GTC Biotherapeutics and Ovation Pharmaceuticals, Inc. have announced hat they are on the verge of receiving the US FDA approval for ATryn to treat hereditary antithrombin deficiency, a rare clotting disorder.
An expert panel voted overwhelmingly Friday that it is safe and effective. Atryn will become the first drug from a genetically engineered animal to be approved in the U.S. The agency is expected to make a final decision in early February.
GTC is raising genetically engineered goats on a farm in central Massachusetts to make a human protein in their milk that prevents dangerous blood clots from forming. The company extracts the protein and turns it into Atryn to fight strokes, pulmonary embolisms and other life-threatening conditions.
"We are very pleased with the Advisory Committee's recommendation in support of the safety and efficacy of ATryn," said Geoffrey F. Cox, GTC's Chairman and Chief Executive Officer. "ATryn is the first transgenically produced therapeutic to achieve approval in Europe and undergo review by the FDA. ATryn is also a testament to our established strength in recombinant technology, and has the potential to provide an important new treatment option for patients with hereditary antithrombin deficiency."
"The committee's recommendation takes us a step closer to making ATryn available to people in the U.S. with hereditary antithrombin deficiency, a rare clotting disorder associated with severe complications for which there are few treatment options," said Jeffrey S. Aronin, Ovation President and Chief Executive Officer. "Consistent with our overall focus on addressing unmet medical needs of small patient populations, bringing ATryn to market would give us the opportunity to make a meaningful difference in the lives of people suffering from this rare disorder."
Antithrombin works as a natural anticoagulant in the human body by regulating thrombin, which plays an important role in controlling the formation of blood clots. ATryn was developed with the key objective to provide the purity, safety and consistency of an unlimited supply of recombinant antithrombin. Purified recombinant antithrombin has the same amino acid sequence as antithrombin derived from human plasma.
People with hereditary antithrombin deficiency are at increased risk for venous blood clots, including pulmonary embolism and deep vein thrombosis. The prevalence of hereditary antithrombin deficiency in the general population is approximately one in 2,000 to one in 3,000. Half these patients may experience a thrombosis before 25 years of age 7 and based on one study, up to 85 percent may suffer a thromboembolic event by age 50.8.
To make ATryn, GTC used a microinjection technique to insert the human gene for antithrombin alfa into goat embryos. The protein is essential for preventing blood clots, but about 1 in 3,000 to 5,000 people are born with a genetic defect that prevents them from making enough of it.
Most patients are treated with standard blood thinners like warfarin, which can be dangerous for those undergoing surgery or childbirth. In those situations, patients are treated with antithrombin protein extracted from human plasma.
But the supply is limited. If all the plasma donated in the U.S. each year were used to make antithrombin, the most that could be produced would be about 100 kilograms. "We can match that with 150 goats," Tom Newberry, GTC's vice president for government relations said. GTC plans to expand the use of the protein beyond patients with the genetic defect to include people who have a short-term deficiency due to burns or other traumatic injuries, he said. The European Commission approved ATryn in 2006.
The company's scientists have made more than 100 proteins in the milk of genetically engineered animals.
But why goats in the first place? GTC says: Goats are an ideal dairy species. They have reasonably short gestation and maturation times, produce large volumes of milk with a high protein content, and are generally accepted as a source of dietary milk. They are relatively easy to breed and maintain. Goat milk has been extensively characterized biochemically, and this makes it more straightforward to develop protein purification procedures.
The most common adverse events listed in the approved European labeling that may occur during ATryn treatment include dizziness, headache, bleeding, nausea, bleeding at injection site and increased bleeding during treatment. As with any intravenous protein product, allergic type hypersensitivity reactions are possible.
The company is considering clinical trials for factor VIIa and factor IX proteins to treat hemophilia, along with alpha-1 antitrypsin to treat severe respiratory problems, Newberry said.
If approved, the drug would be followed by perhaps hundreds of others made from milk produced by genetically engineered goats, cows, rabbits and other animals. Other products in the pipeline are designed to treat people with hemophilia, severe respiratory disease and debilitating swollen tissues.
"As soon as we were able to make genetically engineered animals, this was an obvious thing to do," said James Murray, a geneticist and professor of animal science at UC Davis. "It's totally cut-and-paste. This is kindergarten stuff with molecular scissors."
The biotechnology industry is rooting for ATryn. The FDA's endorsement would signal to Americans that they have nothing to fear from the futuristic technology -- and suggest that the millions of dollars they've invested in the technology could soon begin to pay off.
If the drug is approved, "it takes a big question mark off the table in terms of products that are developed from this technology," said Samir Singh, president of U.S. operations for Pharming Group, which is developing medicines using milk from genetically engineered cows and rabbits.
The public has had misgivings about eating food from genetically modified animals, and some vocal critics of such technology say the wariness could extend to medicines.
"I think many people are going to have the same revulsion," said Jaydee Hanson, a policy analyst at the Center for Food Safety, a Washington advocacy group that opposes genetic manipulation of food and animals.
GTC is denying it is producing part-human goats. It says, "No, the piece of DNA coding for the human therapeutic protein that GTC introduces into the goat's genome is a small sequence that is linked to a goat milk-production sequence. Therefore, the new DNA will only be switched on in the mammary gland when the animal produces milk. It is not possible for such a small piece of DNA to create any kind of human tissue or features beyond its ability to express the human protein."
For scientists, the appeal is obvious. Many drugs are now synthesized in bioreactors by bacteria or Chinese hamster ovary cells, and they require extensive processing to be suitable for human use. Genetically engineering animals is a more straightforward alternative for producing proteins, which form the basis of all biological drugs, Karen Kaplan writes in Los Angeles Times.
"We're taking advantage of the fact that the mammary gland was designed by nature to make proteins," said Newberry of GTC.
Pharming, based in the Netherlands, plans to seek U.S. and European approval this year for Rhucin, made from a human protein purified from the milk of genetically engineered rabbits. The protein, C1 esterase inhibitor, helps control inflammation. Patients with hereditary angioedema have a genetic mutation that prevents their bodies from making enough of the protein, and the result can be severe swelling, abdominal pain and airway obstruction.
Pharming is focusing on cows to make other proteins in larger quantities. The company is working with the U.S. Army on cow milk containing human fibrinogen, a protein that helps blood to clot, Singh said.
Other companies are using genetic engineering to make milk with proteins for vaccines, a class of cancer drugs called monoclonal antibodies, and nutritional supplements.
Regulators will have their work cut out for them as they try to anticipate all the potential risks posed by genetically engineered animals and the medicines they produce, said Greg Jaffe, biotechnology director at the Center for Science in the Public Interest, a consumer advocacy group in Washington.