Clinical Trials MPS I Aldurazyme™, administered once-weekly, has been approved in the 15 countries of the European Union for long-term enzyme replacement therapy in patients with a confirmed diagnosis of MPS I, to treat the non-neurological manifestations of the disease. Aldurazyme™ was developed by BioMarin and Genzyme under a joint venture agreement that assigns commercial manufacturing responsibilities to BioMarin, and worldwide sales and marketing responsibilities to Genzyme. Genzyme will launch Aldurazyme™ in the European Union on a country-by-country basis, as pricing and reimbursement approvals are obtained. As the first orphan drug approved for MPS I in the European Union, Aldurazyme™ has been granted ten years of market exclusivity. Additional information can be obtained at www.aldurazyme.com or by contacting Genzyme at 800-745-4447. MPS I Intrathecal ERT for Spinal Cord Compression Enzyme replacement therapy (ERT) has been developed for mucopolysaccharidosis I (MPS I), a lysosomal storage disorder. ERT helps many physical ailments due to the disease, but does not treat the central nervous system, due to inability to cross the blood brain barrier. The purpose of this study is to test delivery of ERT to the spinal fluid via intrathecal injection in patients with MPS I. In this pilot study, recombinant human á-L-iduronidase will be administered intrathecally once per month for four months to individuals age 16 and older with the Hurler-Scheie and Scheie forms of MPS I and spinal cord compression. The age requirement may be changed in the near future to allow younger individuals to enter the study. For questions regarding age, please contact Dr. Dickson. If successful, intrathecal delivery could represent a practical, straightforward method of treating central nervous system disease due to lysosomal storage. Primary Outcomes: safety of intrathecal enzyme treatment by blood and spinal fluid tests each month; improvement in neurologic signs related to spinal cord compression, by neurologic examination and Japanese Orthopedic Association Scale each month; improvement in neurologic symptoms related to spinal cord compression, by subjective assessments and independence of functioning scale each month; improvement in mobility, by six-minute walk test each month; improvement in spinal cord compression by MRI imaging and somatosensory evoked potentials at baseline and 4 months; improvement in lysosomal storage by spinal fluid glycosaminoglycan levels at each treatment. Secondary Outcomes: improvement in spinal fluid pressure, by opening pressure measurements at each intrathecal treatment; improvement in hydrocephalus and other brain lesions by MRI at baseline and 4 months Expected Total Enrollment: 10 Additional information can be obtained at http://www.clinicaltrials.gov/ct/show/NCT00215527?order=1 or by contacting the Principal Investigator, Dr. Patricia Dickson, 310-222-4145 pdickson@ucla.edu MPS II Shire announced July 24, 2006 that the FDA has granted marketing approval for ELAPRASE, a human enzyme replacement therapy for the treatment of Hunter syndrome, also known as Mucopolysaccharidosis II (MPS II). Hunter syndrome is a rare, life-threatening genetic condition that results from the absence or insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. Without this enzyme, cellular waste products accumulate in tissues and organs, which then begin to malfunction. ELAPRASE is the first and only treatment approved for people suffering from Hunter syndrome. The product, which is given as weekly infusions, replaces the missing enzyme that Hunter syndrome patients fail to produce in sufficient quantities. Shire expects to launch ELAPRASE in the United States within the next 30 days. Shire submitted a Marketing Authorization Application (MAA) for ELAPRASE to the European Medicines Agency (EMEA) on December 1, 2005. Based on average evaluation times, Shire anticipates completion of the EMEA review by year end. In European countries that have mechanisms for pre-approval access, Shire has also submitted applications. Clinical Trial Results A 53-week, randomized, double-blind, placebo-controlled Phase II/III trial demonstrated that ELAPRASE provides clinically important benefits to Hunter syndrome patients. The primary efficacy endpoint of the trial was a composite analysis of changes from baseline in two clinical measures: a 6-minute walk test and percent predicted forced vital capacity. Shire is pleased to report that this endpoint achieved statistical significance compared to placebo. After one year of treatment, patients receiving weekly infusions of ELAPRASE experienced a mean increase in the distance walked in six minutes of 35 meters compared to patients receiving placebo. Safety Data Treatment with ELAPRASE was generally well-tolerated by patients in the Phase II/III trial. Adverse reactions were commonly reported in association with infusions, and were generally mild to moderate. The ELAPRASE label includes a boxed warning with information on the potential for hypersensitivity reactions. The boxed warning states that "Anaphylactoid reactions, which may be life threatening, have been observed in some patients during ELAPRASE infusions. Therefore, appropriate medical support should be readily available when ELAPRASE is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring." In all phases of clinical study for ELAPRASE, 11 patients experienced significant hypersensitivity reactions during 19 of 8,274 infusions (0.2%) and no patients discontinued treatment permanently as a result of a hypersensitivity reaction. The most common adverse events observed in >30% of patients during the Phase II/III trial were pyrexia, headache and arthralgia. Fifty-one percent (32 of 63) of patients in the weekly ELAPRASE treatment arm in the pivotal clinical study (53-week placebo-controlled study with an open-label extension) developed anti-idursulfase IgG antibodies. About ELAPRASE ELAPRASE is a purified form of the lysosomal enzyme iduronate-2-sulfatase and is produced by recombinant DNA technology in a human cell line. In conjunction with the market approval of ELAPRASE, Shire Human Genetic Therapies (the Shire business unit focused on genetic diseases) has introduced a new product support center called OnePathSM for the U.S market. OnePathSM is a single source of product support for healthcare providers, patients and their families, where personalized, comprehensive information about ELAPRASE is available from a case manager. Case managers can provide information about coding, reimbursement and insurance verification, authorization letters, product access and treatment center locations. OnePathSM also offers education about Hunter syndrome and can refer patients to additional support services, if needed. Additional information can be obtained at www.shire.com or by contacting OnePathSM toll free 866-888-0660. MPS III Shire Pharmaceuticals Group, formerly TKT, as part of their research to evaluate new approaches to the problem of treatment of the central nervous system, is hoping to move their MPS III-A program forward. If the trial to directly administer the enzyme into the central nervous system of individuals with MPS II is successful, they hope to expand their research initiatives to include MPS III-A. The Shire website is www.shire.com. MPS IV The Carol Ann Foundation and International Morquio Organization announced in December, 2005 that the Swiss company, Inotech will be promoting a clinical trial of enzyme replacement therapy for MPS IV-A. The company is aiming for the clinical trial to begin in 2007. They are encouraging families to enroll their children in the MPS IV registry, or if already enrolled, to update the information yearly, www.morquio.com. This natural history information is critical for drug development and follow-up. For more information, contact Mary Smith, President of the Carol Ann Foundation and International Morquio Organization, 520.744.2531, mbs85705@yahoo.com. MPS VI BioMarin Pharmaceutical Inc. announced June 1, 2005 that the U.S. Food and Drug Administration (FDA) has granted marketing approval for Naglazyme(TM) (galsulfase), the first specific therapy approved for the treatment of mucopolysaccharidosis VI (MPS VI). As the first drug ever approved for MPS VI, Naglazyme has been granted orphan drug status in the United States, which confers seven years of market exclusivity. Naglazyme is indicated for patients with MPS VI. Naglazyme has been shown to improve walking and stair-climbing capacity. As post-marketing clinical commitments, BioMarin has agreed with the FDA to evaluate the effect of Naglazyme treatment on skeletal dysplasia in patients under the age of 1 and to maintain a clinical surveillance program to monitor patients on commercial therapy; no extension study of Phase 3 patients was required. On September 15, 2005 BioMarin Pharmaceutical announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Evaluation Agency (EMEA), has issued a positive opinion on the company's Marketing Authorization Application for Naglazyme. The committee's proposed label states that Naglazyme is approved in the European Union as a long-term enzyme replacement therapy in individuals with MPS VI to treat the clinical manifestations of the disease. For more information, please contact BioMarin Patient and Physician Support (BPPS) at 866-906-6100 or bpps@bmrn.com. MPS VII A gene therapy clinical trial for mucopolysaccharidosis type VII (MPS VII), also known as Sly Syndrome in planned to begin as early as Fall 2006 at Washington University in St. Louis, MO. The target of this clinical trial will be the hematopoietic (blood) system. In this clinical trial blood stem cells from the bone marrow of patients with MPS VII will be isolated and a functional copy of the defective gene will be added into those cells. Not all patients with MPS VII will meet the criteria for inclusion into the clinical trial. Each patient will be evaluated by a team of physicians to determine eligibility. For additional information please contact: Mark S. Sands, Ph.D. Associate Professor of Medicine and Genetics Washington University School of Medicine Box 8007 660 South Euclid Avenue St. Louis, MO 63110 314.362.5494 (office) msands@im.wustl.edu