there may be a reduction in the level of antithrombin as a result of a trauma. It may be severe coronary bypass surgery, sepsis, where your antithrombin actually gets consumed in the bloodstream.

This is potentially a very large market for us, so we certainly intend to go on and do that clinical development.
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