BIOMED: Down on the Pharm

Date: Sat Jun 10 2000 - 09:02:20 MDT

>From The Philadelphia Inquirer,
Sunday, June 4, 2000
Cures of the future are growing on 'pharms' today
Genetically altered goats are producing milk that contains drugs. Sales
could begin in months.

By Andrea Knox
CHARLTON, Mass. - The GTC Farm oozes a storybook charm, with its shaded
brook, old-fashioned clapboard farmhouse, and gamboling goats that rush from
their barns and thrust their noses over fences to inspect visitors.

But the aura of times past masks a scene straight out of a science-fiction
future. This is no farm. It is a pharm, a 21st-century pharmaceutical plant.

In the hilltop laboratory, scientists inject goat embryos with strips of
synthetic human DNA to create four-legged drug factories - animals that
produce pharmaceuticals in their milk.

The goats are churning out 12 potential drugs, some of which are being
tested in people.

One, a blood-clotting agent for use in heart bypass surgery, could be on the
market by next year.

Opening a momentous new chapter in pharmaceutical history, this would be the
first commercial drug produced in a transgenic animal - one that scientists
have given a gene for a trait it doesn't naturally possess. The gene is
inserted into a fertilized embryo, which is carried to birth in an adult.

The added gene in the GTC goats spurs the secretion of a protein that has
potential therapeutic use in people.

And amid some unease about whether it's all moving a bit too fast, this
pharm has plenty of company. Transgenic cows in Virginia and Wisconsin,
sheep in New Zealand, and rabbits in Europe are making milk containing
proteins that may one day be used as drugs.

Among the drugs are potential treatments for HIV, rheumatoid arthritis,
Crohn's disease, and osteoporosis. There's a protein to help premature
infants digest fats, and another to help in tissue repair. There's Factor
VIII, which stops bleeding in hemophiliacs, and a therapy that's being
tested against Pompe's disease, a rare genetic disorder that kills infants
within months of diagnosis.

In every case, the protein is extracted from the animal's milk and purified
into a treatment before being administered to patients in the traditional
forms of pill, shot, or intravenous drip. The animals are killed and
incinerated when their useful lives are over, so they do not become human or
animal food and cannot be adopted as pets.

Although scientists have been adding genes to animal embryos for nearly
three decades, no transgenic drug has yet been through enough human trials
to assure that it is both safe and effective.

But several - besides the blood-clotting agent produced by the GTC goats -
have shown enough promise that their developers expect to seek marketing
approval from the U.S. Food and Drug Administration within two years.

The prospect that transgenic drugs might soon be a viable treatment option
is a heady one for scientists and patient advocates, not to mention
investors and entrepreneurs who have staked hundreds of millions of dollars
and more than a decade of work on the technology.

They hold out hope that animal production could cut production costs of some
drugs, although making no promises that the savings would be passed on to
consumers. But they also say that transgenic animals could increase the
supply of some drugs, including Factor VIII, and could produce new
treatments that are impossible to make by other methods.

"This is the drug-production technology of the 21st century," says George J.
M. Hersbach, president and CEO of Pharming, N.V., a Netherlands company that
is working with the American Red Cross on Factor VIII and is developing the
Pompe's disease treatment with Genzyme Transgenics Corp. of Framingham,
Mass., which owns the GTC Farm.

"It's all about getting new drugs to people who need them, in a
cost-effective way," adds Genzyme chief executive officer Sandra Nusinoff
Lehrman. She estimates that in some cases, her goats can produce drugs for a
quarter of what it would cost otherwise.

She also points out that it is quicker to expand production by breeding a
few more goats than by building a new plant.

Skeptics, however, wonder whether the industry isn't rushing into unknown
territory too quickly.

Margaret Mellon, director of the agriculture and biotechnology program for
the Union of Concerned Scientists in Washington, D.C., says: "There are a
lot of novel problems that come with treating animals as a drug production

One issue is how to assure that no viruses or other infectious agents -
including the prions that cause mad cow disease - creep into the finished
products, Mellon says. The FDA has no regulations governing either
transgenic animal health or the process of purifying drugs from milk, she

The drug producers respond that they are meticulous in quarantining and
testing their herds to assure that they are free of infection.

The FDA, for its part, points to the guidelines it issued in 1995 for drug
production in transgenic animals, which cover both animal health and drug
purification. These "provide sufficient guidance on what we consider
important," says spokeswoman Lenore Gelb, who says the agency has no plans
to issue formal regulations on the topic.

The guidelines were written in consultation with the transgenic drug
companies, which say they continue to discuss the issues with the FDA.

But guidelines aren't the same as regulations, says Mellon, and working them
out in private discussions with industry excludes the public from the

"Before these products start appearing in our pharmacies, there should be a
much broader debate about whether they are needed and what standards are
being used to assure safety," she says.

Mixing genes to create a drug-producing animal may still sound a bit
fantastic, but it is built on a technology that is nearly three decades old.
The first successful transfers of genes into mammal embryos were carried out
in the 1970s, most famously by Ralph Brinster at the University of

By the late 1980s, the ability to create transgenic animals had moved from
the research laboratory to the world of commerce, and Scotland's PPL
announcing the first transgenic sheep in 1987. Still, the process was slow
and building a herd big enough for drug-production was arduous until
scientists got the hang of cloning in 1996, when Dolly the sheep was born.

The drug Genzyme expects to take to the FDA by the end of this year is
antithrombin III, for use in heart bypass operations to make the clotting
agent heparin more effective in some patients.

Next year, Pharming and Genzyme hope to request FDA authorization to sell
the Pompe's disease treatment.

PPL Therapeutics Ltd. of Scotland has a target date of 2002 to enter the
U.S. market with a protein, made by some of its 1,000 New Zealand sheep,
that fights cystic fibrosis and congenital emphysema.

Sometime in the next few years, Centocor Inc., of Malvern, will seek FDA
approval to use goats to expand production of Remicade, the drug it already
markets to fight rheumatoid arthritis and Crohn's disease, an intestinal

The transgenic pipeline also includes collagen, a protein used by the body
in tissue repair; fibrinogen, a protein that can stanch bleeding from
wounds; additional rheumatoid arthritis drugs; and a treatment for
hereditary angioedema, a potentially fatal swelling of tissues and organs.

Though this roster suggests the breadth of possibilities for transgenic
drugs, many are still in early stages of development and may not pan out.

Development so far has cost hundreds of millions of dollars - Pharming has
spent nearly $100 million and Genzyme has raised $180 million - and profits
are still two to four years away.

If they come, companies may not pass lower production costs on to patients
but may instead keep the profits. This could boost the share price,
rewarding the investors who financed development but haven't yet earned a
penny of return.

Pharming, for one, is cautious in promising lower costs. For Factor VIII,
which induces blood clotting in hemophiliacs, "the goal is to lower
treatment cost, but that will depend on how efficiently we can make it, and
we don't yet know that for sure," says CEO Hersbach. Factor VIII is now
extracted from human blood plasma and made in cell culture. Animal
production is expected to increase the supply and perhaps to lower the price
to patients.

But the other promise of transgenics is to make more or better drugs

At Centocor, "I think of transgenic production as a way [to generate]
savings that can be invested into additional research on cures for other
diseases," says Fred Bader, vice president for worldwide operations at

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