GTC Biotherapeutics ("GTC", NASDAQ: GTC and OVATION Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (FDA) approved ATryn® (Antithrombin [Recombinant]) for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. It is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients. ATryn is the first ever transgenically produced therapeutic protein
and the first recombinant antithrombin approved in the U.S. Along with the approval of ATryn, the FDA's Center for Veterinary Medicine also approved GTC's New Animal Drug Application, the first of its kind to regulate genetically engineered animals. This is now required for a recombinant technology used to develop transgenic animals, such as the goats that produce recombinant antithrombin. GTC has granted OVATION the right to market ATryn in the U.S. and pursue further clinical development. The companies expect ATryn to be available in the second quarter of 2009.
People with hereditary antithrombin deficiency are at increased risk for venous thromboembolic events, including pulmonary embolism and deep vein thrombosis, which can be life-threatening, particularly in high risk situations. Antithrombin is a natural anticoagulant that plays an important role in controlling the formation of blood clots. Purified recombinant antithrombin has the same amino acid sequence as antithrombin derived from human plasma.
"The approval of ATryn marks a significant milestone in the development of this innovative recombinant technology and delivers a new therapeutic option to benefit hereditary antithrombin deficient patients who are undergoing surgery or childbirth procedures," said Geoffrey F. Cox, Ph.D., GTC's Chairman and Chief Executive Officer. "Advancing this novel technology from the early days of demonstrating its capability to the daily practice of producing a safe and efficacious product for the U.S. and the European Union, is a testament to the persistence and capability of our employees."
ATryn was developed to provide a safe and consistent supply of recombinant antithrombin.
"With FDA approval of ATryn, we can help ensure that patients with hereditary antithrombin deficiency, a rare clotting disorder associated with severe complications, have access to much needed therapy," said Jeffrey S. Aronin, OVATION President and Chief Executive Officer. "Bringing ATryn to market gives us the opportunity to make a meaningful difference in the lives of people with this rare disorder and is consistent with Ovation's mission of addressing unmet medical needs of small patient populations."
The safety and efficacy of ATryn was established in clinical studies conducted in hereditary antithrombin deficient patients with a history of thromboembolic events in the U.S., Europe and Canada. During these studies, ATryn was shown to prevent the formation of clinically overt thromboembolic events. Post-marketing studies will be performed to assess safety and immunogenicity after repeat dosing.
The prevalence of hereditary antithrombin deficiency in the general population is approximately one in 2,000 to one in 5,000. Half these patients may experience a thrombosis before 25 years of age and, based on a study, up to 85 percent may suffer a thromboembolic event by age 50.
About ATryn
ATryn is the first recombinant antithrombin product approved in the world and the first antithrombin product that has been approved through the centralized procedure in the European Union. It is now also the first recombinant antithrombin product approved by the FDA.
Important Safety Information
ATryn is contraindicated in patients with known hypersensitivity to goat and goat milk proteins. Allergic-type hypersensitivity reactions, including anaphylaxis are possible. If these reactions occur during administration, treatment must be discontinued immediately and emergency treatment should be administered.
The anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, coagulation tests suitable for the anticoagulant used (e.g., aPTT and anti-Factor Xa activity) are to be performed regularly, at close intervals, and in particular in the first hours following the start or withdrawal of ATryn. Additionally, patients must be monitored for the occurrence of bleeding or thrombosis in such situations.
The serious adverse reaction that has been reported in clinical studies is hemorrhage (intra-abdominal, hemarthrosis and post procedural). The most common adverse events reported in clinical trials at a frequency of ? 5% are hemorrhage and infusion site reaction.
For more information including full prescribing information go to www.ovationpharma.com.
About Transgenic Production
The process for producing ATryn involves scientists inserting DNA for the human antithrombin protein into a single-celled goat embryo. This embryo is implanted into a surrogate doe. The resulting transgenic offspring are able to produce high levels of antithrombin in their milk. This protein is collected and purified from the milk to produce ATryn, which is administered to patients by intravenous infusion
GTC Biotherapeutics develops, supplies, and commercializes therapeutic proteins produced through transgenic animal technology. In addition to ATryn, GTC is developing a portfolio of recombinant human plasma proteins with known therapeutic properties. These proteins include recombinant forms of human coagulation factors VIIa, VIII, and IX, which are being developed for the treatment of hemophilia, and alpha-1 antitrypsin.
GTC also has a monoclonal antibody portfolio that includes a monoclonal antibody to CD20 and a monoclonal antibody to CD137. GTC's intellectual property includes a patent in the United States through 2021 for the production of any therapeutic protein in the milk of any transgenic mammal. GTC's transgenic production platform is particularly well suited to enabling cost effective development of proteins that are difficult to express in traditional recombinant production systems as well as proteins that are required in large volumes. Additional information is available on the GTC web site, www.gtc-bio.com .
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including without limitation statements regarding the commercial launch of ATryn in the U.S. and the prospects for further clinical development of ATryn. Such forward-looking statements are subject to a number of risks, uncertainties and other factors that could cause actual results to differ materially from future results expressed or implied by such statements. Factors that may cause such differences include, but are not limited to, the risks and uncertainties discussed in GTC's most recent Annual Report on Form 10-K and its other periodic reports filed with the Securities and Exchange Commission, including the uncertainties associated with dependence upon the actions of collaboration partners and regulatory agencies.
GTC cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this document, and GTC undertakes no obligation to update or revise the statements, except as may be required by law.
About OVATION Pharmaceuticals
OVATION is a fast growing ***aceutical company that develops and commercializes medically necessary therapies to satisfy unmet medical needs for patients with severe illnesses. Headquartered in Deerfield, Ill., with products available in more than 85 countries, OVATION is committed to having a significant impact on patients' lives through its focus on central nervous system (CNS), hematology/oncology, and hospital-based therapies. The company expects five new launches over the next three years, fueled largely by its late-stage CNS pipeline, which is one of the most robust in the industry. OVATION has been recognized for excellence in the global pharmaceutical and biotechnology industries with the 2006 and 2007 "Pharma Company of the Year" award from Scrip magazine for small to mid-sized enterprises. More information about the company, its products and full prescribing information may be found at www.ovationpharma.com .
欧洲药监部门专家组逆转先前决定，改为推荐批准ATryn上市
Reversal boosts ATryn prospects European panel now recommends GTC anti-clotting drug’s surgical use
By Lisa Eckelbecker TELEGRAM & GAZETTE STAFF leckelbecker@telegram.com
FRAMINGHAM — A European drug regulation committee reversed itself yesterday and recommended that a GTC Biotherapeutics Inc. anti-clotting drug drawn from the milk of genetically altered goats be approved for use in surgical patients.
The move clears away another hurdle for ATryn, a long labored-over drug that could become the world’s first human medicine produced in genetically engineered, or transgenic, animals. It also boosts GTC, which saw its stock tumble in February after European regulators said the company’s studies were insufficient to approve the drug.
“Certainly, for the company as a whole, this is a tremendous validation,” said Thomas E. Newberry, vice president of corporate communications.
GTC stock, which trades under the symbol GTCB, nearly doubled in value yesterday, rising 83 cents, to $1.81, on the Nasdaq Stock Market.
ATryn’s key ingredient is recombinant human antithrombin, a blood protein that blocks one of the body’s clotting substances. GTC has developed goats that carry the human gene for antithrombin. Female goats with the gene produce the protein in their milk, and the protein can be extracted and purified for use in human treatments.
The company operates a farm in Charlton for genetically altered, or transgenic, goats.
Final approval to sell ATryn could come from the European Commission in about three months, according to GTC. The initial European market for ATryn would be surgical patients with an inherited antithrombin deficiency, a relatively small population that regulators estimate could total one in every 3,000 to 5,000 patients.
Yet ATryn could be a foot in the door for GTC as it seeks to widen the use of ATryn and the acceptance of transgenic medicines. GTC is working with LEO Pharma A/S to develop ATryn in Europe as a treatment for clotting in sepsis patients who have acquired an antithrombin deficiency, a market with an estimated 220,000 Europeans a year.
GTC is also conducting U.S. studies of ATryn in an effort to seek Food and Drug Administration approval in mid-2007.
Rodman & Renshaw analyst Navdeep S. Jaikaria, who yesterday raised his rating on GTC stock to “outperform,” told clients in a note that ATryn approval was “in fact a milestone achievement for GTCB. This is the first time ever that a transgenic goat product is approved for any indication, which serves to validate GTCB’s proprietary technology platform.”
In a written release issued yesterday in London, the European Medicines Agency Committee for Medicinal Products for Human Use said it had initially considered GTC’s patient studies too small. The studies contained information on five surgical patients and nine women in childbirth. At first, the committee disregarded the data from the pregnant women and told GTC it had not provided data on at least 12 patients, as required.
The European committee also questioned manufacturing changes that GTC made after the data had been collected.
GTC asked the committee to re-examine the data, and the committee convened a panel of European experts on blood and blood clotting. Yesterday, the committee reported that it concluded it could use the data from all the patients because all faced the risk of blood clotting, but it restricted the drug’s use to nonpregnant patients.
The committee also reported that manufacturing changes made by GTC were slight and that “the benefits of ATryn outweigh its risks.”
Regulators have been cautious about the use of animals to produce medicines, even as many researchers have devoted their careers to the field and companies have labored on limited funding to advance the technology, said Eric W. Overstrom, professor and head of the department of biology and biotechnology at Worcester Polytechnic Institute.
“The whole concept of a bioreactor, an animal-based bioreactor, this will really push that forward now,” Mr. Overstrom said. “If they’re (GTC) the first ones in, then I think you’re going to see a rollout, a domino effect.”
News of GTC’s advance raised the price of at least one other transgenics company. Shares of Pharming Group NV of the Netherlands rose 15 percent, to 3.71 euros, in European trading.
GTC has long collaborated with corporate partners interested in exploring new production methods, such as Abbott Laboratories and Bristol-Myers Squibb. The company has also worked, with government backing, on a malaria vaccine that could be produced in goat milk.
An approval in Europe, however, could bolster GTC’s ability to raise money and attract partners. The company ended the first quarter of this year on April 2 with a net loss of $8.5 million, or 14 cents a share, and a cash cushion of $15.6 million.
Mr. Newberry of GTC said the European recommendation allows the company to look at a variety of new options.
“Clearly, with this sort of validation, ‘Great science, but can you do anything with it?’ is a long way to being answered,” he said.
Drugs from genetically engineered animals poised to debut in US
Friday, January 23, 2009 By Kristen Minogue
Medication from genetically engineered animals could appear as early as next month if, as anticipated, the Food and Drug Administration approves ATryn, a blood thinner made from the milk of genetically engineered goats.
An FDA committee gave a green light to the drug, manufactured by Framingham, Mass.-based GTC Biotherapeutics, on Jan. 9. The European Commission already approved the drug in August 2006, and the FDA could formally approve it for sale in the U.S. as soon as Feb. 7.
If the agency approved it, the drug could help treat patients with a rare blood-clotting disorder called hereditary antithrombin deficiency.
ATryn is just one of several drugs from gentically engineered animals that could start appearing on the market soon.
“Transgenic animals are probably going to be the drug stores of the future,” said biologist Bryan Pickett, who works with genetically engineered zebra fish at Loyola University of Chicago.
The FDA guidelines for such drugs, released on Jan. 15, outlined a much more stringent review process for genetically engineered animal products than cloned animal products. Unlike clones, which are supposed to be genetically identical to animals that already exist, genetically engineered animals have DNA from other organisms, often other species, inserted into their genome. Milk and meat from cloned cows, pigs and goats received a blanket approval from the FDA in January 2008.
The FDA evaluates every different "recombinant DNA construct "– foreign DNA inserted into an animal – on a case-by-case basis. Developers who want to market products from transgenic animals have to submit a new animal drug application to the FDA. Approval can take up to 10 months.
So far the only genetically engineered animals for sale in the U.S. are a glow-in-the-dark zebra fish sold in pet stores and laboratory animals like mice. The FDA hasn’t received any applications for genetically engineered meat.
Consumers are wary of the new technology. Of the 28,000-plus comments the FDA received on the draft guidelines last fall, the overwhelming majority opposed genetic engineering.
But that isn’t stopping developers, according to University of Illinois at Urbana-Champaign biologist Matthew Wheeler, who co-authored a report on the animals’ potential benefits last June.
Wheeler's report showed genetically engineered animals are popping up in dozens of sectors, including:
New Medicines – ATryn may become the first transgenic animal-produced drug to hit U.S. markets, but it’s not the only one that’s been developed. Researchers have created milk from genetically engineered sheep and pigs that can treat a rare type of hemophilia. Another strain of genetically altered pigs secretes milk with a hormone to help anemia patients produce more red blood cells.
Eco-friendly Animals – Researchers created the Enviropig in 2001, a pig that can excrete 60 percent less phosphorus than normal pigs, reducing pollution. Scientists at the National University of Singapore engineered the GloFish, a fluorescent zebra fish now sold in the U.S., to detect water pollution.
Human-Animal Transplants – Some have greeted this as the solution to the organ shortage problem. Transgenic pig hearts have lasted in baboons for up to six months. Researchers also hope insulin-producing pig cells could help diabetes patients and transgenic pig livers could act as temporary transplants while patients wait for permanent replacements.
Animal Health – Genetically engineered dairy cows are already able to begin resisting mastitis, an infection that decreases milk production, by secreting the bacteria-killer lysostaphin into their milk. Other possibilities include creating cows resistant to mad cow disease and brucellosis, a bacterial disease that can be transferred to humans.
Pickett said the risk of releasing potentially dangerous genetic materials is very low. But at the same time he respects the FDA’s regulation.
Meanwhile researchers are trying to calm any fears consumers may have about genetic engineering.
“I think all scientists really are for responsible, compliant and responsible, drug policy,” Pickett said.
Associate Director of AstraZeneca Transgenics and Comparative Genomics at AstraZeneca since 2000. Previously, he worked as a Senior Research Scientist for Glaxo Wellcome.
Jan Törnell Director of Transgenics and Comparative Genomics at AstraZeneca since 1996. In 1998, he was appointed Professor of Physiology at Gothenburg University.
Dr Jan Törnell, AstraZeneca Transgenics and Comparative Genomics, AstraZeneca R&D, S-431 83 Mölndal, Sweden Tel: +46 31 776 2469 Fax: +46 31 776 3700 E-mail: Jan.Tornell@astrazeneca.com
Those pharmaceutical companies whose goal is to generate novel innovative drugs are faced with the challenge that only a fraction of the compounds tested in clinical trials eventually become a registered drug. This problem of attrition is compounded by the fact that the clinical trial or development stage is by far the most costly phase of bringing a new drug to market, consuming around 80 per cent of the total spend. Transgenic technology represents an attractive approach to reducing the attrition rate of compounds entering clinical trials by increasing the quality of the target and compound combinations making the transition from discovery into development. Transgenic technology can impact at many points in the discovery process, including target identification and target validation, and provides models designed to alert researchers early to potential problems with drug metabolism and toxicity, as well as providing better models for human diseases. In target identification, transgenic animals harbouring large DNA fragments can be used to narrow down genetic regions. Genetic studies often result in the identification of large genomic regions and one way to decrease the region size is to do complementation studies in transgenic animals using, for example, inserts from bacterial artificial chromosome (BAC) clones. In target validation, transgenic animals can be used for in vivo validation of a specific target. Considerable efforts are being made to establish new, rapid and robust tools with general utility for in vivo validation, but, so far, only transgenic animals work reliably on a wide range of targets. Transgenic animals can also be used to generate better disease models. Predictive animal models to test new compounds and targets will significantly speed up the drug discovery process and, more importantly, increase the quality of the compounds taken further in the research and development process. Humanised transgenic animals harbouring the human target molecule can be used to understand the effect of a compound acting on the human target in vivo. Also, models mimicking human drug metabolism will provide a means of assessing the effect of human-specific metabolites and of understanding the pharmacokinetic properties of potential drugs. In toxicology studies, transgenic animals are providing more predictive models. A good example of this are those models routinely used to look for carcinogenicity associated with new compounds.
1、多肽类激素药：（1）人胰岛素，适应症是糖尿病。1982年第一个重组人胰岛素Humulin (Eli Lilly)上市，目前共有12种制剂（Novo Nordisk的8个速效、中效和长效重组胰岛素突变体在此仅计为1个），包括3个“重磅***”，Humulin（野生型胰岛素）、Humalog (Eli Lilly，胰岛素突变体)、Lantus (Anvents，胰岛素突变体)，2005年重组人胰岛素的销售额至少达75亿美元[14,16,18]。（2）人生长激素，适应症是生长激素缺陷、发育障碍和AIDS相关耗竭病。1985年第一个重组人生长激素Protropin(Genetech) 上市,现有8个品种。重组人生长激素的主要产品Nutropin/Protropin等在2005年的销售总额约为13亿美元[10，18，23]。（3）卵泡刺激激素（3个）和其他激素（7个），适应症是是不育症、调节排卵、更年期骨质酥松等，尚未形成很大的市场。
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