Clinical
Development Programs
Our proprietary HuCNS-SC® product candidate (purified human neural stem cells) is in clinical development for two fatal neurodegenerative disorders.
In January 2009, we completed a Phase I clinical trial of HuCNS-SC cells in Neuronal Ceroid Lipofuscinosis (NCL), a brain disorder in children. Data from this study demonstrated the clinical safety and tolerability of the cells.
In November 2009, we initiated a Phase I trial of our HuCNS-SC cells in Pelizaeus-Merzbacher Disease (PMD), a myelination disorder that primarily affects young children. This trial is being conducted at the University of California, San Francisco (UCSF) Children’s Hospital.
We believe that the human safety data we are accumulating for our HuCNS-SC cells through these clinical trials will facilitate the pathway for future clinical testing of these cells in other central nervous system (CNS) disorders, including spinal cord injury and retinal degenerative diseases such as AMD and retinitis pigmentosa.
Additional information about our clinical trials can be found at clinicaltrials.gov.
Phase I Trial in Neuronal Ceroid Lipofuscinosis (NCL, often referred to as Batten disease)
Our Phase I trial in NCL was the first ever FDA-authorized clinical trial of human neural stem cells. This landmark Phase I study primarily focused on assessing the safety of HuCNS-SC cells as a potential treatment for NCL.
In this open-label, dose-escalating Phase I study, HuCNS-SC cells were transplanted into six patients with either infantile or late infantile NCL. Enrollment in the trial was limited to patients in advanced stages of the disease (patients with significant neurological and cognitive impairment, whose developmental age was demonstrated to be less than two-thirds of their chronological age). Two dose levels were administered, with the first three patients receiving a target dose of approximately 500 million cells; the other three patients receiving a target dose of approximately one billion cells. The HuCNS-SC cells were directly transplanted into each patient’s brain via a neurosurgical procedure. Patients were immunosuppressed for 12 months following transplantation. The patients were evaluated and assessed at regular intervals using a comprehensive range of medical, neurological and neuropsychological tests, both before transplantation to establish a baseline, and over the course of 12 months following transplantation.
In June 2009, we reported positive results from this trial including:
• Favorable safety profile: cells, surgical procedure and immunosuppression well tolerated by all patients
• Engraftment and long-term survival of the donor cells
We are continuing to follow the patients who completed the trial as part of a separate four-year follow-up study.
In November 2009, we met with the FDA to review the results of our Phase I trial in NCL and to discuss our proposed clinical development plans. The discussions with the FDA centered on how we might construct a second study enrolling patients in less advanced stages of NCL to further expand the safety database and to assess whether earlier intervention might alter the course of the disease. The FDA acknowledged our position that the risk-benefit profile shown by the Phase I data merits further clinical evaluation of HuCNS-SC cells in NCL, and we obtained constructive feedback and guidance with respect to additional clinical testing of the cells in this fatal disease. We anticipate that additional discussions with the agency in the coming months will help us define the appropriate next steps for this program.
Preclinical Proof-of-Concept in NCL
Published data from preclinical studies highlight our novel neuroprotective approach to treating neurodegenerative diseases such as NCL, and support the clinical development of our HuCNS-SC product candidate.
We have shown that, when transplanted in a mouse model of infantile NCL (INCL), our neural stem cells engraft, migrate throughout the brain and continuously secrete the missing lysosomal enzyme characteristic of NCL, which is needed to process cellular waste and keep neurons functioning and healthy. When compared with the control (non-transplanted) group, the mice that received the transplanted neural stem cells showed statistically significant reduction in cellular waste build-up, protection of critical host neurons and delayed loss of motor function. Our preclinical studies have demonstrated that these neural stem cells also produce the enzyme missing in late infantile NCL (LINCL), thereby providing the scientific rationale for enzyme replacement via transplantation of these cells in this subtype, as well as in INCL.
A summary of our preclinical data was published in the September 2009 edition of Cell Stem Cell (Tamaki, et al. 2009):
For more information on our work in this area, download our Fact Sheet on NCL.
Phase I Trial in Pelizaeus-Merzbacher Disease (PMD)
In December 2008, the U.S. Food and Drug Administration (FDA) approved our Investigational New Drug application (IND) to conduct a clinical trial of HuCNS-SC cells in patients with PMD, and in November 2009, we announced the initiation of the trial at the University of California, San Francisco (UCSF) Children’s Hospital. This Phase I trial is designed to assess the safety and preliminary efficacy of our HuCNS-SC cells as a potential treatment for PMD. PMD is a fatal neurodegenerative disorder that is most commonly caused by a genetic mutation and that mostly occurs in males. Myelin, which is produced by specialized cells called oligodendrocytes, insulates nerve fibers (also known as axons) to allow electrical signals to be conducted normally. Patients with PMD have insufficient myelination of axons in the brain, leading to neurological impairment and eventually death in the fatal forms of the disease. PMD is most frequently diagnosed in early childhood and is associated with abnormal eye movements (nystagmus), abnormal muscle function, and, in some cases, seizures. Connatal PMD, the most severe form of the disease, is frequently diagnosed in early infancy with symptoms often present at birth.
This Phase I Clinical Trial in PMD is expected to enroll four patients with connatal PMD. All patients will be transplanted with the 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, MRI examination of the brain post-transplant may enable the measurement of new myelin formation. We are planning to follow the effects of this therapy long-term, so, as with our Phase I NCL trial, this trial will also be followed by a separate, four-year observational study.
More information on patient enrollment in this trial can be found here.
Preclinical Proof-of-Concept in PMD
Preclinical studies performed by us and our collaborators provide a rationale for potential therapeutic use of HuCNS-SC cells in myelination disorders. We have demonstrated that, when transplanted into an animal model of hypomyelination (shiverer mouse), our neural stem cells engraft and differentiate into mature oligodendrocytes and form myelin sheaths around host nerve fibers. Our preclinical studies have also shown that, when transplanted into spinal cord-injured mice, our neural stem cells form myelin around the damaged nerve axons and restore the lost motor function. Spinal cord injury is often associated with neuron loss and demyelination.
Our initial preclinical myelination data was published in the Proceedings of the National Academy of Science (Cummings, et al. 2005), and additional data was presented at the International Society of Stem Cell Research (ISSCR) 2008 Annual Meeting.
For more information on our work in this area, download our Fact Sheet on PMD.
About HuCNS-SC Cells
Our lead product candidate, HuCNS-SC cells, is a highly purified composition of human neural stem cells that are prepared under controlled conditions. Our neural stem cells are isolated from the human fetal brain, purified, expanded and then stored and frozen in cell banks until they are transplanted as HuCNS-SC doses. Preclinical research has shown that HuCNS-SC cells can be directly transplanted in the CNS. The transplanted cells 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.
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