Research News

Welcome to the National Information and Advice Centre for Metabolic Diseases Research News Sheet - Vol 1 No 10.

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.

FDA designates Carbaglu® for treatment of NAGS deficiency as a Fast Track product.

The Food and Drug Administration (FDA) in the USA has concluded that Carbaglu® (carglumic acid) for treatment of N-acetylglutamate synthase (NAGS) deficiency meets the criteria for fast track designation.

NAGS deficiency, the most severe among Urea Cycle Disorders (UCD) is a very rare genetic disease presenting with extremely high plasma levels of ammonia, which leads to permanent and irreversible damage of the central nervous system. Rapid diagnosis and prompt effective treatment are essential to prevent patients from neurological damage and life threatening condition.

Children born with this genetic disorder often die before diagnosis due to the severity and fast deterioration of clinical status. The incidence of UCD is 1 in 30’000 births, and NAGS deficiency is the rarest among the UCD.

Carbaglu® is the specific treatment for NAGS deficiency. It is a synthetic analogue of NAG replacing deficient enzyme in the urea cycle. Today there are over 20 NAGS deficiency patients in Europe treated on a long-term basis with Carbaglu®. After initiation of treatment plasma ammonia levels decrease rapidly to normal levels, it decreases the frequency of hyperammonaemic crises and reduces the incidence of significant long-term morbidity. When treatment is started early, patients have normal neurological development, and most of them don’t need dietary restrictions.

Carbaglu® does not only save patients’ lives, but also assures a good quality of life for patients on a continuous treatment.

Carbaglu® has been granted Orphan drug status in USA (1998) and in Europe (2000). It was granted EU marketing authorization in 2003. FDA granted Carbaglu® a fast tract designation in May 2007 as it is intended to treat a serious or life-threatening condition and potentially address an unmet medical need. Carbaglu® has now access to FDA Fast Track Drug Development Programs which are designed to facilitate the development and expedite the review of such very promising new drugs.

Fragile X Study May Hold Autism Clue

Scientists report reversing symptoms of fragile X syndrome, a common genetic cause of autism and mental retardation, in lab tests on mice.

The findings may eventually lead to the development of drugs for fragile X syndrome and perhaps for autism, according to the researchers.

"Our study suggests that inhibiting a certain enzyme in the brain could be an effective therapy for countering the debilitating symptoms of FXS (fragile X syndrome) in children, and possibly in autistic kids as well," says researcher Mansuo Hayashi, PhD, in a Massachusetts Institute of Technology (MIT) news release.

Hayashi worked on the study while at MIT. She now works at Merck Research Laboratories in Boston.

The study appears in the online edition of Proceedings of the National Academy of Sciences.

What Is Fragile X Syndrome?

The National Institutes of Health defines fragile X syndrome as a genetic condition that causes a range of developmental problems including learning disabilities and mental retardation.

Fragile X syndrome is the most commonly inherited form of mental retardation and autism, note Hayashi and colleagues.

They studied mice born with fragile X syndrome. Those mice were hyperactive, had displayed repetitive behaviors, and lacked the normal anxiety of mice when put in an open area.

The scientists blocked a brain enzyme called PAK in the fragile X mice. That reduced fragile X symptoms.

That tactic hasn't been tested in people. But there are chemicals known to inhibit PAK.

"Our findings warrant testing of these inhibitors in FXS animal models with a hope of an eventual development of an FXS drug," write Hayashi and colleagues.

SOURCES: Hayashi, M. Proceedings of the National Academy of Sciences of the United States of America, July 3, 2007; vol 104: pp 11489-11494. News release, Massachusetts Institute of Technology.

Dr Mary Reilly, Consultant Neurologist and Dr Matilde Laura, Clinical research fellow, Centre for Neuromuscular Disease and Department of Molecular Neurosciences, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG

A trial of vitamin C (ascorbic acid) in Charcot-Marie-Tooth Disease type 1a is due to start at the National Hospital for Neurology and Neurosurgery (NHNN), Queen Square, London, in November 2006 [in actual fact the start date was delayed and is just starting now in April 2007]. The trial is being co-ordinated by Dr Mary Reilly, a consultant neurologist at NHNN. Dr Matilde Laura, a clinical research fellow, will be helping run the trial and will be the main person recruiting patients for the trial. CMT United Kingdom have been very helpful in providing pilot funding to prepare a grant application for this trial and we are delighted to report that Dr Reilly has been awarded a grant by the Muscular Dystrophy Campaign (MDC) to conduct this trial. Dr Reilly and her colleagues are very grateful to CMT UK and to MDC for this support.

The main aim of this trial is to assess whether vitamin C is helpful as a treatment for patients with Charcot-Marie-tooth type 1a (CMT1A). The title of the trial is CMT-TRAUK (CMT-Trial with ascorbic acid UK) and this will be the first drug trial conducted in patients with CMT1A. We anticipate that this trial will be a starting point for future trials in other types of CMT. This will also be an international trial. Eight Italian centres are conducting an identical trial (with the same protocol, drug and placebo called CMT-TRIALL (CMT-TRial Italian with ascorbic acid long term). The UK centre and the Italian centres will combine all their results to achieve statistical power, ie to have enough patients to interpret the results accurately.

CMT is the most frequent hereditary neuromuscular disease; between 17 and 41 people in every 100,000 are thought to have the disease. CMT1A is the most common form (it is estimated that 1 person in every 5,000 is affected) and is a demyelinating neuropathy (ie, it affects the myelin sheath , the fatty nerve sheath that acts as an insulator around nerve fibres), which is caused genetically by a duplication (extra copy) of the 11.2 region of chromosome 17. This region contains the gene coding for peripheral myelin protein 22 (PMP22). PMP22 is located in the myelin sheath of the peripheral nerves, and plays a crucial role in forming and maintaining myelin, and probably also in controlling cell growth and shape. In patients with CMT1A, as a result of a duplication in chromosome 17, PMP22 is produced in excessive quantities, leading to the neuropathy. There is at present no specific drug treatment for CMT disease. The only possible treatments are physiotherapy and correction of skeletal and soft tissue deformities by surgery.

The background of this trial is a recent research report demonstrating that vitamin C is helpful in treating a laboratory model of the disease. There is evidence that the vitamin works by reducing the amount of the PMP22 protein in the nerve. It is very important to know if vitamin C will be helpful in treating actual CMT1A patients rather than just a laboratory model. If vitamin C is an effective treatment for CMT1A, then we will have an effective therapy for this common condition and if vitamin C does not work we will be able to advise our patients not to take it unnecessarily.

Vitamin C is a vitamin and not a drug, and as such, it is widely used and know to be safe and well tolerated. Therefore, a clinical trial evaluating the effectiveness of vitamin C in CMT1A can be done easily, and is certainly necessary.

In the UK, 50 adult patients with a genetically proven diagnosis of CMT1A are being recruited. The total number of patients involved will be 272 (UK and Italy together).

All patients will to participate will undergo a screening visit with Dr Reilly in which some blood tests and a physical examination will be performed to assess eligibility for the trial. This trial will be a placebo controlled trial. This means that patients will receive either vitamin C or a drug which looks and tastes exactly like vitamin C but which contains no vitamin C (a placebo). For a trial to give useful information it is important that the trial is placebo controlled. After the screening visit, if the patients are found to be eligible, participants will be randomised to receive oral vitamin C or placebo tablets. In other words, the type of treatment to be used will be assigned randomly, regardless of the doctor’s or patient’s preferences or of any other factors. Every patient will have the same probability of receiving vitamin C or placebo treatment. The type of study is also double blind, ie. Neither the patient nor the doctor will know which treatment the patient has received until the trial is finished. This design of the study is an essential requisite in order for the findings of this study to have scientific validity.

The ascorbic acid will be given daily in two divided doses in the morning and in the evening. The dose that will be given is higher than the normal dose of vitamin c, but, from the laboratory studies, it is considered the most appropriate dose to obtain a therapeutic response. This dose has also been shown to be safe dose.

The treatment will last 2 years and all participants will be followed up very closely by the neurologists running the trial and they will be assessed every six months. During the follow up visits assessment scales specifically designed for CMT will be used every 6 months to compare patients taking AA with those taking the placebo. Moreover pain as a feature of the neuropathy will be investigated by some special neurophysiological tests and some questionnaires.

Participants will be asked not to change their usual diet in any significant way for the two years of the study and not to take extra vitamin C tablets during the study. To be eligible for the study, patients cannot take any vitamin C tablets for three months before the study starts.

This trial is very important because as well as answering the question as to whether vitamin C is an effective therapy for CMT1A, it will give researchers the opportunity to develop expertise in assessing patients with CMT for trials in the future and to establish an international network of centres with extensive experience in CMT for future research.

CMT is the most common inherited neuromuscular disease and we are very keen to develop therapies as the condition usually starts in childhood and is a life long disabling disease. It is very exciting that we are finally at the stage of doing therapeutic trials in CMT but it is crucial that these trials are rigorously conducted to ensure the maximum benefit is achieved for patients.

As the trial will involve visits to NHNN every 6 months, we are keen to recruit patients that live in or near London. Any patient interested in receiving more information about the trial should contact Dr Matilde Laura on 0207 837 3611 (ext 3153) or by email m.laura@ion.ucl.ac.uk

Scientists are finally tackling a genetic disease first discovered more than a century ago, according to results to be presented at the international Alkaptonuria (AKU) Society conference to be held at University College London Hospital on Wednesday 13 June 2007.

World medical experts will hear from US genetic specialist Dr William Gahl who will present data from trials of a potential treatment, Nitisinone. They will also hear from the AKU Society’s research team at the Royal Liverpool University Hospital, which is exploring avenues for genetic therapy.

AKU is a progressive, inherited condition that affects up to 250 people in the UK. Genetic mutations in these people cause malfunction of a single enzyme involved in breakdown of tyrosine, an amino acid “building block” of protein. This malfunction causes dangerous accumulation of the pigment ‘homogentisic acid’ throughout the body. The pigment build-up causes serious complications for patients, including arthritis of the spine and large joints and heart problems.

Presenting his work, Dr Gahl, Clinical Director of the US National Human Genome Institute, will say: ‘The trial results show that Nitisinone offers hope of a treatment for AKU patients. Over a century after AKU was discovered, we’re getting close to being able to help those people affected, but crucial hurdles still remain in understanding the disease before we have a certain treatment.’

The AKU Society works with the only AKU research group in the UK, at the Royal Liverpool University Hospital, where it has developed a strong partnership with the Department of Clinical Biochemistry and Metabolic Medicine and the Department of Human Anatomy and Cell Biology. On a European scale, the AKU Society has worked with the Royal Liverpool University Hospital to build a consortium of research centres with the University of Sienna (Italy), the University of Leon (Spain), the University of Warsaw (Poland) and a biotechnology company in Malta called GenSeq. The project will explore whether gene therapy can be used to treat this illness.

Dr L Ranganath, Consultant in Clinical Biochemistry and Metabolic Medicine at the Royal Liverpool University Hospital, who was instrumental in setting up this research group, is closely involved in the clinical and research programme being developed into AKU. He said: 'I think we are in for an exciting time to try and understand Alkaptonuria better and possibly develop new treatment approaches for this condition.'

Professor Jim Gallagher, Head of the Department of Human Anatomy and Cell Biology at the University of Liverpool, said: ‘Thanks to our partnership with the AKU Society, we are researching how homogentisic acid affects AKU patients and whether gene therapy can be used as a treatment. If successful, this could have serious positive implications for many other genetic diseases.’

The AKU Society also educates UK health professionals about the symptoms of the disease and is warning parents to watch out for the tell-tale signs of darkened urine. Robert Gregory, co-founder of the AKU Society and an AKU sufferer himself, said: ‘Today there is no cure or treatment that can help me and the many other people affected by this debilitating disease. Research so far is promising, but there’s still a long way to go to provide a real cure for patients, which is why the AKU Society needs all the support it can get.’

Mr Gregory, Lord Kenneth Ward-Atherton, Dr Ranganath and chairman Dr Nick Sireau set up the AKU Society in 2003. Lord Ward-Atherton, as patron of the AKU Society, has been instrumental in fostering the growth of the organisation and obtaining public profile for people with AKU. For more information and to support the AKU Society visit www.alkaptonuria.info

Children suffering from a group of rare, progressive diseases have been given new hope with the granting of a special prescribing licence to Birmingham Children’s Hospital NHS Foundation Trust (BCH). For the first time these Midland children can be treated close to home with drugs capable of slowing down the progress of their disease.

The National Commissioning Group (NCG) is an NHS agency, covering the UK, which pays for very specialist treatments like liver transplants and drugs for uncommon conditions. It has granted the Inherited Metabolic Disorders Unit at BCH permission to prescribe drugs to young patients affected by ‘lysosomal storage disorders’ (LSDs) so they will no longer have to travel to Manchester, Cambridge or London for treatment.

LSD is an umbrella term used to describe about 40 rare, genetic conditions caused by faults in the enzymes which break down waste or dead material in cells. This matter accumulates in the cells and causes symptoms. The symptoms range from very mild, with people leading normal lives, to very severe, causing progressive mental and physical disabilities from early childhood. Until about 10 years ago, when new drugs started to become available, little could be done and, in their severest forms, the conditions were fatal.

Dr Chris Hendriksz, consultant in clinical inherited metabolic disorders and Director of Lysosomal Storage Disorders at the BCH said: “We are very pleased to have been granted the NCG licence. We can now deliver a service to local children bringing them hope of an improvement in the quality of their lives. Some of these families have a very difficult time. The condition can upset every aspect of family life. Our aim is that after the first treatment in hospital the children can return home and continue their treatment there.”

Nearly half of all the patients, 48 per cent, come from ethnic minorities and some of these families have found it difficult to travel outside of the Midlands. The unit provides translation services as well as care in the community. Around 1,400 patients attend the metabolic unit and about 120 of these are children who have an LSD. Only about 10 per cent of these children will be suitable for treatment with current drugs.

In addition to the children already seen at the unit, Dr Hendriksz believes there is a “lost tribe” of up to 100 Midland children with an LSD not receiving specialist care. They are looked after at district general hospitals but their families or their doctors may not know there are now treatments available in Birmingham.

Dr Anupam Chakrapani, consultant in inherited metabolic disorders and head of the Inherited Metabolic Disorders Unit said: “LSDs are very rare conditions with just eight to ten new cases diagnosed in the entire West Midlands per year.

“But they are so rare that they are not readily recognized and diagnosis is often delayed by several months or even years.

“There are now effective therapies and it is crucial that we diagnose these disorders as early as possible so that treatment can start.

“Even families affected by conditions for which there is no specific treatment will benefit from early diagnosis as they will gain access to appropriate support and genetic counselling,” he said.

Although the number of children that can be treated is small, Dr Chakrapani and Dr Hendriksz believe they will soon be able to help many more families with promising new treatments in the pipeline.

Doctors are recording a remarkable victory over a set of rare but potentially fatal inherited conditions affecting what's known as the urea cycle.

That cycle uses six enzymes to get rid of the nitrogen that builds up as the body processes proteins and other chemicals. If something goes wrong with any one of those enzymes, "after a certain point, you get ammonia, which is very damaging to the brain," explained said Dr. Ada Hamosh, clinical director of the Johns Hopkins University Institute of Genetic Medicine.

She's the lead author of a report that found that people with these conditions now experienced a 25-year survival rate of 84 percent.

Estimates of the incidence of urea cycle disorders range from 1 in 3,000 births to 1 in 40,000 births. Because such disorders can be difficult to diagnose, and because patients die early, "we can't really get good incidence data," Hamosh noted.

One indication of the rarity of the disorder is the fact that the 100 hospitals involved in the study accumulated just 299 cases over the quarter-century of the study.

There was one key development boosting the effective treatment of urea cycle disorders, Hamosh said. In 1979, a researcher, Dr. Saul W. Brusilow, a Baltimore pediatrician, "had the really brilliant and very elegant idea of using the body's own methods of getting rid of the extra nitrogen," she said. Brusilow was then at Hopkins and has since retired.

The treatment uses a combination of two chemicals -- sodium phenylacetate and sodium benzoate -- delivered intravenously to bring down ammonia levels

"Those two chemicals had been used for many years," said Dr. Gregory M. Enns, director of the biochemical genetics program at Stanford University and another author of the paper. "Dr. Brusilow had the vision to combine them. The beauty of these compounds is that they work by shunting ammonia away from the urea cycle, shunting nitrogen out of the body. Instead of having urea come into the liver, the medications shunt it away."

Other treatments, including kidney dialysis, can also be used. In very severe cases of the condition, "the standard of care now is to get the young patients big enough for a liver transplant," Hamosh said. Persons with mild forms of the disorders can survive for many years on the two medications, which now are available in a combination product approved by the U.S. Food and Drug Administration.

"The data set in this paper is what was presented to get FDA approval of the drug," Hamosh said. The paper was published in the journal this week because of a report from Europe two years ago that showed worse results there than in the United States, indicating that some doctors were not familiar with the treatment, she said.

There are indications that cases are still being missed in the United States as well, because of the elusive nature of the disorder, Enns said. Often, there is no specific set of symptoms that mark a child with a disorder of the urea cycle, he said, "and in my personal experience, the thing that makes the most difference is to identify it quickly."

If tests show that a child is carrying high levels of ammonia, "you typically start [him or her] on medication," Enns said. "If the ammonia level comes down nicely, that often is enough, with no need for dialysis."

Shire’s ELAPRASE™ (idursulfase) Approved by Health Canada for Treatment of Hunter Syndrome

Shire plc (LSE: SHP, NASDAQ: SHPGY, TSX: SHQ) announces that Health Canada (under priority review) has approved ELAPRASE, a human enzyme replacement therapy for the treatment of Hunter syndrome, for sale and marketing in Canada. Hunter syndrome, also known as Mucopolysaccharidosis II (MPS II), is a rare, life-threatening genetic condition mainly affecting males that results from the absence or insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. Without this enzyme, cellular waste products accumulate in tissues and organs, which then begin to malfunction.
ELAPRASE is the first and only enzyme replacement therapy approved for people suffering from Hunter syndrome. The product, which is given as weekly infusions, replaces the missing or deficient enzyme that Hunter syndrome patients fail to produce in sufficient quantities. ELAPRASE has been shown to improve walking capacity in these patients.

ELAPRASE has been made available on a limited basis to Canadian patients since January 2007 through Health Canada’s Special Access Program (SAP) but will now be available on a more widespread basis across the nation. Health Canada’s approval follows the July 2006 marketing approval of ELAPRASE by the U.S. Food and Drug Administration and the January 2007 marketing authorization of ELAPRASE by the European Commission. At the end of the first quarter 2007, 291 patients are being treated with ELAPRASE worldwide. Shire estimates that there are approximately 2,000 patients worldwide afflicted with Hunter syndrome in areas where reimbursement may be possible.

“Health Canada’s approval of ELAPRASE is another important step in bringing this much-needed treatment to Hunter syndrome patients around the world,” said Matthew Emmens, chief executive officer of Shire. “Also at this time we want to thank the Canadian patients for their participation in the ELAPRASE clinical trials; without their commitment and determination, we would not have been able to bring this treatment to Canada and others would continue to suffer the debilitating symptoms of Hunter syndrome.”

According to Dr. Lorne Clarke, Medical Director of the Provincial Medical Genetics Program and researcher at the University of British Columbia, “The approval of ELAPRASE is an exciting advancement. There is potential to make a significant improvement in this progressive disorder by treating patients early.”

Clinical Trial Results

A 53-week, randomized, double-blind, placebo-controlled Phase II/III trial demonstrated that ELAPRASE provides clinically important benefits to Hunter syndrome patients. The primary efficacy endpoint of the trial was a composite analysis of changes from baseline in two clinical measures: a 6-minute walk test and percent predicted forced vital capacity. Shire is pleased to report that this endpoint achieved statistical significance compared to placebo. Also, after one year of treatment, patients receiving weekly infusions of ELAPRASE experienced a significant mean increase in the distance walked in six minutes of 35 meters compared to patients receiving placebo. The change in percent predicted forced vital capacity was not statistically significant compared to placebo.

Safety Data

Anaphylactoid reactions, which have the potential to be life threatening, have been observed in some patients treated with ELAPRASE. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious exacerbation of their respiratory dysfunction due to infusion related reactions. These patients require additional monitoring. Late-emergent anaphylactoid reactions have been observed after ELAPRASE administration. Patients who have experienced severe and refractory anaphylactoid reactions may require prolonged observation times. Due to the potential for severe infusion reactions appropriate medical support measures should be readily available when ELAPRASE is administered.

In all phases of clinical study for ELAPRASE, 11 patients experienced anaphylactoid reactions during 19 of 8,274 infusions (0.2%) and no patients discontinued treatment permanently as a result of an infusion reaction. The most common adverse events observed in >30% of patients during the Phase II/III trial were pyrexia, headache and arthralgia.

Fifty percent of patients across all studies (53 of 106) developed anti-idursulfase IgG antibodies.

Adverse reactions that were reported during the 53-week placebo-controlled study were almost all mild to moderate in severity.

Studies have not been performed in patients under 5 or over age 65.

For further information on Shire, please visit the Company’s website: www.shire.com

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.

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.

Climb provides the above third-party links as a convenience and makes no assurances and/or warranties, implied or otherwise, and is not responsible for the information you receive from the linked sites or any supporting information related to the subject. The inclusion of any link does not imply endorsement of Climb or the sites or the information contained therein. Climb is not responsible for the contents of any linked site or any link contained in a linked site or any changes or updates to such sites. This newsletter is provided for information only.