The Study

The commentary about the study that I was a part of is as I see it.  This article was written by me Brian Daugherty and I have gotten my information from being in the study and doing some research on the Internet, as well as from talking with other people who were also involved in  the study. All information in this article has come from informaiuton that is readily available to the public.

Naglazyme™, a specific form of recombinant human N-acetylgalactosamine 4-sulfatase (also known as arylsulfatase B), is an investigational enzyme replacement therapy for the treatment of mucopolysaccharidosis VI (MPS VI).

MPS VI is a genetic disorder affecting approximately 1,100 people in the world and is characterized by a deficiency of an enzyme normally needed to breakdown certain complex carbohydrates. Without sufficient quantities of this enzyme, the normal breakdown of the carbohydrates is incomplete or blocked. The carbohydrate residue then accumulates in the cells, giving rise to MPS VI. Basically the stuff that is not broken down stays where it is, causing physical problems such as dwarfism and problems with mobility due to joints that look swollen, and swollen livers and spleens are common as well as respiratory problems and thickening of the valves of the heart. Naglazyme™ is designed to address the underlying cause of MPS VI and deliver the enzyme that MPV VI patients are lacking.

What is the Development and Regulatory Status of Naglazyme™?

BioMarin had three phases of evaluations for Naglazyme™ and it was approved for use by the FDA in late 2005 after being placed on a fast track due to the abnormal nature of the disease and the lack of any other drugs to prevent the disease from causing damage to the victims of MPS VI. Additionally, the European Commission (EC) has designated Naglazyme™ for the treatment of MPS VI as an orphan medicinal product in the EU.

What Data Exist on the Treatment of MPS VI Patients with Naglazyme™?

Phase 3 Data

In June 2004, BioMarin announced data from its Phase 3 multi-center, double-blind, placebo-controlled trial of Naglazyme™. The trial, which was designed to evaluate the safety and efficacy of Naglazyme™, enrolled 39 patients, ranging in age from 5 to 29 years, at six sites located throughout the world. Patients were randomized on a one-to-one basis into one of two groups: a Naglazyme™ treatment group or a placebo control group. Each group received a weekly intravenous infusion of 1.0 mg/kg of either Naglazyme™ or placebo solution for 24 consecutive weeks. During the 24-week period, 19 patients received weekly intravenous infusions of Naglazyme™ and 20 patients received weekly placebo infusions. One patient in the placebo group dropped out of the trial for reasons unrelated to treatment. Patients were evaluated at pre-defined, six-week intervals to assess changes in primary and secondary efficacy endpoints and the safety and tolerability of weekly Naglazyme™ infusions. Results of the trial are summarized below:

The clinical trial demonstrated a statistically significant improvement in endurance in patients receiving Naglazyme™ compared to patients receiving placebo as measured by the distance walked in 12 minutes, the primary endpoint in the trial. The data from the trial demonstrated a statistically significant reduction in glycosaminoglycans (GAGs) excreted in the urine in patients receiving Naglazyme™ compared to patients receiving placebo. GAG reduction was one of two secondary endpoints measured in the clinical trial. The 3-minute stair climb, another measure of endurance and also a secondary endpoint, demonstrated a positive trend in patients receiving Naglazyme™ compared to patients receiving placebo. The results of the clinical trial indicate that treatment with Naglazyme™ was generally well-tolerated. Adverse events during infusions were more common in patients receiving Naglazyme™ but were generally mild to moderate in nature. The frequency of serious adverse events was more common in the placebo group.

Long-term Results from Phase 1 and Phase 2 Studies

In November 2003, BioMarin reported encouraging long-term results from Phase 1 and Phase 2 clinical studies of Naglazyme™ in patients with MPS VI. Long-term data from both studies indicate that Naglazyme™ is generally well-tolerated and that patients continue to benefit from treatment.

Phase 2 Long-term Results

The Phase 2 open-label study enrolled 10 patients with MPS VI and evaluated a dose of 1.0 mg/kg, the higher of two doses investigated in the Phase 1 dose-ranging study. The study enrolled patients at two sites, one in the US and one in Australia. Data following 24 weeks of treatment with Naglazyme™ were reported in March 2003. Results after 48 weeks of treatment are summarized below:

Endurance as measured by distance walked in 12 minutes improved by an average of 139 percent (211 meters) over the baseline distance. This represents an average incremental improvement of 56 meters over the improvement observed after 24 weeks of Naglazyme™ treatment. The 12-minute walk test was the primary endpoint in the Phase 3 clinical study.
Endurance as measured by the number of stairs climbed in three minutes increased by an average of 147 percent (61 stairs) over the baseline number. This represents an average incremental improvement of an additional 13 stairs over the improvement observed after 24 weeks of Naglazyme™ treatment. The 3-minute stair climb was a secondary endpoint in the Phase 3 study.
Urinary GAG level, another secondary endpoint in the Phase 3 study, was reduced by 76 percent on average after 48 weeks of treatment with Naglazyme™. Reduction in GAG level was 71 percent after 24 weeks of treatment. GAG, the carbohydrate residue that accumulates in tissues of patients and causes MPS VI disease, is a biomarker for enzyme activity in vivo.
Sustained improvements were also observed in joint pain and stiffness, and variable improvements were observed in joint range of motion. Reduction in liver and spleen size was observed in all five patients presenting with hepatosplenomegally at baseline, and four of the five now have liver volumes in the normal range. Pulmonary function improvements were observed in several patients, primarily between 24 and 48 weeks.

Phase 1 Long-term Results

The randomized, double-blind, Phase 1 study initially investigated two doses of Naglazyme™ (0.2 mg/kg and 1.0 mg/kg) in two groups of three patients. Following positive results (announced in September 2001) after 24 weeks of treatment, all six patients continued to receive treatment at 1.0 mg/kg in an open-label extension study. Results after 96 weeks of treatment are summarized below:

Endurance as measured by the distance walked in six minutes improved by an average of 96 percent (120 meters) over baseline after 96 weeks of therapy. Gains in the 6-minute walk test were maintained or improved from week 48 to week 96 for the four evaluable patients in the study at the 96-week time point.
Urinary GAG level was reduced by 75 percent on average after 96 weeks of treatment. Patients who initially received the lower of the two doses experienced an incremental decrease in GAG level after receiving treatment with the higher dose.
Initial Results from Phase 1 and Phase 2 Studies

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