Summary of MPS Clinical Trials - December 2004

MPS I

Aldurazyme (laronidase), the pharmaceutical form of alpha-L-iduronidase, is an enzyme replacement therapy for the treatment of MPS I.

In the second quarter of 2003, BioMarin and joint venture partner, Genzyme Corporation, received U.S. Food and Drug Administration (FDA) and European Commission (EC) marketing approval for Aldurazyme for the treatment of MPS I. Subsequently, Aldurazyme was approved in Norway, Iceland, Israel, the Czech Republic, Australia, and Canada. Applications are currently pending in several other countries.

As the first therapy to be approved in the United States and European Union for the treatment of MPS I, Aldurazyme has been designated by regulatory authorities as an orphan drug, and as such, has been granted seven years of market exclusivity within the United States and 10 years within the European Union.

In May and June 2003, respectively, Aldurazyme became commercially available in the United States and European Union.

As of December 31, 2003, approximately 220 patients were receiving treatment with Aldurazyme of which approximately 65 percent were receiving commercial therapy. BioMarin and Genzyme continue to make progress in both its MPS I patient identification and Aldurazyme reimbursement efforts.

MPS II

Transkaryotic Therapies (TKT), Inc. released research findings October 28, 2004 at the American Society of Human Genetics 54th Annual Meeting evaluating intrathecal delivery of iduronate-2-sulfatase (I2S) in an animal model. The results showed that repeated injections of I2S were well tolerated and resulted in the accumulation of enzyme in various cells of the central nervous system (CNS). I2S is TKT's investigational enzyme replacement therapy for the treatment of Hunter syndrome, MPS II. In addition to the I2S CNS program, TKT is conducting a pivotal trial known as the AIM study (Assessment of I2S for MPS II) that is evaluating I2S as a treatment for the non-CNS aspects of Hunter syndrome through repeated intravenous infusion. TKT expects top-line data from the AIM study in the second quarter of 2005.

The primary goal of TKT's I2S CNS research initiative was to determine if I2S could be successfully delivered to cells of the central nervous system by way of intrathecal injections. I2S was administered as 1 ml bolus injections via the cisterna magna. Key research findings include:

  • Intracisternal injection of I2S results in a dose-dependent accumulation of I2S in the brain.  In contrast, intravenous injection of I2S does not elevate CNS I2S levels.
  • I2S is taken up primarily by the meninges after intracisternal injection, but also by perivascular cells, neurons and glial cells.
  • I2S was detected in lumbar cerebrospinal fluid after intracisternal injection with a peak at four to six hours and an elimination half-life of two to three hours.
  • I2S injected into the cisterna magna distributes throughout the cerebrospinal fluid and penetrates into the parenchyma of the brain.

TKT has advanced a program evaluating delivery of I2S directly into the central nervous system into preclinical development. If data from the preclinical testing are positive, TKT expects to file an Investigational New Drug Application to commence human clinical trials of its I2S CNS program in the first half of 2006.

On July 15, 2004, TKT announced that it had received fast track designation from the U.S. Food and Drug Administration (FDA) for iduronate-2- sulfatase (I2S) to treat Hunter syndrome (MPS II). TKT commenced a pivotal study with I2S in September 2003. The study, referred to as AIM (Assessment of Iduronate-2-sulfatase in MPS II) is a twelve-month, randomized, double-blind, placebo-controlled trial evaluating I2S in 96 patients. TKT expects top-line results from the AIM study in the second quarter of 2005 and, if positive, the company expects to submit applications for marketing approval in both the United States and Europe in the second half of 2005.

MPS III

TKT’s researchers have been working to understand how to administer treatments to specifically target the central nervous system of certain disorders.  TKT has been evaluating new approaches and if the results support it, the company hopes to conduct a trial to directly administer the enzyme into the central nervous system in MPS II patients in 2006, at the earliest.  TKT believes success with this program may enable the company to develop treatments for other lysosomal storage disorders with significant CNS involvement, including Sanfilippo syndrome MPS III.

MPS IV

In August 2004 Transkaryotic Therapies (TKT) announced that after a rigorous review process, they had made the difficult decision to suspend work on their Morquio program.  TKT believe the technical and regulatory challenges are greater than with other lysosomal storage diseases and plan to reallocate resources from the Morquio program to other programs in their pipeline.  TKT have decided to advance their Hunter CNS program, and believe success with that program may enable them to develop therapies for other lysosomal storage diseases with significant CNS involvement, such as Sanfilippo syndrome.   While they know this news will be disappointing, program development decisions such as these are part of TKT’s overall development strategy.

MPS VI

BioMarin Pharmaceutical Inc. announced 6th December that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency for Aryplase(TM) (galsulfase), an investigational enzyme replacement therapy for the treatment of mucopolysaccharidosis VI (MPS VI).

BioMarin has received orphan medicinal product designation for Aryplase in the European Union. Orphan medicinal product designation is conferred upon investigational products for diseases that affect fewer than five in 10,000 patients in the European Union. Products with orphan medicinal product designation that are the first to be approved for a specific indication have 10 years market exclusivity within the European Union.

BioMarin Pharmaceutical Inc. announced November 29, 2004 that it has submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for AryplaseTM (galsulfase), an investigational enzyme replacement therapy for the treatment of MPS VI.

At a pre-BLA meeting in September of this year BioMarin met with FDA to discuss key information on Aryplase to be included in the BLA. Consistent with this meeting, the fully electronic BLA filing includes a comprehensive set of preclinical, clinical and manufacturing related information on Aryplase. As part of the BLA submission, BioMarin has requested priority review, a request considered by the FDA for new product applications that address unmet medical needs. If the FDA accepts the BLA and grants the request for priority review, the FDA is expected to complete all aspects of the review and to take action on the application within six months of its submission. Aryplase has received fast track status and orphan drug designation. Orphan drug designation is conferred upon investigational products for diseases that affect fewer than 200,000 people in the United States. Products with orphan drug status that are the first to be approved for a specific indication have seven years of market exclusivity within the United States.

BioMarin Pharmaceutical Inc. announced June 3, 2004 positive phase III data on Aryplase™ for MPS VI. The company reported the following results:

  • The clinical trial demonstrated a statistically significant improvement in endurance (p=0.025) in patients receiving Aryplase 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 (p<0.001) in patients receiving Aryplase 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 (p=0.053) in patients receiving Aryplase compared to patients receiving placebo.
  • The results of the clinical trial indicate that treatment with Aryplase was generally well-tolerated. Adverse events during infusions were more common in patients receiving Aryplase but were generally mild to moderate in nature. The frequency of serious adverse events (SAEs) was more common in the placebo group.

MPS VII

Drs Emil Kakkis and William Sly have received a grant to develop enzyme replacement for MPS type VII. They are making steady progress with BioMarin Pharmaceutical, but no timeline for human clinical trials is projected.

Information regarding MPS VII taken from an article published www.emedicine.com May 12, 2003 titled Mucopolysaccharidoses Types I-VII Author: Janette Baloghova, MD, Lecturer, Department of Dermatology, Medical  Faculty, University of PJ Safarik at Kosice, Slovak Republic (Could not verify the above at the time of publishing)

News items for this article are sourced from the following:

http://www.biomarinpharm.com

http://www.tktx.com

BioMarin and TKT have provided additional information.  Please do not rely on the contents of this article without obtaining independent substantiation from your treating medical practitioner.

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