Neuralstem Pharmaceuticals:

Creating a New Class of Neuroregenerative Drugs

Neuralstem's technology uniquely enables the creation of stable neural stem cell lines from the human hippocampus, a part of the brain involved in memory and the generation of new neurons. From these cell lines, the com­pany can create practically unlimited amounts of mature human hippocampal neural stem cells.

Neuralstem's human hippocampus cell lines are the world's only such cell lines. They enable the com­pany to screen vast libraries of chemical compounds, searching for those that protect hippocampal neurons against various toxic insults. They create, in essence, disease models in a dish: living human neurons against which Neuralstem can test multiple chemical compounds.

Neuralstem has been engaged in its own drug discovery program with these human hippocampal stem cell lines. In 2009, Neuralstem was granted patents on four first-in-class chemical entities that boost the generation of new neurons. NSI-189, the first of these to be in a clinical trial, in major depressive disorder, significantly stimulates the generation of new neurons (neurogenesis) in vitro and in animal models.

Assaults on neurons in the human hippocampus are now suspected to be linked to many devastating diseases of the mind and brain, such as Alzheimer's disease and major depressive disorder. Drugs that stimu­late the generation of new neurons -- an aspect of the healthy brain that seems to be negatively impacted by many CNS conditions -- could address these conditions at their root cause.

NSI-189 is in an FDA-approved Phase I safety and dose escalation trial for the treatment of major depressive disorder, initiated in 2011.

Other CNS diseases and conditions the company may be able to address with neuroregenerative pharmaceuticals are Alzheimer's disease, anxiety, bipolar disorder and schizophrenia. The company believes that all of these indications may be treated by reversing hippocampal atrophy. This is an entirely new approach to treating these devastating diseases and conditions.

NSI-189: First in This New Class of Compounds

Neuralstem's Initial Application Addresses a New Theory on Depression

A new hypothesis on major depressive disorder, implicates brain physiology rather than brain chemistry alone. Depressed patients have reduced hippocampal volume. While once it was believed that the adult brain did not generate neurons, scientists now know that new neurons develop in the hippocampus throughout life. Could the shrunken hippocampal volume observed in depressed patients be attributable to a reduction in normal new neuronal generation and/or atrophying hippocampal neural stem cells?

Neuralstem believes the answer is yes. There is also a broadening consensus in the research commu­nity that this is the case. In multiple animal model studies, Neuralstem's compounds have demonstrated clear evidence of increased hippocampal volume.

Using the Brain to Repair Itself

Neuralstem's lead compound, NSI-189, appears to stimulate the brain's capacity to generate new neurons. While current antidepressant therapies seek to modulate brain chemistry, NSI-189 has the potential to address directly the pathology of the disease itself, potentially reversing the hippocampal atrophy associated with depression. A Phase I safety and dose escalation trial of NSI-189 in major depressive disorder, initiated in February 2011, gained FDA approval in December 2011 to advance to Phase Ib, which is expected to commence in March 2012. More

Other CNS diseases and conditions the company may be able to address with NSI-189 are: Alzheimer's disease, anxiety, bipolar disorder and schizophrenia.