Research News

Welcome to the National Information and Advice Centre for Metabolic Diseases Research News Sheet - Vol 1 No 9.

The contents of this news sheet has been gathered from around the globe during our research to update our information on metabolic diseases. The contents are general and not specific to our cause.

A £20m programme to develop medicines specifically for children is to be carried out in Liverpool.

A national research network, based at Alder Hey Children's Hospital, will conduct studies into the effectiveness of medicines used by children.

Health bosses hope the initiative will also help give doctors more information for judgements on prescribing drugs, which are often designed for adults.

A consortium led by the University of Liverpool will co-ordinate the Medicines for Children Research Network at the hospital's Institute for Child Health.

Researchers are already developing treatments for a range of diseases in children such as meningitis, asthma and epilepsy at the institute.

Health Minister Andy Burnham said: "Establishing the Medicines for Children Research Network will ensure that children benefit directly from the latest medical advances and treatments designed, developed and licensed specifically for their use.

"By bringing together the research expertise of the University of Liverpool and the world renowned children's care at Alder Hey, this initiative is a significant boost to Liverpool - putting it at the forefront of research of children's medicines in this country."

The network will also seek the involvement of young people from schools and youth groups in the city.

Seventeen young people, aged nine to 18, will work as ambassadors to encourage young people receiving hospital care to take part in research projects.

Rosalind Smyth, director of the centre said: "This is the most important development towards improving children's health that has happened during my professional career."

NOVATO, Calif., Sept. 11 -- BioMarin Pharmaceutical Inc. (Nasdaq and SWX: BMRN) announced today that investigators presented data from preclinical studies of Phenylase(TM) (phenylalalanine ammonia lyase) that suggest the company has successfully addressed key technical challenges associated with its development for the treatment of phenylketonuria (PKU). BioMarin plans to conduct additional preclinical studies of Phenylase, with the intention of filing an Investigational New Drug application (IND) with the U.S. Food and Drug Administration in late 2007.

"Data from preclinical studies of Phenylase suggest that we have successfully addressed important technical hurdles required for the development of a potentially safe and effective treatment for individuals with PKU," stated Emil Kakkis, M.D. Ph.D., Chief Medical Officer of BioMarin. "The data suggest that we have a molecule with the essential characteristics required for clinical development, and we expect to file an Investigational New Drug application in late 2007."

Preclinical data demonstrate that Phenylase administered once weekly via subcutaneous injection in a PAH(enu2) murine model of PKU resulted in a sustained decrease in blood phenylalanine (Phe) to normal levels for a 12-week period. Baseline blood Phe levels ranging from 1500uM to 2000uM decreased to less than 100uM after treatment with Phenylase. Researchers observed restoration of pigmentation and increase in weight in the Phenylase-treatment groups relative to placebo groups. Antibodies did not have an impact on observed efficacy in either group, nor were there signs of systemic allergic reaction or local injection site reactions. These data were presented on Sunday, September 10, 2006, at a meeting entitled, "Tetrahydrobiopterin and Alternative Treatment in PKU. Cardiovascular Disease, and Diabetes," held in conjunction with the International Congress on Inborn Errors of Metabolism taking place this week in Chiba, Japan. The studies were conducted in collaboration with researchers in the laboratory of Charles Scriver, M.D., at McGill University, located in Montreal, Quebec and the laboratory of Ray Stevens, Ph.D., at The Scripps Research Institute, located in La Jolla, California.

Phenylase is an investigational enzyme substitution therapy currently being evaluated in preclinical studies for the treatment of severe PKU. The active ingredient in Phenylase, PEGylated phenylalanine ammonia lyase, is designed to catabolize the Phe that builds-up in the body due to lack of activity of the enzyme phenylalanine hydroxylase. BioMarin is seeking to develop Phenylase as a once-weekly, self-administered subcutaneous injection.

Phenylase is one of two investigational product candidates currently being evaluated by BioMarin for the treatment of PKU. The second, Phenoptin(TM) (sapropterin dihydrochloride), is a small-molecule oral therapeutic currently in Phase 3 clinical development. Phenylase and Phenoptin are both partnered with Serono S.A. as part of a strategic alliance established in May 2005.

PKU, a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world, is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is required for the metabolism of phenylalanine (Phe), an essential amino acid found in most protein-containing foods. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and brain, resulting in a variety of complications including severe mental retardation and brain damage, mental illness, seizures and tremors, and cognitive problems. As a result of global newborn screening efforts implemented in the 1960s and early 1970s, virtually all PKU patients in developed countries have been diagnosed at birth. The only treatment currently available for PKU patients is a highly restrictive and expensive medical food diet that most patients fail to adhere to the extent needed for achieving adequate control of blood Phe levels. To learn more about PKU, please visit www.PKU.com. Information on this website is not incorporated by reference into this press release.

BioMarin develops and commercializes innovative biopharmaceuticals for serious diseases and medical conditions. The company's product portfolio is comprised of two approved products and multiple clinical and preclinical product candidates. Approved products include Naglazyme(R) (galsulfase) for mucopolysaccharidosis VI (MPS VI), a product wholly developed and commercialized by BioMarin, and Aldurazyme(R) (laronidase) for mucopolysaccharidosis I (MPS I), a product which BioMarin developed through a 50/50 joint venture with Genzyme Corporation. Investigational product candidates include Phenoptin(TM) (sapropterin dihydrochloride), a Phase 3 product candidate for the treatment of phenylketonuria (PKU), and 6R-BH4 for cardiovascular indications, which is currently in Phase 2 clinical development for the treatment of poorly controlled hypertension. For additional information, please visit www.BMRN.com. Information on BioMarin's website is not incorporated by reference into this press release.

This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including, without limitation, statements about: the development of its product candidates Phenoptin and Phenylase for the treatment of PKU; and expectations regarding filings with regulatory agencies. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: the results of preclinical and clinical trials related to Phenoptin and Phenylase; results and timing of current and planned clinical trials of Phenoptin for the treatment of PKU and; the content and timing of decisions by the U.S. Food and Drug Administration, the European Medicines Agency and other regulatory authorities; and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's 2005 Annual Report on Form 10-K and the factors contained in BioMarin's reports on Forms 10-Q and 8-K. Stockholders are urged not to place undue reliance on forward- looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation, to update or alter any forward-looking statements.

09/11/2006

CONTACT: Investors, Joshua A. Grass, Senior Director, Business
Development & Finance, +1-415-506-6777, or Media, Susan Ferris, Senior
Manager, Corporate Communications, +1-415-506-6701, both of BioMarin
Pharmaceutical Inc.

Orphan Europe and Peptimmune Partner to Develop Specific Immunotherapy for Life-Threatening Skin Disease

Paris, France and Cambridge, MA, USA, November 9th, 2006 --- Orphan Europe sarl and Peptimmune Inc. have signed a Scientific Collaboration and License Agreement regarding the development of a peptide immunotherapy for the treatment of pemphigus vulgaris. The aim of the collaboration is to bring to market a new efficient drug to treat this rare, life-threatening, autoimmune skin disease.

Pemphigus vulgaris is characterized by blistering of the skin and the mucous membranes, and the patient will suffer progressive skin loss until sepsis occurs. If the disease is left untreated, the mortality rate is over 95% within five years. Today patients are treated with high-dose steroids for many years which may have serious, debilitating side effects, as well as with drugs suppressing the immune system. Pemphigus vulgaris is a rare disease: about 30 – 40,000 patients suffer from it worldwide with a concentration among the Ashkenazi Jewish population.

The goal of this new therapy is to selectively suppress the production of anti-desmoglein 3 autoantibodies, the pathogenic agent in pemphigus vulgaris. It is hoped that this will reduce or potentially eliminate the need for high dose steroids and immunosuppressants.

Peptimmune has conducted a phase 1 trial establishing the safety of the treatment and an orphan drug designation has been obtained in the USA. Orphan Europe will continue the development and conduct clinical trials to take the product through the regulatory process in Europe up to marketing authorization. Orphan Europe will then market the product in Europe, the Middle East and Africa.

“The collaboration with Peptimmune reinforces our strategy to provide new treatments for rare diseases with an unmet medical need”, says Mr. William Gunnarsson, founder and CEO of Orphan Europe. “We have already taken several orphan drugs from laboratory test environment to market authorization and worldwide distribution. This project has a great potential to help patients who are in need of an effective and safe treatment.”

"This relationship leverages Peptimmune's fundamental research of pemphigus vulgaris and Orphan Europe's expertise in development and commercialization towards a new treatment paradigm for this very difficult to treat disease," commented Thomas P. Mathers, President and CEO of Peptimmune.

Peptimmune, Inc. is a privately held clinical stage biotechnology company developing a pipeline of peptide based therapeutics for the treatment of chronic inflammatory diseases. The company is developing second generation therapeutics that are expected to result in safer and more effective therapies for multiple sclerosis, pemphigus vulgaris, rheumatoid arthritis and obesity. Founded by a team of world class scientists and led by an experienced management team, Peptimmune's mission is to reduce the burden these diseases place on the individuals, their families and the healthcare system.

Founded in 1990, Orphan Europe is a privately held pharmaceutical company developing and distributing orphan drugs for the treatment of rare diseases. The company has a unique experience in this field and has taken several products through development process to market authorization. Today Orphan Europe provides a dozen different medicinal products to patients all over the world. The company headquarter is located in Paris and it has subsidiaries in most European countries, as well as in the Middle East. Orphan Europe is committed to the improvement of knowledge about rare disorders and has founded the Orphan Europe Academy.

Junctional Epidermolysis Bullosa - A First Patient Successfully Treated by Gene Therapy

A team of Italian researchers led by Michele De Luca (University of Modena and The Veneto Eye Bank Foundation) and financed by the French and Italian Téléthons in the framework of a joint call for tender has – for the first time – succeeded in treating by gene therapy a patient affected with a serious genetic skin disease, junctional epidermolysis bullosa. In this disease, deficiency of the laminin 5 gene is expressed by an absence of dermal-epidermal adherence. By the transplant of skin stem cells treated by gene therapy and expressing laminin 5, the researchers were able to reconstitute an epidermis which adhered to the dermis on two chronic blisters situated on the thighs. This was observed from the 8th day and during the twelve months of follow-up.

This pilot trial in a first patient should lead to the setting up of a clinical trial for the same disease in France in the near future.

These results have been published today on the Internet site of the review Nature Medicine.

Epidermolysis bullosas are a group of rare and hereditary pathologies in which blisters form at the surface of the skin and mucous membranes, either spontaneously or following minor rubbing. There are three groups of epidermolysis bullosa, of variable seriousness.

The junctional form of epidermolysis bullosa (JEB) can be lethal and is generally due to mutations of laminin 5, an adherence protein. JEBs are characterised by blisters which form between the epidermis and the dermis leading to widespread, and sometimes haemorrhagic, skin and mucous membrane detachment causing the formation of scabs and infected lesions. The patients concerned can also present with height-weight growth retardation.

The patient in the Italian study, a man of 36, is the carrier of a mutation in one of the three chains (the β3 chain) constituting laminin 5, an essential protein of the basal membrane which induces the formation of adherence complexes which ensure the attachment of the epidermis to the underlying dermis.

In order to recreate adherence of the epithelium and reconstitute a functional epidermis, the researchers carried out skin biopsies on different parts of the patient’s body and identified the sample richest in epithelial stem cells – essentially following a technique used to reconstitute the epidermis of serious burns victims. This technique was adapted to this particular case by - among other ways - introducing into these cultured cells a retrovirus (Moloney Leukemia Virus) containining the gene-drug. Thus the researchers were able to obtain grafts expressing laminin 5 protein which they transplanted onto the right and left thigh of the patient (4 and 5 grafts respectively), as these were the places presenting chronic ulcerations. From the 8th day they could observe that the graft had “taken.” This was followed by the complete regeneration of the epidermis which had self-regenerated during the twelve months of follow-up. It is important to note that rubbing and even pinching did not raise blisters on the surface of the grafted areas, whereas large blisters formed spontaneously on the adjacent tissue. The progressive replacement of the patient’s epidermis using this technique is programmed over the next 2 to 3 years.

The different forms of epidermolysis bullosa affect 500 000 persons throughout the world. The success of this gene therapy opens up the field for the development of gene therapies for all the forms of epidermolysis and other just as incapacitating skin diseases. The preclinical studies concerning this research were supported by the AFM and the CEE (European Skintherapy Project, coordinated by Dr. Guerrino Meneguzzi, director of research at Inserm).

A clinical trial which the AFM wishes to finance is already programmed in France. This ohase I/II trial will be led by Dr Guerrino Meneguzzi and Prof Jean-Philippe Lacour (University Hospital, Nice) in collaboration with the Italian team. The stem cells taken from the patients participating in the trial will be sent to Venice for the constitution of an epidermis containing the gene-drug, which will then be grafted onto the patients in Nice. The patients have already been identified by the coordinators of the trial, who are at present awaiting the authorisation of Afssaps (the French Health Products Safety Agency).

Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells – Fluvio Mavilio, Graziella Pellegrini, Stefano Ferrari, Francesca Di Nunzio, Enzo Di Iorio, Alessandra Recchia, Giulietta Maruggi, Giuliana Ferrari, Elena Provasi, Chiara Bonini, Sergio Capurro, Andrea Conti, Cristina Magnoni, Alberto Giannetti and Michele De Luca. Nature Medicine (on line), 2006.

Studies Published in PNAS on the Mechanism of Amicus’ Experimental Treatment for Gaucher Disease

Cranbury, NJ, September 20, 2006 – Amicus Therapeutics, a biopharmaceutical company developing small molecule, orally-administered pharmacological chaperones for the treatment of a range of human genetic diseases, today announced that studies of the mechanism of action of its investigational treatment for Gaucher disease were published in the September 12 edition of the Proceedings of the National Academy of Sciences of the United States of America (PNAS). Gaucher disease results from an inherited genetic mutation, which causes a deficiency in the key enzyme acid b-glucosidase, also known as glucocerebrosidase (GCase). AT2101, Amicus’ lead compound for Gaucher disease, is designed to selectively bind to the GCase enzyme and help it fold into its correct three-dimensional shape. This binding and stabilization helps increase the proper movement of the enzyme from the endoplasmic reticulum (ER) to the lysosomes, the compartments in the cell where it performs its intended biological function.

In the current study, researchers performed several experiments with AT2101 on fibroblasts from a Gaucher patient with one of the most common disease-causing mutations, designated as N370S. After discovering that N370S GCase activity was increased in cells by as much as three-fold by AT2101 treatment for five days, researchers sought to understand in more detail the mechanisms by which AT2101 increased cellular GCase activity. Among the key findings:

“We’ve known for some time that the pharmacological chaperone AT2101 increases the activity of the key enzyme deficient in Gaucher patients, but now we have evidence of how it actually works, which is very exciting,” said study investigator Stuart A. Kornfeld, M.D., Washington University School of Medicine, St. Louis. “There is a real need for new treatment options for Gaucher disease, and these study results are very promising.”

Amicus has filed an investigational new drug application for AT2101 for the treatment of Gaucher disease and Phase I clinical trials are underway.

Gaucher disease is the most common lysosomal storage disorder, affecting an estimated 8,000-10,000 people worldwide. Symptoms can be severe and

debilitating, including an enlarged liver and spleen, abnormally low levels of red blood cells and platelets, and skeletal disease. In rare cases, there can be significant impairment of the central nervous system.

therapeutics known as pharmacological chaperones for the treatment of a range of human genetic diseases. Pharmacological chaperone technology involves the use of small molecules to restore or improve biological activity in cells by selectively binding to a misfolded protein caused by a genetic mutation. Amicus is initially targeting lysosomal storage disorders, which are severe, chronic genetic diseases with unmet medical needs. Amicus is currently conducting Phase II clinical trials for its lead compound, Amigal™, for Fabry disease, and is conducting Phase I clinical trials of AT2101 for Gaucher disease. The company plans to file an IND for AT2220 for the treatment of Pompe disease in the second half of 2006.

New genetic link to cot death identified

Babies born with specific variants of three key genes are 14 times more likely to die from cot death, new research has found.

The findings - published in Human Immunology - build on earlier research by The University of Manchester team that had already associated one of these genes with the condition.

The discovery of two further risk genes, say the paper's authors, is a major step forward in understanding the causes of cot death or `sudden infant death syndrome' (SIDS).

"We first identified an association between SIDS and specific variants of a gene called Interleukin-10 five years ago," said microbiologist Dr David Drucker, who led the research. "Quite simply, a baby who had particular variations of this gene was at greater risk of SIDS than other babies.

"Now, we have discovered two more genes implicated in SIDS and when a baby has certain genetic variants or `polymorphisms' of all three of these genes he or she can be up to 14 times more likely to die from the condition."

The genes investigated by the team all play a roll in the body's immune response to infection. Previous research, carried out with colleagues at Lancaster University, had shown that SIDS is associated with commonly occurring bacteria that babies up to the age of one year may lack immunity to.

Infants aged two to four months, in particular, have very weak immune systems and may not cope well with infectious agents they encounter in their environment.

Interleukin-10 (IL-10), as well as the other two genes - Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) - are involved in the production of chemicals called cytokines which are important for the correct functioning of our immune system.

Specific variants of these cytokine-producing genes, says the research, leads to an excessive inflammatory response to bacterial infection resulting in cot death. In the case of VEGF, the polymorphism associated with SIDS could conceivably result in poor fetal lung development.

"This research greatly advances our understanding of the basic causes of SIDS, which is not a single disease but a collection of different causes of death," said Dr Drucker, who carried out the work in collaboration with paediatric pathologist Dr Anthony Barson.

"Being able to detect high-risk babies means that health care and social provision can be aimed at the most vulnerable infants. In theory, commercially available and licensed human immune serum could be given to those children most at risk."

Dr Drucker, whose previous work has also explained why smoking and sleeping position are also risk factors in SIDS, says this latest research will help establish the cause of death in certain cases.

"Forensic scientists would be able to assess the likelihood of a baby dying from SIDS through genetic measurements and so help prevent the sort of tragic miscarriages of justice that have happened in the past.

"But ultimately, this research will improve our ability to identify in advance which babies will be at risk of SIDS so their mothers can be personally advised to eliminate other risk factors such as dangerous sleeping position for their infant."

Aeron Haworth
Media Officer
Faculty of Life Sciences
The University of Manchester

A tiny artificial liver has been grown from stem cells by Newcastle University scientists and is set to revolutionise the medical world.

Dr Nico Forraz and Professor Colin McGuckin made the breakthrough using stem cells taken from umbilical cords.

Having worked with Nasa scientists in Houston, Texas, they were able to create the miniature livers which may now be used for drug and pharmaceutical testing, eradicating the need to test on animals and humans.

Professor McGuckin, professor of regenerative medicine in the department of clinical and laboratory sciences, said the transplant of a section of liver - grown from cord blood - could be possible within the next ten to 15 years.

He said the use of mini-livers could prevent another Northwick Park Hospital disaster, where six human guinea pigs almost died after taking an experimental drug.

"We take the stem cells from the umbilical cord blood and make small mini-livers. We then give them to pharmaceutical companies and they can use them to test new drugs on.

"It could prevent the situation that happened earlier this year when those six patients had a massive reaction to the drugs they were testing."

Dr Forraz, a researcher at the university, and Prof McGuckin have now co-founded a company called ConoStem and have teamed up with the Tyneside-based Centre of Excellence for Life Sciences (CELS) to look at marketing their work.

Last year, Prof McGuckin, while working at London's Kingston University, announced he had obtained stem cells from babies' umbilical cord blood, which appeared to be very similar to human embryonic stem cells, and used them to grow liver tissue.

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