Effective treatment is available for Fabry disease,
but early diagnosis remains a challenge

Genzyme Corp. announced today that results of its Phase 4 (post-approval) study of Fabrazyme^® (agalsidase beta) were well received by physicians attending the 5th European Roundtable on Fabry disease in Warsaw last Friday. The study shows that Fabrazyme slows progression of this very rare, and potentially life-threatening, hereditary disease. The findings also highlight the importance of early diagnosis and treatment, a theme reinforced by a number of speakers at the meeting.

The study – a multinational, multicentre, double-blind, placebo-controlled trial – is the largest ever conducted among Fabry patients, and measured the efficacy of enzyme replacement therapy on patients’ clinical symptoms and disease progression.

It was initiated by Genzyme in January 2001, and enrolled 82 male and female patients with mild to moderate Fabry disease. The participants were randomized in a 2:1 ratio to receive Fabrazyme at a dose of 1 mg/kg of body weight given every 2 weeks, or a placebo.

None of the patients had previously received targeted therapy for Fabry disease.

The trial’s primary endpoint sought to determine whether Fabrazyme would reduce the rate of occurrence of certain clinically significant events that mark the progression of Fabry disease.

Detailed results of the three-year study were presented at the Warsaw meeting by the trial’s principal investigator, Dr Stephen Waldek of Hope Hospital in Manchester, UK. The data show that Fabrazyme therapy slows the rate of progression of Fabry disease, as measured by the occurrence of clinically significant complications involving the kidneys, heart or cerebrovascular system (for example, stroke).

Subgroup analysis revealed that these clinical benefits of Fabrazyme therapy were most obvious among patients who started receiving the drug when their disease was at an early stage. “This underscores the importance of early diagnosis and prompt initiation of enzyme replacement therapy”, Dr Waldek said in his concluding remarks.

European regulatory authorities approved Fabrazyme as a treatment for Fabry disease in 2001, on the basis of results from a Phase1/2 dose-ranging study and a Phase 3 study which showed that Fabrazyme cleared GL-3 – globotriaosylceramide, a fatty substance – from tissues in the kidneys, heart and skin. The genetic defect underlying Fabry disease results in a deficiency of the enzyme needed to clear GL-3 from the body’s cells. Build-up of GL-3 in these organs is a hallmark of Fabry disease. Fabrazyme replaces the deficient enzyme, thereby preventing the damaging accumulation of GL-3. The study that has now been completed provides the first direct proof that dose-dependent clearance of GL-3 translates into clinical benefit.

Analysis of the data for all 82 patients enrolled in the Phase 4 study (the ‘intent-to-treat population’) showed that those who received Fabrazyme were 53% less likely to experience a clinically significant event compared to those with placebo, when adjusted for baseline proteinuria. A statistically significant 61% reduction in risk was achieved in the 74 patients who met the predefined study requirements (the per-protocol population). There was no difference among the Fabrazyme and placebo-treated groups in the incidence of serious adverse events during the study. As expected, infusion reactions occurred at a higher rate in the treatment group and most frequently consisted of mild fever and chills.

Improving care

The development of strategies to find patients with Fabry disease and get them started on effective therapy before potentially life-threatening complications have a chance to develop was identified by Roundtable participants as a key priority for improving patient care.

Despite considerable progress made over the past few years in raising physician awareness of Fabry disease – and other rare genetic diseases like it – a substantial proportion of patients are still receiving treatment too late, or not at all. “Quantification is difficult”, said Waldek, “but there are many Fabry patients worldwide who are not receiving the therapy they need”.

Genzyme and orphan diseases

Fabrazyme typifies the progress made through biotechnology and genetic research to bring breakthrough treatments for rare disorders to market. An estimated 6,000 diseases fit the regulatory authorities’ definition of a rare disease, in that each affects fewer than 5 in every 10,000 people in Europe. These disorders have been termed ‘orphan diseases’ because they are too rare to attract widespread interest from researchers and pharmaceutical companies. Taken together, they affect an estimated 20–30 million Europeans, which makes them a major health problem.

Fabrazyme is one of several enzyme-replacement therapies for orphan diseases developed and marketed by Genzyme, which pioneered this breakthrough approach to treatment in the 1990s. Other Genzyme products of this kind include Cerezyme^® (imiglucerase) for Gaucher disease and Aldurazyme^® (laronidase) for MPS I. A fourth product, Myozyme^® (alglucosidase alfa) for Pompe disease, is now in the final phase of clinical development and Genzyme plans to submit a marketing application for the product in Europe in December of this year.

About Fabry Disease

Fabry disease affects less than 10,000 people worldwide. The average life expectancy of patients with the disease is 43 years. The disease is caused by a deficiency of the enzyme alpha-galactosidase A, which leads to the progressive accumulation of lipids -- primarily GL-3 -- within cells of the kidneys, heart, and other organs. Clinical manifestations of the disease include renal failure, stroke, heart disease and debilitating pain. The accumulation of GL-3 in renal endothelial cells is thought to play an important role in renal failure.

About Genzyme

Genzyme Corporation is a global biotechnology company dedicated to making a major positive impact on the lives of people with serious diseases. The company’s broad product portfolio is focused on rare genetic disorders, renal disease, osteoarthritis and immune-mediated diseases, and includes an industry-leading array of diagnostic products and services. Genzyme’s commitment to innovation continues today with research into novel approaches to cancer, heart disease, and other areas of unmet medical need. More than 6,400 Genzyme employees in offices around the globe serve patients in over 80 countries.

Genzyme^®, Fabrazyme^®, Cerezyme^® and Myozyme^® are registered trademarks of Genzyme Corporation. Aldurazyme^® is a registered trademark of BioMarin/Genzyme LLC. All rights reserved.

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