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Glyko Biomedical Ltd.'s 21%-owned affiliate, BioMarin Pharmaceutical Inc. and Genzyme General have announced detailed results from the six-month double-blind Phase 3 clinical trial of Aldurazyme(TM) (laronidase) and preliminary six-month findings from the trial's ongoing open-label extension study. Aldurazyme is an investigational enzyme replacement therapy for patients with mucopolysaccharidosis I (MPS I). Data from the extension study indicate that patients who received Aldurazyme for twelve months continued to improve upon the results seen in the first six months of treatment.

Ed Wraith, M.D., of the Willink Biochemical Genetics Unit at the Royal Manchester Children's Hospital, Manchester, UK, and one of the trial's clinical investigators, presented findings from both the double-blind and extension study portions of the Phase 3 trial the International Symposium on Mucopolysaccharide and Related Diseases in Paris, France. BioMarin and Genzyme will submit the six-month interim extension study data to the U.S. Food and Drug Administration (FDA) in the third quarter to complete their "rolling" Biologics License Application (BLA).

"The data presented... indicate that this is a promising treatment for the complex array of symptoms experienced by MPS I patients, who currently have no specific treatment available to them," said Dr. Wraith. "I am particularly encouraged by the results seen in patients who have now been on treatment for a full year."

Extension Study Results

All 45 MPS I patients from the six-month, randomized, double-blind, placebo-controlled Phase 3 trial were enrolled in the open-label extension study in order to further evaluate the safety and efficacy of Aldurazyme. Patients who were previously on placebo were switched to Aldurazyme for the extension study, while those patients who received Aldurazyme during the first six months of the trial continued to receive Aldurazyme via weekly infusions in the extension study.

The extension study includes analysis of the same two primary endpoints that were evaluated in the double-blind portion of the Phase 3 trial: pulmonary function, as measured by forced vital capacity (FVC), and endurance, as measured by the distance covered in a six-minute walk test. Patients who received Aldurazyme in the double-blind portion of the trial and who continue to receive treatment in the extension study maintained improvement in FVC, moving from a 5.3 percentage point mean increase in percent of predicted normal FVC during the first six months of treatment to a 5.9 percentage point mean increase after an additional six months of treatment as part of the extension study. These same patients improved from a 19.7 meter mean increase in the six-minute walk test over the first six months of treatment to a 42.9 meter mean increase after six additional months of treatment as part of the extension study.

During the extension study, patients who were switched from placebo to Aldurazyme experienced a slight decline in FVC compared to baseline (-0.6%) but began to improve during the second half of the six-month extension period. In the six-minute walk test, patients who were switched from placebo to Aldurazyme showed a mean improvement of 23.8 meters, which is consistent with the increase seen among patients who received six months of treatment with Aldurazyme during the double-blind portion of the trial.

Additional findings from the extension study have been generally consistent with results seen in both the Phase 1 trial and the double-blind portion of the Phase 3 trial: statistically significant reductions in liver size and in the excretion of urinary glycosaminoglycans (GAGs), the carbohydrate substances that accumulate in patients with MPS I. Patients who received Aldurazyme in both the double-blind and extension study periods maintained the reductions in liver size and urinary GAG excretion that were seen in the first six months of treatment.

The safety profile in the extension study has been comparable to the double-blind period. The most commonly reported reactions were fever, headache, rhinitis, and rash. One patient in the extension study died of causes considered by the principal investigator to be unrelated to treatment.

Double-Blind Phase 3 Results

In addition to the extension study data, Dr. Wraith presented a comprehensive review of data from the double-blind portion of the Phase 3 trial, from which preliminary results were announced last November. In the first six months of the trial, patients treated with Aldurazyme achieved a 5.3 percentage point mean increase in pulmonary capacity as measured by FVC compared to patients treated with placebo (p=0.016). In November, BioMarin and Genzyme reported a p-value of 0.028 for the FVC test, but subsequent analysis led to the revision to 0.016. In addition, patients demonstrated a positive trend in endurance as measured by a six-minute walk test, where they improved by a mean of 38.1 meters compared to patients treated with placebo (p=0.066). When analyzed by a prospectively defined parametric statistical analysis that accounts for pre-existing differences in individual patients, the six-minute walk test reached statistical significance (p=0.039).

Patients in the Aldurazyme group achieved statistically significant mean reductions in liver size (p=0.001) and urinary GAG excretion (p<0.001), consistent with the findings in the Phase 1 trial.

The sleep study, as measured by the apnea-hypopnea index, showed a positive trend (p=0.145) in the overall patient population. One post-hoc subset analysis of the 21 patients judged by the investigators to have clinically significant sleep apnea at baseline demonstrated a statistically significant improvement (p=0.037). Two additional secondary endpoints did not reach statistical significance: a health assessment questionnaire and shoulder range of motion.

The safety profile in the double-blind portion of the Phase 3 trial was comparable between the treatment group and the placebo group, with no Aldurazyme-related serious adverse events. The most commonly reported reactions were fever (14 patients on the placebo and 10 in the treatment group); headache (16 on placebo and 11 in the treatment group); rhinitis (10 on placebo and 8 in the treatment group); and rash (5 on placebo and 8 in the treatment group).

On Friday, June 21, Joseph Muenzer, M.D., Ph.D., associate professor of Pediatrics at the University of North Carolina, Chapel Hill, and also one of the clinical trial's investigators, presented new perspectives on the burden of illness among MPS I patients, which were derived from baseline evaluations of the 45 patients enrolled in the Phase 3 trial of Aldurazyme. Dr. Muenzer's analysis highlights the heterogeneity of the clinical effects of MPS I, which include organ damage, particularly to the liver and spleen, respiratory problems, musculoskeletal disorders, a high rate of infections, and gastrointestinal problems.

About MPS I

MPS I (also known as Hurler, Hurler-Scheie, and Scheie syndromes) is a life-threatening genetic disease caused by a deficiency of the enzyme alpha-L-iduronidase. This deficiency leads to the accumulation of complex carbohydrates (GAGs) in the lysosomes of cells, leading to the progressive dysfunction of cellular, tissue and organ systems. Resulting symptoms can include impaired cardiac and pulmonary function, delayed physical development, skeletal and joint deformities, reduced endurance, and in some cases, delayed mental function. A majority of patients die before adulthood from complications of the disease.

BioMarin and Genzyme formed a joint venture in 1998 to develop and commercialize Aldurazyme worldwide. Under the terms of the joint venture, if approved for commercial sale, BioMarin will manufacture Aldurazyme and Genzyme will have responsibility for the commercialization of the product. BioMarin and Genzyme have obtained Orphan Drug designation and Fast Track status for Aldurazyme for MPS I from the FDA and orphan medicinal product designation from the European Agency for the Evaluation of Medicinal Products (EMEA).

Glyko Biomedical Ltd.'s principal asset is a 21% ownership in the capital stock of BioMarin Pharmaceutical Inc.

Genzyme General develops and markets therapeutic products and diagnostic products and services. Genzyme General has five therapeutic products on the market and a strong pipeline of therapeutic products in development focused on the treatment of genetic diseases and other chronic debilitating disorders with well-defined patient populations. Genzyme General is a division of Genzyme Corp.

BioMarin Pharmaceutical specializes in the development and commercialization of therapeutic enzyme products to treat serious, life-threatening diseases and conditions.

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Publication:Worldwide Biotech
Geographic Code:1USA
Date:Aug 1, 2002

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