Metachromatic Leukodystrophy Research

In this therapy, the missing enzyme (Arsyl A) is replaced by a man-made recombinant biotech ASA enzyme called HGT-1111 (an interim name as of August 2008 for the product formerly called Metazyme) that is injected into the MLD affected person in place of the missing natural enzyme. A Danish company, Zymenex, has been pioneering this research and have created the recombinant biotech ASA enzyme called "Metazym". They started their research in 2004, moved to Phase 1 (safety) Clinical Trials in Denmark in late 2006, and European Phase II (efficacy) Clinical Trials in early 2007.

[May 2008] Metazyme was sold by Zymenex to Shire HGT in April 2008. The product's interim name has been changed to HGT-1111. The schedules, trials, and projects remain intact as best we know. Shire is "digesting" the acquistion and will update us shortly. As we get updated information we will update this page.

A US Natural History Study started in February 2008 and the enzyme has received FDA IND approval, the first step to starting US Phase II Clinical Trials. Details follow.

NOW RECRUITING - MLD NATURAL HISTORY STUDY - ALL LATE INFANTILE FAMILIES ARE ENCOURAGED TO REVIEW THE INFORMATION HERE.

May 2007 - European Phase I clinical trials, update to the MLD Foundation, and press release

For clarity - a listing of Shire's currently underway and announced studies and trials:

Phase 1 & 2 European Clinical Trials (at 52 week P-II stage) #NCT00418561
A European continuation "trial" to continue the same 12 European patients on the current European Phase II trial. #NCT00633139
US Natural History Study at UNC - approved by the FDA 2/2008 (now recruiting)
US Phase II Clinical trials for Metazym Formal press release here.
- IND Approval from the FDA - completed 2/2008
- IRB approval from UNC - anticipated late summer 2008 (recruiting starts after IRB approval)
- Clinical Trial to start - anticipated late summer/early fall 2008 ... as of November 2008 Shire has not started Clinical Trials ... we expect another few months of delay.
- Clinical Trial to run - anticipated 12-18 months completion late 2009/early 2010

April 24, 2008 Update - Shire Acquires Metazym from Zymenex

Shire HGT has acquired Metazym from Zymenex for $135M. Shire will continue to expedite the testing and market release of Metazym. Shire can and will likely apply significant corporate resources to these later stage tests and an expedited market release.

This is exciting for MLD affected families. Shire can and will likely apply significant corporate resources to these later stage tests and an expedited market release. In addition, this external endorsement of Metazyme seems to validate the effectiveness of this ERT in advance of seeing Zymenex's published Phase II European clinical trial results.

Metazym is nearing completion of Phase II clinical trials in Europe. An IND has been granted by the FDA to prepare for Phase II clinical trials in the US. In addition, Orphan Drug Status has been granted in both Europe and the US for Metazym.

The Zymenex press release can be seen here.

We will post more details as they come available.

April 15, 2008 Update - Metazym Receives Orphan Drug Status

The FDA has granted Zymenex's Metazym enzyme replacement therapy drug Orphan Designation status. Metazym already has European Orphan Drug Designation by the EMEA.

The Orphan drug act of 1983 established an "orphan drug" status to encourage the development of drugs for rare diseases that would otherwise be too expensive or un-profitable to develop based on the small target markets fro these drugs. To offset the high costs of research and development of drugs for rare diseases companies are incentivesed with tax credits and seven year post-approval marketing exclusivity. There is also now the potential of seeking a federal government grant to offset some of the costs of clinical trials but this was not part of the Zymenex announcement.

We know that Zymenex has been working for more than a year to obtain this designation in the US and we expect orphan designation will further encourage them in their pursuit of FDA approval in the US market.

In earlier discussions with Shire, the US pharmaceutical company working on an Enzyme Replacement Therapy, they indicated that they thought their therapy was different enough that they would not be inhibited by the marketing exclusivity incentives if orphan designation were granted to Zymenex, however, we have not had a formal response from Shire since this announcement.

Read the press release here.

March 10, 2008 Update - US Phase II Clinical Trials Announced

The FDA has approved the Metazym IND (Investigative New Drug) application enabling Zymenex (now Shire HGT)to start US Phase II Clinical Trials for their ERT (enzyme replacement therapy) Metazym (now HGT-1111). The Clinical Trials will be done in conjunction with Dr. Maria Escolar at the University of North Carolina. It is anticipated the actual Metazym MLD Clinical Trial will start in late summer or early fall.

The IND is the FDA's approval to proceed and the first step before the actual Metazym MLD Clinical Trial can start. The second is formal approval by the UNC IRB (institutional review board) of the specific protocols of the trial, and the third is the contract and logistics between Zymenex and UNC. These next two steps are expected to take 6 months and then the trial can begin. It's kind of like getting the building permit for a new home - the contracts have to be signed and the house built before we can move in.

The details of the inclusion/exclusion criteria have not been formally announced and will likely not be announced until the IRB approval is obtained. We will post the details as soon as they are announced. However, the criteria is likely to be similar to the criteria used in the Danish Clinical Trials that started in 2007. Click to see the Danish Phase II criteria.

Patients are not yet being recruited for the trial. We will announce this as soon as recruiting starts.

The results of the Clinical Trials will be compared to the background of the Natural History captured in the Natural History Study (see below) to show the efficacy (effectiveness) of the Metazym ERT.

The US Phase II trial will include 10 patients with late-infantile MLD and will be performed by Dr. Maria L. Escolar at the Program for Neurodevelopmental Function in Rare Disorders, Center for the Study of Development and Learning, University of North Carolina (UNC), Chapel Hill, North Carolina, USA. University of North Carolina, Chapel Hill, North Carolina, USA and is being performed by Dr. Maria Escolar at the University of North Carolina, Chapel Hill, North Carolina, USA, with support from the Danish biotech company Zymenex. Read the formal press release here.

The MLD Foundation continues to advocate for families as we meet, under NDA, with ZYmenex, most recently in late February in Copenhagen, to discuss the progress in getting Metazym tested and approved. We will continue to work closely with Zymenex and Dr. Escolar to provide timely information about research and study progress.

The MLD Foundation is pleased to have been a financial supporter of Zymenex in the research that has lead to these US-based trials. We have also been active at the NIH/ORD and the FDA's Office of Orphan Products facilitating bringing these trials to the US.
Contact information

Dr. Maria Escolar, MD
FPG Child Development Institute
University of North Carolina
Chapel Hill, North Carolina, USA
telephone: +1 919-966-4810
Maria.Escolar@CDL.UNC.EDU

February 29, 2008 Update - US MLD Natural History Study Underway

The FDA has approved a Natural History Study of MLD to formally describe how the untreated disease develops to provide the details of an untreated baseline for the progression of MLD to enable a comparison of the outcome of a planned US clinical trial of Shires ERT, HGT-1111 (formerly Zymenex's ERT, Metazym).

Patients are currently being recruited for this Natural History Study. The study will includes 10 patients with late-infantile MLD, and has been approved by the IRB (Internal Review Board) at University of North Carolina, Chapel Hill, North Carolina, USA and is being performed by Dr. Maria Escolar at the Center for the Study of Development and Learning and FPG Child Development Institute, University of North Carolina, Chapel Hill, North Carolina, USA, with support from Shire HGT. Read the full press release here.

[Summer 2008 update] The ClinicalTrials.gov information can be seen here.

Please see the update below on the Phase II clinical trial now at the 1 year point in Denmark. The US clinical trail has not been announced, however, this Natural History Study is a key precursor to the anticipated trial.

The MLD Foundation met with in Copenhagen with Dr. Fogh, the president of Zymenex, on February 27th, 2008 to discuss the Natural History Study and the anticipated US Clinical Trial. We will continue to work closely with Zymenex and Dr. Escolar at UNC to provide timely information about research developments, including an announcement of the Clinical Trial as soon as such information is made public.

Early February 2008 Update

Zymenex has indicated that the first patients are now at the 52 week point of their Phase II studies. The patients started the study in a staggered fashion so they will complete the 52 week milestone over the next couple of months. They are understandably quiet about additional details and status because of regulatory requirements on how they may share information.

June 2007 Update

Zymenex has confirmed the start of Phase II clinical trials to test the efficacy (effectiveness) of Metazym on human patients. They are enrolling the Phase I participants the Phase II trial.

They are also publicly stating their interest in a formal US Clinical Trial, a topic that the MLD Foundation has discussed with Zymenex several times, and one which we are advocating with the NIH and FDA.

They provided us with the following press release regarding the status of their trials. With clinical trials underway, the communications from Zymenex have become more formal as they honor patient privacy and the needs of the various approval and review agencies involved.

Phase II trial for Zymenex lethal disease treatment candidate

Zymenex has initiated the Phase II part of the clinical trial in seriously ill children with MLD. The trial will hopefully show the way to a cure for the rare and until now incurable disease, Metachromatic Leukodystrophy (MLD), which is diagnosed in children between the ages of 2-5 years and paralyses the nervous system in such a way that the children die.

"We have covered a good part of the ground, but we still have a way to go before we can say we have a breakthrough," says CEO Jens Fogh, Zymenex A/S. "He sees 2007 as a challenging year, with crucial phases for the development of the company's lead project, the enzyme Metazym. If good progress is made in the experimental treatment of the children, it is already planned to start a parallel clinical trial with the enzyme in the United States.

Chief physician Dr. Allan M. Lund, University Hospital Copenhagen, Denmark, coordinates the clinical trial, which takes place at the Danish private clinical trial unit PhaseOneTrials A/S. Dr. Christine i Dali, who is a specialist in paediatrics, employed at the University Hospital Copenhagen, is responsible for testing the enzyme in the patients. "The patient families and specialists from around the world are following this field very closely. The disease is due to a gene-defect and the disease is lethal and no therapy exists today," says Dr. Christine i Dali.

Supplemental information:

Metachromatic Leukodystrophy (MLD), is one of 45 diseases within the family of Lysosomal Storage Diseases.

MLD is caused by an increased concentration of sulphatide in cells and an ensuing breakdown of "myelin", a substance that protects the nerves in the brain and the rest of the body. The disease occurs due to a lack of the enzyme Arylsulfatase A (ASA), which causes irreparable neurological damage. The disease is lethal and no therapy exists today. Children with MLD are often diagnosed at the age of two years and are quickly bound to a wheelchair and become bedridden until they die within three to four years. The disease is rare and therefore unknown to the general public. The disease can in some ways be compared to Multiple Sclerosis, which also exists in several forms and can have a very quick and lethal progression.

Experimental treatment of subjects in Denmark must, in each case be approved by the authorities. In order to give permission to treat subjects in clinical trials, the authorities require that the trial product be developed using strict quality requirements cGMP and that it has been demonstrated in animal studies that the trial product is safe. Permission must be obtained from the Danish Medicines Agency and the Independent Ethics Committee who, secure that the trial is performed according to applicable regulations and guidelines and ethics requirements.

Zymenex A/S has developed Metazym. The company is a Scandinavian biopharmaceutical company, founded in 1998, with headquarters in Hillerød north of Copenhagen, Denmark and research laboratories in Stockholm, Sweden. The company is focused on research and development of pharmaceutical products for the treatment of rare, genetic diseases, for which there is no treatment today and which, due to the small patient populations, fall within "Orphan Diseases" and the Orphan Drug Acts. Zymenex is supported financially by the Danish venture capital investors BankInvest and Sunstone Capital.

Further information:

President, CEO, Jens Fogh, DVM, Zymenex A/S, Hillerød, Denmark, telephone: + 45 48 25 00 54, www.zymenex.com

Specialist in Pediatrics, Christine i. Dali, MD, University Hospital Copenhagen, Copenhagen, Denmark, telephone: + 45 25 22 91 55

Chief Physician, Allan Lund, MD, PhD, University Hospital Copenhagen, Copenhagen, Denmark, telephone: + 45 35 45 38 87

source: http://www.zymenex.com/composite-61.htm

Contact: Dr. Christine i Dali, MD
               University Hospital Copenhagen, Denmark
               Tel: + 45 25 22 91 55
               e-mail: cid@zymenex.com

Zymenex has confirmed the start of the Phase I clinical trials this past January and that Phase I patients will be rolled into the Phase II dosing study which is anticipated to start the middle of 2007.

They provided us with the following public statement regarding the trial. Now that the trial is underway, the communications from Zymenex will become more formal as they honor patient privacy and the needs of the various approval and review agencies involved.

The US NIH (National Institute of Health) has a link to the formal description and criteria of the Metazym Phase I/II trial in Denmark here.

This information might be in conflict with some of the information floating around. This might be due to several reasons ... the timing of information, the logistics of implementing the proposed plan, perhaps practical assumptions made by some involved with pre-trial evaluations, etc. There are many non-Zymenex people, including doctors, researchers, and government agencies involved in various aspects of the communications and decisions made about particular families.

Zymenex has been very forthright with The MLD Foundation about the status of the trial - we have agreed some of that information in confidence, but we can assure you that we will continue to keep you posted on what is happening.

Metazym is the name given to the replacement for the enzyme Arylsulfatase-A, the enzyme that MLD patients lack. In this therapy, the missing enzyme (Arsyl A) is replaced by a man-made recombinant biotech ASA enzyme that is injected into the MLD affected person in place of the missing natural enzyme. The enzyme behaves just like normal ARSA would in breaking down sulfatides.

The enzyme is made using recombinant DNA technology, which is defined as "... the task of cutting DNA from one organism and pasting it into a new organism that reproduces to make proteins of potential therapeutic value."

The ASA enzyme is produced in a mammalian cell (a Chinese Hamster cell). The human DNA for the ASA enzyme is incorporated into the hamster cell so that it produces ASA enzyme which is equivalent to the human enzyme. The cells are propagated in large tanks, the cells secrete the enzyme, which is then purified on special columns and finally filled into vials.

The enzyme will lose its effectiveness over a number of days, and since a MLD patient does not produce enough Arsyl A on their own, they will need periodic doses of Metazym. Similar to a diabetes patient, regular injections, perhaps every week or two, will be required to keep the enzyme levels and effectiveness up. The clinical trials will eventually establish the dosing frequency and amounts.

Zymenex is engaged in the development of pharmaceutical products to treat rare, serious, genetic diseases, for which there is no treatment available today. MLD is the second disease for which Zymenex is developing an enzyme replacement therapy. They have been granted a patent for rhPBGD used in the treatment of Acute Intermittent Porphyria, another rare disease.

Phase I clinical trials for Metazym, their Enzyme Replacement Therapy started early in 2007 with good results, and Phase II clinical trials started in June of 2007 in Denmark. Zymenex has expressed interest in clinical trials and approval for Metazym in the US, but no formal plans or schedule have been publicly announced.

Zymenex was founded in 1998 by Jens Fogh and Pär Gellerfors. Zymenex is a privately held Danish company based in Hillerød, north of Copenhagen, and with R&D facilities on Lidingö in Stockholm. Key investors include Danish Venture Investors BankInvest, Vækstfonden, and the Danish pension fund PenSam.

The R&D laboratory on Lidingö does the initial product development. This includes characterization of the expressed clones, development of methods of analysis and development of new product concepts and technologies.

Zymenex does not operate its own production facilities. The company has outsourced the manufacturing of pre-clinical and clinical material to contract manufacturers in Sweden, Denmark and Germany.