News Bulletin - United Leukodystrophy Foundation

In 1998 it was reported in the New England Journal of Medicine that the cholesterol reducing agent lovastatin reduced very long-chain fatty acids (VLCFA) in blood from patients with X-linked adrenoleukodystrophy. Since the publication many X-ALD patients worldwide are using lovastatin with the hope that it will have a positive effect on the clinical outcome. In the following years, other researchers raised doubt on the beneficial effect of lovastatin on VLCFA. A subsequent study with simvastatin (a structurally related statin) in patients with childhood cerebral ALD showed no effect on VLCFA. And treatment of X-ALD mice had no effect on VLCFA levels in brain and adrenal.

To resolve whether lovastatin can truly reduce plasma VLCFA in patients with X-ALD, a randomized double-blind placebo controlled cross-over trial was carried out. Fourteen patients with the adrenomyeloneuropathy (AMN) phenotype participated in the trial. Patients were treated with lovastatin for 6 months and 6 months with a placebo, or vice versa. Neither the patients nor the researchers knew who was using what kind of medication during the treatment period. At the end of the trial the samples and data were analyzed.

As expected, treatment with lovastatin reduced plasma cholesterol levels. The plasma VLCFA levels reduced by about 20%, but they remained between 2 and 3 times above the normal level. In addition, VLCFA levels in red and white blood cells remained unchanged after lovastatin treatment. Since VLCFA are virtually water insoluble, most of the VLCFA in blood are transported as cholesterol-esters in lipoprotein particles like LDL. No effect on VLCFA levels was observed in these particles.

The authors conclude that lovastatin leads to a small decrease in VLCFA levels in plasma which has to be considered a non-specific result of the LDL-cholesterol decrease. Physicians should not prescribe lovastatin as a VLCFA lowering therapy to patients with X-ALD, since evidence does not support it.

This announcement is to inform you about the forthcoming opening of a clinical experimentation of gene therapy for the treatment of Metachromatic Leukodystrophy (MLD) in our San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), in Milan.

The HSR-TIGET (http://www.fondazionesanraffaele.it) was funded in 1995 as joint venture among the Scientific Institute of San Raffaele and the Telethon Foundation for the research and treatment of rare genetic diseases. Main goal of the Institute is to be a center of excellence in all the phases of the research from basic to clinical gene and cellular therapy, from the experimentation of new therapeutic strategies in the animal models of disease up to their clinical testing in the patients. Particularly remarkable effort is related to the development of protocols of gene therapy based on the use of hematopoietic stem cells. The therapeutic success for us obtained in the treatment of a serious form of congenital immunodeficiency (ADA-SCID) represents today the most convincing demonstration of the effectiveness and safety of such approach.

Gene therapy is based on the principle that every illness caused by an alteration of a known gene can be cured by inserting, through viral vectors, a functional copy of the gene in the sick cells of the patient. In the case of the MLD, it is problematic to insert the functional gene in the sick cells of the central and peripheral nervous system for the inaccessibility of these organs. It is, however, possible, by using appropriate gene transfer systems, to correct in a stable way hematopoietic cells that can transport then the functional enzyme to the affected nervous system. With the purpose to realize this, we have drawn a gene therapy strategy based on the transplantation of hematopoietic stem cells transduced with a lentiviral vector containing the human normal Arylsulfatase A (ARSA) gene, able to generate by their differentiated progeny a permanent source of the functional enzyme for the affected tissues. Such strategy, for many aspects similar to the transplantation of hematopoietic cells from healthy donors, is set as a less risky and more effective alternative to allogeneic transplantation thanks to the use of autologous, patient’s cells genetically corrected by means of lentiviral vectors (which allow an above physiological expression of the enzyme in the hematopoietic cells.

The safety and the effectiveness of this approach have been shown in the preclinical model of the disease, in which we documented the prevention and the correction of the signs and symptoms of the pathology following the treatment. To the light of such results, we have therefore implemented a clinical protocol for the transfer of such therapeutic strategy to MLD patients.

The clinical experimentation, already approved by the Institutional Ethical Committee and waiting final authorization from the Italian Competent Authorities (expected by March 20, 2010), has as objective the evaluation of the effectiveness and the safety of the treatment in study in a cohort of 8 MLD patients.

The study is single center, in open, not randomized, perspective, comparative with a non-contemporary population of controls from us studied within a clinical study of natural history of the disease. As expected from the criterions for experimentation in pediatric patients, the study is a Phase I / II, therefore facing the evaluation not only of the safety but also of the effectiveness of the treatment. On the base of such indication, the inclusion criteria and the end points of the study have been defined. The recruitment of the patients is international. The costs of the study are entirely to load of the HSR-TIGET.

The study will include patients in the pediatric age affected from MLD, diagnosed through dosing of ARSA enzymatic activity and/or genetic analysis that fulfill the following characteristics:

Late infantile MLD in pre-symptomatic phase (in presence of a case index in the family);
Early juvenile MLD in pre-symptomatic (in presence of a case index in the family);

Bone marrow explants of the patient with isolation of the stem cells to be submitted to gene transfer;
Manipulation of the cells and gene transfer with the lentiviral vector;
Patient’s conditioning, based on the alkylating agent Busulfan;
Re-infusion of the manipulated stem cells.

Besides the safety end points of the treatment (related to the conditioning regimen and to the use of the lentiviral vectors), we will evaluate as primary efficacy end points an improvement / stability in the motor performances assessed by the “Gross Motor Function Measure, GMFM” 24 months after the treatment, in comparison to the scores obtained in a cohort of untreated patients of peer age, and a significant increase of the ARSA activity in the patients’ hematopoietic cells measured 24 months after the treatment, in comparison to the pre-treatment values.

The follow-up post-treatment will be performed in the three years following the gene therapy, and an additional follow-up is anticipated for the 5 following years at the end of the study, according to the Italian Regulation (D.M. 2 March 2004).

This research will be developed within the Fondazione Centro San Raffaele del Monte Tabor in Milan, in the Pediatric Clinical Research Unit of HSR-TIGET and in the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR.

Study promoter is the Fondazione Centro San Raffaele del Monte Tabor, in the person of the HSR-TIGET Director Prof. Lugi Naldini. The main financial sponsor is the Italian Telethon Foundation.

Dr. Alessandra Biffi (Principal Investigator: Project leader at HSR-TIGET & Staff Pediatrician in the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR);

Dr. Maria Sessa (Principal Investigator; Project Leader at HSR-TIGET & Staff Neurologist in the Neurology Department at HSR)

Dr. Attilio Rovelli (Co-Principal Investigator; Director of the Bone Marrow Transplantation Center of the Pediatric Department, San Gerardo Hopsital, Monza); Prof. Luigi Naldini (Co-Principal Investigator and Director of the Pediatric Immunohematology and Bone Marrow Transplant Unit at HSR; HSR Scientific Director)

Shire HGT had planned to initiate a Phase 2/3 study with intravenous (IV) enzyme replacement therapy (ERT) for treatment of MLD in 2009. However, clinical data from the ongoing Phase 1/2 extension study, collected on an ongoing basis over the last few years, demonstrates that the IV route of administration is not succeeding. Therefore, Shire has decided to suspend further development of an IV formulation of arylsulfatase A (ASA) derived from CHO cells, also known as HGT-1111. Shire plans to share these clinical data publicly at an upcoming scientific meeting and is working closely with the clinical investigators caring for participants continuing to receive HGT-1111 to evaluate next steps for these patients.

Going forward Shire believes that direct delivery to the central nervous system (CNS) offers the best chance for development of a successful treatment for MLD. Shire plans to develop HGT-1110, a formulation of ASA derived from human cells and compatible with direct CNS delivery for MLD patients. This human cell line has been used successfully by Shire for the development of other ERTs for Hunter syndrome, Fabry disease, and type 1 Gaucher disease. Shire’s CNS platform was recently advanced with the initiation of a Phase 1/2 trial using direct delivery of idursulfase to the CNS in Hunter patients. Development of the HGT-1110 formulation suitable for direct delivery to the CNS is ongoing, and preclinical studies are planned for 2010.

Shire is committed to the MLD community. We continue to work diligently to bring a much-needed therapy to patients and their families.

STEMCELLS, INC. ANNOUNCES first human neural stem cell TRANSPLANT in LANDMARK myelination disorder trial

Phase I Study Targets “Communication Highway” of the Brain in Children with PMD

PALO ALTO, Calif., February 10, 2010 – StemCells, Inc. (NASDAQ: STEM) announced today that its proprietary HuCNS-SC® human neural stem cells have been used to treat the first patient enrolled in its Phase I clinical trial in Pelizaeus-Merzbacher Disease (PMD), a myelination disorder that afflicts male children. The stem cells were administered yesterday at the University of California, San Francisco (UCSF) Children’s Hospital by direct injection into the brain of a patient with connatal PMD, the most severe form of the disease. This marks the first time that neural stem cells have been transplanted as a potential treatment for a myelination disorder, and the second clinical trial involving the use of HuCNS-SC cells in a neurodegenerative disease.

Myelin is the substance that surrounds and insulates nerve cells’ communications fibers (also known as axons). Without sufficient myelination, these fibers are unable to properly transmit nerve impulses, leading to a progressive loss of neurological function. Multiple sclerosis, transverse myelitis and certain types of cerebral palsy are more commonly known myelination disorders that also affect the central nervous system. Patients with PMD are born with a defective gene, which leads to insufficient myelin in the brain. Those with the most severe form of the disease, connatal PMD, lose the ability to walk and talk and eventually die, often before the age of 10. Currently, there are no effective treatments for PMD.

Stephen Huhn MD, FACS, FAAP, Vice President and Head of the CNS Program at StemCells, Inc., said, “The dosing of this first patient marks the beginning of a new chapter in the search for novel approaches to treat PMD and other myelination disorders. Cell therapy represents hope for those with diseases that small molecules and other biologics have been unable to address. Our ultimate goal in this clinical development program is to improve the outlook for these patients by establishing the basis for a safe and effective treatment option that could significantly slow or prevent the progression of the disease. While the primary focus in this first trial is safety, we will also be looking for evidence of new myelin formation in the patients’ brains following the transplantation of our cells, as well as any signs of improved neurological function.”

President and CEO Martin McGlynn stated, “We are extremely grateful to the family of this child, and to the clinicians and staff at UCSF, for bringing us one step closer to our goal of realizing a cell-based treatment for devastating myelination disorders that impact the central nervous system.”

The trial is being directed by a team of prominent researchers at UCSF Children’s Hospital, one of the leading medical centers in the United States for neonatology, pediatric neurology and neurosurgery. The principal investigator is David H. Rowitch, M.D., Ph.D., Chief of Neonatology at UCSF Children’s Hospital, Professor of Pediatrics and Neurological Surgery, member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and a Howard Hughes Medical Institute investigator. The study co-investigators are Nalin Gupta, M.D., Ph.D., Chief of Pediatric Neurological Surgery, and Jonathan B. Strober, M.D., Director of Clinical Services for Child Neurology and Director of the Muscular Dystrophy Clinic at UCSF Children's Hospital.

The Phase I trial is designed to assess the safety and preliminary effectiveness of HuCNS-SC cells as a potential treatment for PMD. The trial is expected to enroll four patients with connatal PMD. All patients will be transplanted with HuCNS-SC cells, and will be immunosuppressed for nine months. Following transplantation, the patients will be evaluated regularly over a 12-month period in order to monitor and evaluate the safety and tolerability of the HuCNS-SC cells, the surgery, and the immunosuppression. In addition, magnetic resonance imaging (MRI) of the brain post-transplant may enable the measurement of new myelin formation. As the Company intends to follow the effects of this therapy long-term, a separate four-year observational study will be initiated at the conclusion of this trial. Interested parties may find more information on patient enrollment at http://neonatology.ucsf.edu/nbri/pmd-trial/ or by visiting www.stemcellsinc.com. Additional information about this clinical trial can also be found at www.clinicaltrials.gov.

StemCells’ lead product candidate, HuCNS-SC cells, is a highly purified composition of human neural stem cells that are expanded and stored as banks of cells. The Company’s preclinical research has shown that HuCNS-SC cells can be directly transplanted in the central nervous system. The transplanted cells are able to engraft, migrate, differentiate into neurons and glial cells, and possess the ability to survive for as long as one year with no sign of tumor formation or adverse effects. These findings show that HuCNS-SC cells, when transplanted, behave like normal stem cells, suggesting the possibility of a continual replenishment of normal human neural cells.

Preclinical studies performed by StemCells and its collaborators provide a rationale for potential therapeutic use of HuCNS-SC cells in myelination disorders. The Company has demonstrated that, when transplanted into an animal model of hypomyelination (shiverer mouse), HuCNS-SC cells engraft and differentiate into mature, specialized cells called oligodendrocytes, and form myelin sheaths around host nerve fibers. The initial myelination data in the shiverer mouse was published in the Proceedings of the National Academy of Science (Cummings, et al. 2005) and the results of additional myelination studies were presented at the International Society of Stem Cell Research (ISSCR) 2008 Annual Meeting in Philadelphia.

StemCells has completed a Phase I clinical trial of its HuCNS-SC cells for the treatment of Neuronal Ceroid Lipofuscinosis (NCL), a fatal brain disorder in children. Data from this trial demonstrated the clinical safety and tolerability of these cells. The Company’s HuCNS-SC cells are also in preclinical development for other central nervous system disorders, including retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa, and spinal cord injury.

One of the nation’s top children’s hospitals, UCSF Children’s Hospital creates an environment where children and their families find compassionate care at the healing edge of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 2,000 babies born in the hospital. Medi-Cal patients constitute more than half of the patient population.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

StemCells, Inc. is focused on the development and commercialization of cell-based technologies. In its cellular medicine programs, StemCells is targeting diseases of the central nervous system and liver. StemCells’ lead product candidate, HuCNS-SC cells (purified human neural stem cells), is in clinical development for the treatment of two fatal neurodegenerative disorders that primarily affect young children. StemCells also markets specialty cell culture products under the brand SC Proven®, and is developing its cell-based technologies for use in drug screening and drug development. The Company has exclusive rights to approximately 55 issued or allowed U.S. patents and approximately 200 granted or allowed non-U.S. patents. Further information about StemCells is available at www.stemcellsinc.com.

Apart from statements of historical fact, the text of this press release constitutes forward-looking statements within the meaning of the Securities Act of 1933, as amended, and the Securities Exchange Act of 1934, as amended, and is subject to the safe harbors created therein. These statements include, but are not limited to, statements regarding the potential for the Company’s therapies to treat PMD, NCL and other serious neurodegenerative diseases, the potential for its cell-based therapeutics to treat other diseases or disorders, and the future business operations of the Company, including its ability to conduct clinical trials as well as its other research and product development efforts. These forward-looking statements speak only as of the date of this news release. The Company does not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Such statements reflect management’s current views and are based on certain assumptions that may or may not ultimately prove valid. The Company’s actual results may vary materially from those contemplated in such forward-looking statements due to risks and uncertainties to which the Company is subject, including the fact that additional trials will be required to demonstrate the safety and efficacy of the Company’s HuCNS-SC cells for the treatment of any disease; uncertainty as to whether the FDA or other applicable regulatory agencies will permit the Company to continue clinical testing in PMD, NCL or in future clinical trials of proposed therapies for other diseases or conditions given the novel and unproven nature of the Company’s technologies; uncertainties about the design of future clinical trials and whether the Company will receive the necessary support of a clinical trial site and its institutional review board to pursue future clinical trials in PMD, NCL or in other diseases or conditions; uncertainties regarding the ability of preclinical research, including research in animal models, to accurately predict success or failure in clinical trials; uncertainties regarding the Company's ability to recruit the patients required to conduct this clinical trial or to obtain meaningful results based on the limited number of patients expected to be enrolled; uncertainties arising as a result of the serious condition of the patients expected to be enrolled; the fact that results obtained in any clinical trial in PMD may not be predicative of results that would be obtained in regard to other myelination disorders; uncertainties regarding the Company’s ability to obtain the increased capital resources needed to continue its current and planned research and development operations, including such operations of the company for non-therapeutic applications, and to conduct the research, preclinical development and clinical trials necessary for regulatory approvals; uncertainty as to whether HuCNS-SC and any products that may be generated in the future in the Company’s cell-based programs will prove safe and clinically effective and not cause tumors or other adverse side effects; uncertainties regarding the Company’s ability to commercialize a therapeutic product and its ability to successfully compete with other products on the market; uncertainties regarding the Company’s manufacturing capabilities given its increasing preclinical and clinical commitments; and the increased risks associated with commercializing future cell-based therapeutics, including the potential for product liability claims; and other factors that are described under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended December 31, 2008, and in its subsequent reports on Form 10-Q and Form 8-K.

WASHINGTON – May 20, 2009 – Earlier today, the National Institutes of Health (NIH) announced the establishment of a new initiative called the Therapeutics for Rare and Neglected Diseases (TRND) Program, a federally mandated effort to encourage and speed the development of new drugs for rare and neglected diseases. Sharon Terry, president and chief executive officer of Genetic Alliance, a nonprofit health advocacy organization, issued the following comments in response to the establishment of TRND:

“Today marks a leap forward in transforming the rare and neglected disease drug development pipeline. NIH is a crucial entity working in this space. In the United States, a rare disease is defined as a condition affecting fewer than 200,000 people, and diseases lacking substantial therapeutic development activity are considered neglected diseases. Many genetic diseases are both rare and neglected, and collectively there are more than 6,000 rare and neglected diseases affecting over 25 million Americans. Fewer than 200 of these diseases have any therapy available, and progress in this area is limited within the current system.

Clinical trial design is a unique challenge for rare and neglected diseases for reasons such as small patient populations and the need for global recruitment. Because of these challenges, it is critical to conduct effective trials from the onset, as subsequent opportunities may not be possible. Flexible, adaptive trial design and close interaction with the U.S. Food and Drug Administration will be especially important to consider in this context. In addition, engaging disease-specific groups in preparation for clinical trials to characterize the natural history of diseases and determine clinical trial endpoints is also essential and can begin right away through the application of existing tools, technologies and networks.

Genetic Alliance applauds the federal government for development of the TRND Program and views meaningful collaborations with external partners as a key element in the program. We have been collaborating with stakeholders in the health community including, disease-specific groups, umbrella organizations, and industry corporations while engaging in dialogue around regulatory and policy issues to bring about systems change in this area. This experience has shown us that collaborations through open and transparent processes are essential for change that will benefit health outcomes for all stakeholders.

We are excited for the potential the TRND Program holds and hope to collaborate with the program and its partners in system transformation.”

About Genetic Alliance – Genetic Alliance transforms health through genetics, promoting an environment of openness centered on the health of individuals, families, and communities. Genetic Alliance brings together diverse stakeholders that create novel partnerships in advocacy; integrates individual, family, and community perspectives to improve health systems; and revolutionizes access to information to enable translation of research into services and individualized decision making. For more information about Genetic Alliance, visit http://www.geneticalliance.org.

Dr. Connor's special interest was in atherosclerosis, nutrition and lipid metabolism. He received his medical degree from the University of Iowa College of Medicine in 1950. He completed his residency training in Internal Medicine at San Joaquin General Hospital in Stockton, Ca., Veterans Administration Hospital in Iowa City, and at the University of Iowa. Dr. Connor completed his fellowships in Internal Medicine at the Veterans Administration Hospital in Iowa City, and in Pathology at Oxford University.

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March 11, 2010

Lovastatin in X-linked adrenoleukodystrophy

Marc Engelen, M.D. & Stephan Kemp, Ph.D

New England Journal of Medicine 2010 Jan 21;362(3):276-277.

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