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Genzyme General and Pharming Group Report Results From First Two Clinical Trials for Pompe Disease

Posted on: October 06, 2000

Excerpt From Press Release—October 5, 2000

Genzyme General and Pharming Group N.V., announced today that results from the first two clinical trials ever conducted for Pompe disease were presented this week at the American Society of Human Genetics (ASHG) meeting in Philadelphia. Genzyme and Pharming are working in partnership to develop a treatment for Pompe disease and are associated with both clinical studies.

There is currently no effective therapy for patients who have Pompe disease, a rare and fatal genetic disorder caused by the lack of the lysosomal enzyme alpha-Glucosidase, which breaks down glycogen into glucose. The accumulation of glycogen in the heart and skeletal muscles of patients results in severe organ and tissue degradation. Pompe disease manifests itself in early or late-onset forms. Infants generally die before reaching 12 months of age, and the disease is typically fatal for those who develop symptoms as juveniles. Pompe disease affects an estimated 5,000-10,000 people in the developed world.

“The very encouraging clinical results achieved in both of these studies give us tremendous confidence about moving forward to complete the development of the first treatment for patients who are suffering from Pompe disease,” said Henri A. Termeer, chairman and chief executive officer of Genzyme Corp. “These results reveal the great progress that has been made and give us hope that a therapy for all patients with this devastating disease will be available in the near future.”

On Tuesday, Y.T. Chen, M.D., Ph.D., of Duke University presented results from an ongoing Phase 1-2 study being conducted at Duke Medical Center, in which three infants with Pompe disease have received enzyme replacement therapy for over one year. The patients have been receiving intravenous infusions of a recombinant form of the enzyme human alpha-Glucosidase produced in CHO cells.

The preliminary results from the trial indicate that the product is capable of improving cardiac and skeletal muscle functions. In two patients, left ventricular mass measurements decreased during therapy. The infants have each passed the critical age of one year (currently 15-, 17-, and 20-months old) and continue to show improved cardiac function, thus averting the progressive cardiomyopathy and heart failure that normally lead to death prior to age one in untreated patients.

Improvements of skeletal muscle functions have also been noted, although the significance and extent have been more variable than with improvements in cardiac function. One patient showed marked improvement and currently has normal muscle tone and strength, as well as normal neurological and motor development evaluations. Muscle biopsies confirmed that significant reductions in glycogen accumulation occurred in one patient after enzyme replacement therapy. The study data showed that the CHO-cell product was generally well tolerated.*see Excerpt of Chen’s Presentation that follows

Also at the ASHG (American Association of Human Genetics) meeting in Philadelphia (10-3-00), Dr. Ans T. van der Ploeg of Sophia Children’s Hospital in Rotterdam presented the results from a 36-week Phase 2 clinical trial of transgenic human alpha-Glucosidase. The trial results were published in The Lancet in July. The study was sponsored by Genzyme and Pharming.

In the trial, four infants with Pompe disease ranging in age from 2.5 to 8 months received weekly infusions of transgenic human alpha-Glucosidase. The starting dose was 15-20 milligrams of enzyme per kilogram of body weight. The dose was later increased to 40 mg/kg.

Results showed that transgenic human alpha-Glucosidase lowered lysosomal glycogen storage and improved tissue morphology. Total tissue glycogen content did not change. Skeletal muscle and strength improved, most significantly for the patient who had the least severe disease at the start of treatment. This infant reached milestones that are beyond expectations for a patient with the disease, including crawling and standing with the support of one arm at the age of 12 months. Improvements in motor function were also observed for all patients.

The most prominent effect of treatment was on the heart. By 36 weeks, cardiac size had decreased significantly to less than 30 percent of baseline. Left-ventricular posterior-wall thickness and left-ventricular mass index decreased in all patients.

All patients remain on therapy and have been treated for over a year. Adverse events such as fever, rashes, and flushing were transient and manageable by adaptation of the infusion rate and premedication.

Patient enrollment in the clinical trial evaluating the use of transgenic alpha-Glucosidase has been completed. All patients will continue to receive treatment with the transgenic product and will have the option of transitioning to the CHO-cell derived product.

Earlier this year, Genzyme obtained exclusive, worldwide rights from Synpac (North Carolina) Inc. to develop and commercialize the human alpha-Glucosidase product derived from CHO cells, shifting its focus from the development of human alpha-Glucosidase produced in the milk of transgenic rabbits. The decision to pursue the CHO-cell product was based on manufacturing considerations. Genzyme and Pharming believe that the CHO-derived product can be scaled to commercial production levels, qualified for use, and made accessible to patients faster than the transgenic product. This decision was not based on efficacy or safety concerns with either product. Clinical results obtained to date suggest that the CHO-derived and transgenic products show comparable clinical effects.

Genzyme and Pharming plan to initiate a second clinical trial of the CHO-cell product by the end of 2000 in patients with infantile-onset Pompe disease. The companies are currently in discussions with the U.S. Food and Drug Administration on the design of the trial, which is expected to involve medical centers in both the United States and Europe. Further details will be announced later this fall once the trial’s protocol has been finalized.. . . . . . . . .

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