GERMANTOWN, Md., Dec. 8, 2015 /PRNewswire/ -- Neuralstem, Inc.
(NASDAQ: CUR) today announced the publication of Phase 1b data in
Molecular Psychiatry for their lead small molecule drug,
NSI-189, in patients with major depressive disorder (MDD).
Neuralstem is a biopharmaceutical company developing treatments for
central nervous system diseases based on its proprietary neural
stem cell platform. The report showed that NSI-189, a
benzylpiperizine-aminiopyridine compound with neurogenic and
synaptogenic mechanism of action, was well tolerated for 28 days at
escalating doses and showed potential as a treatment for MDD. The
paper, "A Phase 1b, Randomized, Double-Blind, Placebo-Controlled,
Multiple-Dose Escalation Study of NSI-189 Phosphate, a Neurogenic
Compound, in Depressed Patients," can be found online here.
MDD is the leading cause of disability among adults in the U.S.,
affecting nearly 15 million people.1 While there are
many treatments available for depression, only one-third of
patients with MDD achieve full remission of symptoms,2-5
demonstrating the high unmet need for safe and effective therapies
with mechanisms of actions that differ from current treatment
options.
The Phase 1b study was a randomized, double-blind,
placebo-controlled safety study (n=24) designed to evaluate the
tolerability of NSI-189 in adult patients with MDD. Three doses
were tested in equal cohort sizes (n=8/dose): 40 mg administered
once (QD), twice (BID) or three times (TID) daily for 28 days.
Patients in each cohort were randomly assigned to either active or
placebo at 3:1 ratio and dosed and monitored in-clinic during the
28-day treatment period, after which they were discharged and
monitored in periodic follow-up visits for eight additional weeks.
The double-blind was maintained throughout the monitoring period,
although no further treatment was administered. Various safety,
pharmacokinetic, pharmacodynamic, and clinical assessments were
conducted throughout the 84-day study.
NSI-189 was shown to be well tolerated, with no serious adverse
events identified, across all three doses. The mean half-life of
drug was 17.4 to 20.5 hours, with steady-state being reached after
96 to 120 hours. The overall drug exposure increased in a
dose-related and nearly proportional manner across the dosing
levels. Four clinical efficacy measurements were used: Symptoms of
Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale
(MADRS), Clinical Global Impressions - Improvement (CGI-I), and The
Massachusetts General Hospital (MGH) Cognitive and Physical
Functioning Questionnaire (CPFQ). NSI-189 showed a reduction in
depressive and cognitive symptoms across all measures, with
significant improvement in the SDQ and CPFQ, and a medium to large
effect size for all measures. These improvements persisted during
the eight-week, drug-free, follow-up phase.
"This small Phase 1B trial achieved the primary goal of
establishing safety and tolerability of NSI-189 at multiple doses.
However, in addition, it is also encouraging to see the early signs
of benefit this novel treatment may offer for patients living with
MDD," said lead author Maurizio
Fava, MD, Executive Vice Chair, Department of Psychiatry and
Executive Director, Clinical Trials Network and Institute,
Massachusetts General Hospital. "Improvements in depression and
cognitive symptoms, if confirmed in future studies, indicate the
promise NSI-189 holds for the treatment of MDD."
Based on MADRS scores, of the 18 active patients who completed
the study, 12 were responders, defined as those who had either 50%
drop in MADRS score or returned to a normal range (MADRS score
0-6), two were non-responders (MADRS score 20-34), and four were
designated partial responders since the post-treatment MADRS score
indicated a change from moderate to mild depression. Independent
analysis of depression biomarkers from the blood samples of the
study subjects correlated with the clinical response in 17 out of
the 18 cases, further corroborating the clinical efficacy
results.
Researchers also assessed changes in quantitative EEG
(electroencephalography), a measure of electrical brain waves at
resting state. Analysis showed significant effects by NSI-189 but
not by placebo on patients' brain activity, indicated by increased
high frequency alpha waves and amplitude change from baseline to
post-dose assessment in specific locations in the left side of the
brain.
In addition, the study measured changes over time in hippocampal
and amygdala volumes from the MRI images of patients taken
throughout the 84-day study duration. The post-hoc repeated
measures ANOVA suggested a modest, though not statistically
significant, increase in the left hippocampal volume in the
NSI-189-treated patients, but not in the right side. In amygdala
volume analysis, the trend of volume increase over time was
non-significant on the left side but significant on the right side
of the brain.
"These results are promising, as it is unusual to see medium to
large clinical effects from such a small study, particularly in the
case of depression where placebo effects can be quite large," said
Karl Johe, PhD, Neuralstem Chairman
and Chief Scientific Officer. "Similar results were seen across
several outcome measures and corroborated by blood biomarkers and
brain activity and volume. This suggests that the neurogenic
mechanism of action of NSI-189 is targeting the core of depression
disease. If replicated in the upcoming Phase 2 trial, NSI-189 may
have potential as a disease modifying agent as indicated by
positive effects continued after patients stopped receiving the
drug."
Based on these findings, Neuralstem has filed a Phase 2 efficacy
study for treatment of MDD with NSI-189 as a monotherapy compared
with placebo with the U.S. Food and Drug Administration.
About the Trial
In this single-site study, patients with confirmed diagnosis of
recurrent major depressive disorder (MDD) were enrolled into three
dose cohorts (40 mg QD, 40 mg BID, and 40 mg TID) with eight
patients per cohort completing the study. Within each dose cohort,
six were randomized to NSI-189 and two were randomized to placebo.
All subjects stayed in-clinic and received oral administration of
NSI-189 or placebo for 28 days. After this period, the subjects
were discharged and returned to the clinic for follow-up measures
for additional eight weeks post dosing.
About Major Depressive Disorder
Major depressive disorder (MDD), also called major depression, is
characterized by a combination of symptoms that interfere with a
person's ability to function normally. MDD affects approximately
14.8 million American adults and is the leading cause of disability
in the U.S. for ages 15-44, according to the National Institute of
Mental Health.1 While most treatments modulate brain
neurotransmitter levels to treat brain chemistry, new research
suggests that brain physiology could also be involved. Depressed
patients have reduced volume in the hippocampus, a part of the
brain that generates new neurons, altered brain wave pattern, and
diagnostic changes in certain blood components. Neuralstem believes
that certain molecules such as NSI-189 stimulating the generation
of new neurons and promoting synaptogenesis in the hippocampus
could potentially reverse the pathophysiology of the depression
itself.
About Neuralstem
Neuralstem's patented technology enables the commercial-scale
production of multiple types of central nervous system stem cells,
which are being developed as potential therapies for many central
nervous system diseases and conditions.
Neuralstem's ability to generate neural stem cell lines from
human hippocampus, which were used for systematic chemical
screening for neurogenesis effect, has led to the discovery and
patenting of molecules that Neuralstem believes may stimulate the
brain's capacity to generate new neurons, potentially reversing
pathophysiologies associated with certain central nervous system
(CNS) conditions. The company has completed Phase 1a and 1b trials
evaluating NSI-189, its first neurogenic small molecule product
candidate, for the treatment of major depressive disorder (MDD),
and is expecting to initiate a Phase 2 study for MDD in 2016.
Neuralstem's first stem cell product candidate, NSI-566, a
spinal cord-derived neural stem cell line, is under development for
treatment of amyotrophic lateral sclerosis (ALS). Neuralstem has
completed two clinical studies, in a total of thirty patients,
which met primary safety endpoints. In addition to ALS, NSI-566 is
also in a Phase 1 study to treat paralysis due to chronic spinal
cord injury, as well as in a Phase 1 study to treat paralysis from
ischemic stroke.
Neuralstem's next generation stem cell product, NSI-532.IGF,
consists of human cortex-derived neural stem cells that have been
engineered to secrete human insulin-like growth factor 1 (IGF-1)
protein. The treatment is currently in early investigation for
Alzheimer's disease (AD). In animal study reported at the 2015
Annual Meeting of the American Neurological Association, the cells
improved cognition and reduced Aβ plaque load in AD mice.
For more information, please visit www.neuralstem.com or connect
with us on Twitter, Facebook and LinkedIn.
Cautionary Statement Regarding Forward Looking Information:
This news release contains "forward-looking statements" made
pursuant to the "safe harbor" provisions of the Private Securities
Litigation Reform Act of 1995. Such forward-looking statements
relate to future, not past, events and may often be identified by
words such as "expect," "anticipate," "intend," "plan," "believe,"
"seek" or "will." Forward-looking statements by their nature
address matters that are, to different degrees, uncertain. Specific
risks and uncertainties that could cause our actual results to
differ materially from those expressed in our forward-looking
statements include risks inherent in the development and
commercialization of potential products, uncertainty of clinical
trial results or regulatory approvals or clearances, need for
future capital, dependence upon collaborators and maintenance of
our intellectual property rights. Actual results may differ
materially from the results anticipated in these forward-looking
statements. Additional information on potential factors that could
affect our results and other risks and uncertainties are detailed
from time to time in Neuralstem's periodic reports, including the
Annual Report on Form 10-K for the year ended December 31, 2014, and Form 10-Q for the three
and nine months ended September 30,
2015, filed with the Securities and Exchange Commission
(SEC), and in other reports filed with the SEC.
References
- Depression Statistics. Depression and Bipolar Support Alliance.
Available at:
http://www.dbsalliance.org/site/PageServer?pagename=education_statistics_depression.
September 15, 2015.
- Fava M, Davidson KG. Definition and epidemiology of
treatment-resistant depression. Psychiatr Clin North Am.
1996; 19:179-200.
- Fava M. Diagnosis and definition of treatment-resistant
depression. Biol Psychiatry. 2003; 53:649-659.
- Nierenberg AA, Ostacher MJ, Huffman JC, Ametrano RM, Fava M,
Perlis RH. A brief review of antidepressant efficacy,
effectiveness, indications, and usage for major depressive
disorder. J Occup Environ Med. 2008; 50(4):428-36.
- Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D,
Ritz L, et al; STAR*D Study Team. Evaluation of outcomes with
citalopram for depression using measurement-based care in STAR*D:
implications for clinical practice. Am J Psychiatry. 2006;
163(1):28-40.
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SOURCE Neuralstem, Inc.