Genzyme General

April 20, 2000

Genzyme General Obtains Rights to Pompe Disease Therapy from Synpac
Genzyme and Pharming to Fund Commercialization

see press release April 20, 2000

Duke University

Clinical trials--
The following information was released at the AGSD-UK Conference
in Manchester, England on October 9, 1999

Alan Gilfoy, a representative of Synpac Pharmaceuticals, addressed the Pompe group at the fifteenth annual AGSD-UK (Association for Glycogen Storage Disease-United Kingdom) in Manchester, England on October 9, 1999. He stated that although he had little to say for now (it is too early in the trial for information to be released), they are satisfied with the performance of the trial at this point. The trial which has been in progress since May/June 1999, includes three infantile patients. Mr. Gilfoy stressed that Synpac is committed to the project and is hoping to progress the trial into phase III infantile trials next year.

Synpac (North Carolina) Inc., a drug development company and its parent company, Synpac Pharmaceuticals Ltd., of Cambois, England, has supported the research at Duke University (Durham, North Carolina) and is funding the current phase I/II trial under the direction of Y. T. Chen, M.D., Ph.D., Chief of Medical Genetics, Duke University Medical Center.

Synpac Pharmaceuticals Limited
Cambois, Bedlington, Northumberland NE22 7DB
Tel: (01670) 565656 Fax: (01670) 850571

I.S. Hodgson-Direct Line
Tel: 01670 565539
Fax: 01670 522459

Duke University Starts Clinical Trials for Pompe's Disease

The following status statement was released by Synpac (North Carolina), Inc., on June 30, 1999

On May 24, 1999, (see press release above article), Duke University announced the start of clinical trials to test the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) for the treatment of glycogen storage disease type II (Pompe Disease). The initial study will include up to three infantile patients who meet the inclusion criteria defined in the study protocol. Dr. Y.T. Chen, Chief of Medical Genetics at Duke, is the sponsor of the study. Synpac (N.C.), Inc., is funding the study and has provided the rhGAA.

Because it is known that individuals with Pompe disease lack the acid alpha-glucosidase enzyme, it has been proposed that enzyme replacement therapy with rhGAA would treat the symptoms related to Pompe disease, much like synthetic insulin can treat the symptoms of individuals with insulin dependent diabetes. When rhGAA was administered to an animal model of Pompe disease (Japanese quail that lack the same enzyme and have similar clinical features of Pompe disease), significant improvement in muscle strength was observed after three weeks. It is anticipated that if Pompe patients are treated with a manufactured version of acid alpha- glucosidase (rhGAA), the symptoms of Pompe disease may be alleviated. The current clinical trial is designed to test the safety and effectiveness of this enzyme in humans with Pompe disease.

It is important to note that rhGAA is not designed to be a cure for Pompe disease. Rather it is intended as a therapeutic agent to treat Pompe disease. The rhGAA will be administered intravenously to supplement the body’s insufficient supply of enzyme. It is anticipated that patients will require life long therapy with rhGAA.

Synpac plans to expand the trial to include juveniles and adults and to expand the trials to Europe; however, the timing and design of all phases of the clinical trials depend upon a number of factors including:

Analysis of results from the initial trial.
Questions that this first study is designed to answer include: Is the drug well tolerated? Are there side effects? Is there evidence of clinical benefit? In future studies, data will be generated to determine what the effective dose will be and how frequently it will need to be administered.

Review and permission of regulatory agencies.
The Food and Drug Administration (FDA) must review the drug safety and tolerance data generated during this first phase and grant permission to expand the number patients. All efforts are directed at moving this product through the regulatory requirements as quickly as possible, while assuring the safety and clinical benefit of the product. Advantage will be taken of the provisions for rapid approval through the FDA.

Continued manufacturing success
Manufacturing Plans: Manufacturing efforts must continue to be successful as we expand production to meet anticipated demands. Although the trials have just begun, Synpac has already started developing a full scale manufacturing program to generate a drug supply sufficient for the anticipated market of infants, juveniles, and adults. We anticipate the clinical trials will progress in parallel with the manufacturing efforts to increase supply.

Manufacturing Methods: To manufacture the rhGAA, Synpac is using a Chinese hamster ovary (CHO) cell line, which Dr. Chen’s laboratory at Duke genetically engineered to contain the human GAA gene. As the cells grow in a nutrient rich broth, they secrete the rhGAA enzyme into the broth. The enzyme is then purified from the broth through a series of filtering and sieving devices. CHO cell technology is not new and has been used for many years to manufacture a number of medical products on the market.

Manufacturing Capabilities: Synpac initially produced a preliminary drug supply in a small pilot manufacturing facility. However, Synpac has now moved its manufacturing efforts to an established contractor with large scale manufacturing capabilities. By using a contract manufacturer, Synpac avoids the major investments of both time and costs required to build a manufacturing facility and gains the expertise of a team of scientists who have prior experience manufacturing similar proteins.

"It is our goal to insure a continuous drug supply to all patients enrolled in clinical trials."

Pompe disease therapy to be tested

DURHAM, N.C.—Duke University Medical Center has announced the beginning of Phase I/II clinical trials to test an enzyme replacement therapy for Pompe disease, an inherited glycogen storage disease that is usually lethal in children but afflicts people of all ages.

Pompe disease is rare, affecting approximately one child in 100,000. If symptoms appear during infancy, death usually occurs before the age of 2. The disease is usually less severe when symptoms first appear late in childhood, but life expectancy extends only into the second or third decade in such cases. Adults can be affected by a milder form of the disease but are still incapacitated.

Pompe disease is caused by the lack of an enzyme that breaks down glycogen into glucose, a primary source of energy. In patients with the disease, glycogen accumulates, destroying skeletal , heart and lung muscles. The enzyme replacement therapy, to be administered by infusion, is intended to restore glycogen levels in muscle tissue to normal. The treatment, if successful, will be required for the remainder of a patient’s life.

The Phase I/II clinical trials will be conducted at Duke Medical Center under the supervision of Dr. Y.T. Chen, chief of the division of medical genetics in the department of pediatrics. Chen is the principal investigator on an Investigational New Drug (IND) application on file with the Food and Drug Administration.

Chen’s team at Duke spent more that five years developing the recombinant enzyme and has shown that the enzyme helps relieve symptoms of Pompe disease in animals.

Chen said he was delighted to see the research team’s laboratory work become something with a real potential to help families affected by this disease.

"This is something we have been working toward for quite some time," Chen said. "Everyone in the division has been eagerly looking toward this date, and we are pleased to be able to more our work forward to this next step."

In anticipation of this clinical trial, Chen has assembled a comprehensive team of medical professionals. In addition to physicians Dr. Andrea Amalfitano, Dr. Priya Kishuani, and Dr. Dietrich Matern, the Pompe team is composed of David Millington, Ph.D., director of the Duke mass spectrometry laboratory; Joanne Mackey, pediatric nurse practitioner; and Jennifer Sullivan, a genetics counselor—all members for the Division of Medical Genetics. Duke physicians Dr. Richard Morse, in pediatric neurology; Dr. Marc Majure, in pediatric pulmonary; and Dr. Resai Bengur, in pediatric cardiology, also will contribute their expertise to the project.

"We are proud to have played a role in encouraging and supporting this work," said Dr. Michael Frank, chairman of the medical center’s department of pediatrics. "With the addition of the new McGovern-Davison Children's Health Center of the Duke Health System, we hope to continue our department’s rewarding relationship between scientific research and clinical medicine.

The Phase I/II clinical trials is expected to last six months and will, for the first time, test both the safety and efficacy of this product in humans. Up to three infants who meet the admission criteria for the trial will be treated with the genetically engineered form of the enzyme.

Synpac (North Carolina) Inc., a drug development company in Research Triangle Park, and its parent company, Synpac Pharmaceuticals Ltd., of Cambois, England, have supported the research at Duke and the production of clinical grade material, which have made the new therapy possible. Synpac will fund the Phase I/II trial at Duke. If this initial trials is successful, Synpac is expected to extend the infant trials into Phase III clinical trials and will plan clinical trials in juveniles.

"We are delighted to have this great opportunity to collaborate with Dr. Y.T. Chen and Duke University to develop potential therapy for this dreadful disease," wrote Leslie Koo and Dr. Andrew Huang, leaders of Synpac (North Carolina) Inc., in a joint statement. "This joint effort combines the best of academia and industry for the benefit of society."

Synpac acquired rights in the technology from Duke in 1996 and has been working since that time to prepare the enzyme for clinical trials. Duke and Synpac have been assisted in the preparation of the IND and in the development of the product by Cato Research Limited, a contract research organization based in the Research Triangle Park.

Duke
University

Duke Researchers Develop First
Treatment for Rare Muscle Disease

News Release written by Karyn George -
Duke Medical Center News Office 02/14/98  

 
Saturday, Feb. 14, 1998
Contact: Karyn Hede George (919) 684-4148

DURHAM, N.C. – Researchers at Duke University Medical Center have demonstrated for the first time that it is possible to regenerate functional muscle in a rare type of muscular dystrophy. Based on their successful tests in animals, they have been working closely with the federal Food and Drug Administration to begin using the treatment in children with a fatal muscle-wasting condition called Pompe disease. The injectable enzyme treatment was developed by Duke pediatric medical geneticist Dr. Yuan-Tsong Chen. He said it is the first therapy to show promise in any type of a genetic muscle-wasting disease.

Muscular dystrophy is a broad category of inherited diseases in which the body's muscles don't function normally. Usually, an important muscle protein is missing or defective. Many doctors have been unsure if it is even possible to regenerate muscle tissue that has been damaged in these muscle-wasting diseases. Chen has now shown it is possible in principle to replace a missing component of muscle and improve muscle strength. "This is a major milestone is our long-term efforts to develop an effective treatment for this devastating fatal disease," Chen said.

The scientists reported their findings in the Feb. 15 issue of the Journal of Clinical Investigation. The research was supported by grants from Synpac Pharmaceuticals Ltd., the Japan Health Science Foundation and the Muscular Dystrophy Association.

Within this year, Chen and his colleagues expect to treat children born with the rare and always fatal Pompe disease, which is caused by an inherited defect that results in a deficiency in an essential enzyme called acid alpha glucosidase (GAA). Normally the GAA enzyme helps the body break down stored glycogen into glucose, a sugar the body uses for energy. Without the active enzyme, stored glycogen builds up in the body's muscles, eventually destroying them.

About 100 children are born with Pompe disease each year in the United States. In a severe form, the disease is always fatal, usually within the first two years of life. Chen and Duke colleagues Helen Wen Yang, Mark Pennybacker, and Johan L.K. Van Hove had been searching for an effective treatment for Pompe disease for several years. The treatment they developed is similar to that used to treat children with the "bubble boy" disease, a deficiency in the enzyme adenine deaminase (ADA). In each case, the first available treatment was injecting a missing enzyme into the bloodstream.

"But for Pompe disease, previous attempts at enzyme replacement therapy failed because the enzyme was not taken up by the muscle cells," Chen said. "We circumvented this problem by using the body's own system to get the enzyme inside muscle cells." Chen solved the problem by purifying a form of the enzyme that has a modified residue attached to the sugar molecule of the enzyme. The modified molecule is recognized by special muscle cell receptors, which then trigger the cell to engulf the enzyme and direct it to where it is needed.

The researchers used molecular biology techniques to insert the human gene for GAA into a common type of cell grown in the laboratory. These cells act like a mini-factory, churning out human GAA enzyme. After several years of experimentation, Chen and his colleagues obtained enough purified enzyme to begin tests on laboratory animals.Chen collaborated with Tateki Kikuchi and Nobutsune Ichihara of the National Institute of Neuroscience, Tokyo, and Makoto Mizutani of the Nippon Institute for Biological Science, Kobuchizawa, Japan, who developed a strain of Japanese quail also missing GAA. These birds can't fly and when turned on their backs can't right themselves. The team of researchers used three test groups of birds. Two birds were injected with a high dose of purified human GAA, two with a low dose of GAA, and two were injected with salt solution. Each bird received seven injections over a 16-day period. Two days after the last injections, the scientists evaluated the birds' ability to right themselves. The high-dose GAA treatment improved muscle strength so much that both birds could right themselves when flipped on their backs. One bird could even fly a short distance. Tests showed these birds had an increase in GAA activity and decreased muscle glycogen and improved muscle structure. The low-dose birds showed similar improvements, but to a lesser degree. Because quail GAA and its human counterpart are not identical, researchers expected that the human form of the enzyme would not be as effective in quail. Laboratory tests revealed that quail muscle requires a higher dose of human GAA to restore active enzyme levels to normal.

"Based on these results, we believe this enzyme is a promising therapy for the human form of Pompe disease," Chen said. He said he will initially attempt to treat only a small number of children. "If it is successful, children will need a supply of the enzyme for their whole lives," he said. Synpac Inc. of Middlesex, England, will supply the enzyme for the clinical trial.

Chen, one of a handful of experts in Pompe disease worldwide, confirms diagnosis on children born with Pompe disease in the United States. He and his colleague Dr. Andy Amalfitano are also developing a gene therapy strategy for treating Pompe disease. They hope to inject a working copy of the gene into muscle cells using a modified virus to carry the gene into cells. If successful, a gene therapy strategy would allow the muscle to generate its own enzyme and eliminate the need for lifetime injections of the enzyme. "We are hopeful that eventually we will be able to provide a child born with Pompe disease several options for treatment, and even a cure, within our lifetime," Chen said.

Synpac Pharmaceuticals Limited
Cambois, Bedlington, Northumberland NE22 7DB
Tel: (01670) 565656 Fax: (01670) 850571

I.S. Hodgson-Direct Line
Tel: 01670 565539
Fax: 01670 522459

PRESS RELEASE
October 1997

SYNPAC SPONSORS RESEARCH INTO POMPE DISEASE

Synpac Pharmaceuticals Limited (U.K.) Cambois, have been helping to sponsor research into a hereditary condition called Pompe Disease for over 3 years. The research, carried out by Dr. Y.T. Chen and a team of scientists at Duke University in North Carolina, U.S.A., is aimed at finding a treatment for this often fatal disease that can afflict children.

Pompe disease is an incapacitating condition caused by a deficiency of the enzyme known as acid alpha glucosidase. This enzyme normally converts cellular stores of glycogen into glucose. Patients suffering from Pompe disease lack sufficient enzyme for that chemical conversion and as a result, glycogen accumulates and destroys skeletal, heart and lung muscles.

Pompe disease is rare, affecting approximately one child in every 100,000. If symptoms appear during infancy, death usually occurs before the age of 2. The disease is usually less severe when symptoms first appear in later childhood but life expectancy is reduced. Adults can also be affected by a milder form of the disease which can cause respiratory insufficiency.

The U.S. Food and Drug Administration (FDA) has approved Duke University's application for Orphan Drug Designation for the new therapy. This is one of the first regulatory steps in developing a treatment for a rare disease and allows the University to apply for FDA grants to support clinical trials.

The gene for human acid alpha glucosidase has been introduced into a mammalian cell line by Dr. Chen's research team. Initially, the genetically engineered form of the enzyme will be tested in a small number of Pompe disease infants to evaluate the safety and efficiency of the recombinant enzyme treatment. Dr. Chen hopes to begin the first clinical trial in the U.S. in 1998.

The start of the first trial is dependent upon further evaluation for the FDA. It the enzyme replacement therapy is successful and gains FDA approval, Synpac will manufacture and market the treatment initially in the U.S.A.

"Synpac, as part of the Koos Group of Taiwan, have been delighted to support this exciting research by Dr. Chen's team at Duke University. We are still at an early stage of development but if successful, the enzyme therapy will save children's lives. Dr. P.I. Clark, Deputy Managing Director, Synpac Pharmaceuticals Ltd., Cambois, England."

Duke
University

September 2, 1997

Contact: Andrew E. Balber
919-684-6502

DUKE OBTAINS FDA DESIGNATION
FOR POMPE DISEASE THERAPY

Durham, N.C.--The U.S. Food and Drug Administration has approved Duke University's application for Orphan Drug Designation (see general information) for a new therapy for Pompe disease, an inherited and usually lethal glycogen storage disease that often afflicts children, Duke officials announced.

This designation makes Duke eligible for FDA grants to support a clinical trial of the therapy. Duke University Medical Center researchers hope to begin that trial in 1998.

Pompe disease is an incapacitating condition caused by an inherited deficiency of the enzyme acid alpha glucosidase. Acid alpha glucosidase normally degrades cellular stores of glycogen into glucose, a primary energy source. Patients suffering from Pompe disease lack sufficient enzyme for that chemical conversion. As a result, glycogen accumulates and destroys skeletal, heart, and lung muscles.

Pompe disease is rare, affecting approximately one child out of every 100,000. If symptoms appear during infancy, death usually occurs before the age of 2. The disease is usually less severe when symptoms first appear later in childhood, but life expectancy extends only into the second or third decade in such cases. Adults can be affected by a milder form of the disease but are still incapacitated due to respiratory insufficiency.

Initially, the therapy developed at Duke will be tested on infants with.the most severe symptoms and for whom the disease is fatal. The Duke clinical trial will test a genetically engineered form of the enzyme, expressed in a cell line developed in the laboratory of Dr. Y.T. Chen, chief of the Division of Medical Genetics in the department of pediatrics. Initially, the drug will be tested in a small number of Pompe disease infants to evaluate the safely and efficacy of the recombinant enzyme treatment. Enrollment will be based on strict FDA approved clinical criteria.

Chen, who will lead the clinical trial, anticipated that recombinant enzyme injected into infants will be taken up by their muscle cells and restore normal glycogen levels. This treatment, known as an enzyme replacement therapy, would be required for the rest of these patients' lives.

He said he hopes to expand the treatment to additional Pompe disease patients as safety and efficacy are demonstrated and supplies of the enzyme are available.

Chen's team at Duke has spent more than five years developing the cell line that produces the recombinant drug. The work was funded by a combination of private contributions, foundation grants, and industrial support form Synpac Pharmaceuticals Ltd. in the United Kingdom.

If the enzyme replacement therapy proves successful and gains FDA approval, Synpac will continue to manufacture and market the drug.

Commenting on the FDA action, Chen said, "After treating patients who have very little hope and working on this therapy for so many years, I look forward to working with the FDA to bring this therapy into the clinic. This is a major milestone in our efforts to develop an effective treatment of this fatal disease."

Dr. Michael Frank, chairman of the department of pediatrics at Duke, added: "Dr. Chen's efforts are an excellent example of the way that basic research and clinical applications come together at Duke to provide care for children and hope for their families. He is building this new therapy while we are building our new Children's Hospital.

"I hope that his efforts and ours converge in the near future and that we will be able to provide enzyme replacement for Pompe disease as one of the advanced therapies we offer in our new outpatient children's facility in the near future."