- LymPro discriminates Alzheimer's disease (AD) from healthy
controls with comparable accuracy to clinical diagnosis reference
standard
- Data corroborate previously published findings demonstrating
LymPro correctly differentiates patients with AD from healthy
controls
- Fit-for-purpose validation confirms the reproducible analytical
performance of LymPro for use as a diagnostic tool in clinical
trials
- Amarantus to add FDA-approved (CMS reimbursed for research
purposes) PET imaging agents for the evaluation of concordance with
LP-002 data set
Amarantus Diagnostics, a neurology-focused diagnostics company
developing diagnostic tests for multiple sclerosis and Alzheimer's
disease and a wholly-owned subsidiary of Amarantus Bioscience
Holdings, Inc. (OTCQX:AMBS), today reported positive results on the
accuracy of the LymPro Test®, its blood-based diagnostic assay for
Alzheimer's disease (AD), to discriminate between subjects with
clinically diagnosed AD versus healthy controls at the Alzheimer's
Association International Conference® (AAIC) being held July 18-23,
2015, in Washington, DC.
Amarantus Diagnostics presented data from two studies on its
LymPro blood-based diagnostic assay for Alzheimer's disease (AD)
during AAIC poster sessions in abstracts entitled:
"The LymPro Test®: A Biomarker for Alzheimer's Disease Using
Blood Samples from Clinically Diagnosed Alzheimer's Disease and
Cognitively Intact Subjects."
"The LymPro Test®: A Fit for Purpose Validation of a Flow
Cytometric Assay to Assess Lymphocyte Proliferation in Peripheral
Blood Lymphocytes in Alzheimer's Disease."
The Company recently completed a multivariate analysis of
predictive markers in lymphocytes and monocytes obtained from blood
samples and evaluated differences in mitogen-stimulated
proliferative activity between clinically diagnosed AD subjects and
healthy cognitively normal (HC) controls. Results confirmed that
LymPro had comparable AD diagnostic accuracy to this study's
reference standard of clinical diagnosis by dementia experts, as
reported by Beach et al (2102) where accuracy of clinical diagnosis
of probable AD was compared to neuropathology diagnosis of
AD.
"The diagnostic accuracy of LymPro, a unique peripheral
biomarker, demonstrated by this study was comparable to accuracy
obtained using this study's clinical reference standard for
diagnosis, the National Institute on Aging/Alzheimer's Association
2011 criteria. Today's data solidifies LymPro's importance in the
investigational Alzheimer's space for identification and disease
screening," said Gerald E. Commissiong, President and CEO of
Amarantus BioScience Holdings, Inc. "The LymPro blood-based
diagnostic panel is a robust and reproducible measure of a key
pathology of AD. Further, the findings corroborate previously
published LymPro data."
The Company also reported confirmatory Fit-for-Purpose
validation data demonstrating the excellent intra- and inter-assay
precision of LymPro's most relevant and informative diagnostic
biomarkers for AD. Results of this study validate LymPro's utility
for use as a diagnostic assessment tool in therapeutic Alzheimer's
clinical trials. Amarantus Diagnostics provides the pharmaceutical
industry with LymPro biomarker services for Investigational Use
Only (IUO) in clinical development programs. Fit-for-Purpose assay
validation for LymPro was conducted at Icon Central Laboratories in
Farmingdale, NY.
"This additional validation demonstrated for LymPro raises the
importance for its potential use in biomarker-supported selection
of Alzheimer's disease patients for clinical trials. It has the
convenience of being a blood test while reflecting the same type of
cell cycle reentry dysfunction found in the brains of these
patients," said Paula T. Trzepacz, M.D., Clinical Professor of
Psychiatry at Indiana University School of Medicine and member of
the Amarantus Clinical Advisory Board. "LymPro has the potential to
become one of the fundamental diagnostic tools in Alzheimer's drug
development, and we look forward to adding FDA-approved PET imaging
agents to further validate LymPro vis-a-vis diagnostic gold
standards."
The LymPro Test is a flow cytometry assay that measures the
response of peripheral blood lymphocytes and monocytes to mitogenic
stimulation and quantifies the extent to which these cells have
entered the cell division process known as cell cycle (or mitosis).
Cell cycle dysregulation in neurons is a key pathology in AD that
leads to neuronal death and associated cognitive decline, as
neurons enter the mitotic process but are unable to complete cell
division and undergo apoptosis (programmed cell death). With
LymPro, lymphocyte and monocyte measurements are used as a
peripheral surrogate for this neuronal cell dysfunction.
STUDY SUMMARIES
"The LymPro Test®: A Biomarker for Alzheimer's Disease
Using Blood Samples from Clinically Diagnosed Alzheimer's Disease
and Cognitively Intact Subjects."
Methods: 141 whole blood samples were drawn from enrolled study
participants in vacutainer tubes designed for lymphocyte culture.
Samples were shipped overnight, cultured with mitogen (PHA, 4 hrs
or PWM, 4 or 20 hrs) or without in separate culture tubes, and then
stained with an antibody cocktail to reveal subpopulations of
lymphocytes (T, B, and monocytes) as well as expression levels of
CD69 (a surface marker of cell cycle activity) cell surface
expression. Lymphocyte subpopulation specific biomarkers were
measured on an 8 color flow cytometer at a contract lab (Becton
Dickinson). After analytical review of the flow cytometry data,
N=125 of the samples passed blinded quality control (59 AD and 66
controls). Each subject's WBCs were characterized by 14 measured
biomarker features in various permutations for statistical
analyses, as well as two stimulation indices that were calculated
to produce an additional 8 biomarker variables. Thus, results of 22
variables were analyzed statistically. These 22 were measured for
each of three stimulation conditions using mitogens.
Statistical Analysis: Public domain feature selection algorithms
or stepwise methods were used to identify optimal feature sets to
maximize diagnostic prediction performance. These included logistic
regression, discriminant analysis (linear and quadratic), and
decision tree and random forest methods. Prediction performance was
initially assessed with a 65% training set (n=81) and applied to a
35% test set (n=44), All analysis was done in JMP Pro v11.2.1 (SAS,
Cary, NC).
Results and Conclusions:Findings from this expanded analysis of
the LymPro test using multivariate analysis are consistent with the
prior published reports using univariate approaches, with an
overall area under the curve of 0.9229 in the training set and
0.7236 in the test set, where the test set had 87% sensitivity and
83% specificity in the training set, and 76% sensitivity and 70%
specificity in the test set. This lends further support that LymPro
test may have utility as a blood biomarker reflective of AD
pathology. More in-depth analysis of this cohort is underway. These
preliminary findings are encouraging and warrant further studies to
demonstrate the utility of this blood biomarker in the differential
diagnosis of patients with cognitive impairment.
Limitations: The study design was predicated upon cohort
categorization (AD or HC) on clinical grounds only and there were
no biomarkers employed in the confirmation of clinical diagnosis.
Nonetheless, our test sample performed similarly to Beach et al's
(2012) conclusion about clinical diagnosis that "…when optimizing
for both sensitivity and specificity [against neuropathological
diagnosis], the best [clinical] result was 70.9% sensitivity and
70.8% specificity."
Conclusions and Next Steps: Multivariate analysis using random
forest found 5 candidate variables that together generated the best
performance results in ROC analysis. This preliminary algorithm
holds promise as a step in the development of a bioassay algorithm
that can yield both strong sensitivity and specificity. The LymPro
test holds promise for use in evaluating patients though further
clinical validation in diverse clinical samples, in conjunction
with F18-florbetapir PET, is planned.
"The LymPro Test®: A Fit for Purpose Validation of a
Flow Cytometric Assay to Assess Lymphocyte Proliferation in
Peripheral Blood Lymphocytes in Alzheimer's Disease."
Methods: Whole blood samples were obtained from healthy donors,
the lymphocytes were isolated and left unstimulated or subjected to
mitogenic stimulation under three conditions; pokeweed mitogen
(PMW) for four hours, PWM for 20 hours and phytohemagglutinin for
four hours. The frequency of CD69+ and CD28+ cells as
subpopulations of CD19+ B cells, CD14+ monocytes and CD3+, CD4+ and
CD8+ T cells were measured by flow cytometry. Metrics included
percentage, event counts and median fluorescent intensity.
Experimental parameters evaluated were intra-assay and inter-assay
precision and analyst-to-analyst and instrument-to-instrument
performance.
Results and Conclusions:Intra-assay precision (%CV) as measured
by frequency (%) of CD28+ or CD69+ cells in each cell subpopulation
ranged from 0.12 to 37.3%; 32 of 36 results were ≤10%. Intra-assay
precision as measured by median fluorescent intensity (MFI) ranged
from 1.02 to 33.2%; 35 of 36 results were ≤30%. Inter-assay
precision as measured by frequency ranged from 0.1 to 27.9%; 35 of
36 results were ≤10%. Inter-assay precision as measured by MFI
ranged from 1.75 to 20.7%; 36 of 36 results were ≤30%. The
analyst-to-analyst percent difference ranged from 0.07 to 39.4%
when measured by frequency; 30 of 36 results were ≤20%. When
measured by MFI, the analyst-to-analyst difference ranged from 2.87
to 58.4%; 33 of 36 results were ≤30%. The
instrument-to-instrument percent difference ranged from 0.35 to
64.2% when measured by frequency; 30 of 36 results were ≤20%. When
measured by MFI, the instrument-to-instrument difference ranged
from 1.92 to 95.8%; 33 of 36 results were ≤30%. The LymPro Test was
validated in a fit-for-purpose manner. The most relevant and
informative markers demonstrated excellent intra- and inter-assay
precision as well as good agreement between analysts and
instruments. The results of this validation demonstrate the utility
of the LymPro Test for use in clinical trials.
Amarantus BioScience Holdings previously disclosed that it is
exploring strategic options for Amarantus Diagnostics, including
potential sale, co-development or spinoff opportunities, to derive
the full value from its neuro-diagnostics business.
About Alzheimer's Disease
According to the Alzheimer's Association, it is estimated that
over 5.4 million people in the United States suffer from
Alzheimer's disease. Over 500,000 patients are diagnosed annually,
with nearly one-in-eight older Americans affected by the disease.
Alzheimer's disease is the third leading cause of death in the
United States. The cost of unpaid care in the United States is
estimated at over $210 billion annually. Total payments for care
are estimated at over $200 billion annually, including $140 billion
in cost to Medicare and Medicaid. Alzheimer's expenditures in the
United States are expected to exceed $1.2 trillion by 2050. There
is no cure or effective treatment for Alzheimer's disease.
Worldwide, about 35.6 million individuals have the disease and,
according to the World Health Organization, the number will double
every 20 years to 115.4 million people with Alzheimer's by
2050.
About LymPro Test®
The Lymphocyte Proliferation Test (LymPro Test®) is a diagnostic
blood test that determines the ability of peripheral blood
lymphocytes and monocytes to withstand an exogenous mitogenic
stimulation that induces them to enter the cell cycle. It is
believed that certain diseases, most notably Alzheimer's disease,
are the result of compromised cellular machinery that leads to
aberrant cell cycle re-entry by neurons which then leads to
apoptosis. LymPro is unique in the use of peripheral blood
lymphocytes as a surrogate for neuronal cell function, suggesting a
common relationship between PBLs and neurons in the brain.
About Amarantus BioScience Holdings, Inc.
Amarantus BioScience Holdings (OTCQX:AMBS) is a biotechnology
company developing treatments and diagnostics for diseases in the
areas of neurology and orphan diseases. AMBS' Therapeutics division
has development rights to eltoprazine, a small molecule currently
in a Phase 2b clinical program for Parkinson's disease
levodopa-induced dyskinesia and with the potential to expand into
adult ADHD and Alzheimer's aggression. The Company has an exclusive
worldwide license to intellectual property rights associated to
Engineered Skin Substitute (ESS), an orphan drug designated
autologous full thickness skin replacement product in development
for the treatment of severe burns currently preparing to enter
Phase 2 clinical studies. AMBS owns the intellectual property
rights to a therapeutic protein known as
mesencephalic-astrocyte-derived neurotrophic factor (MANF) and is
developing MANF as a treatment for orphan ophthalmic disorders,
initially in retinitis pigmentosa (RP). AMBS also owns the
discovery of neurotrophic factors (PhenoGuard™) that led to MANF's
discovery.
AMBS' Diagnostics division owns the rights to MSPrecise®, a
proprietary next-generation DNA sequencing (NGS) assay for the
identification of patients with relapsing-remitting multiple
sclerosis (RRMS) at first clinical presentation, has an exclusive
worldwide license to the Lymphocyte Proliferation test (LymPro
Test®) for Alzheimer's disease, which was developed by Prof. Thomas
Arendt, Ph.D., from the University of Leipzig, and owns
intellectual property for the diagnosis of Parkinson's disease
(NuroPro).
For further information please visit www.Amarantus.com, or
connect with the Company on Facebook, LinkedIn, Twitter and
Google+.
Forward-Looking Statements
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including estimates, projections, statements relating to our
business plans, objectives, and expected operating results, and the
assumptions upon which those statements are based, are
forward-looking statements. These forward-looking statements
generally are identified by the words "believes," "project,"
"expects," "anticipates," "estimates," "intends," "strategy,"
"plan," "may," "will," "would," "will be," "will continue," "will
likely result," and similar expressions. Forward-looking statements
are based on current expectations and assumptions that are subject
to risks and uncertainties which may cause actual results to differ
materially from the forward-looking statements. Our ability to
predict results or the actual effect of future plans or strategies
is inherently uncertain. Factors which could have a material
adverse effect on our operations and future prospects on a
consolidated basis include, but are not limited to: changes in
economic conditions, legislative/regulatory changes, availability
of capital, interest rates, competition, and generally accepted
accounting principles. These risks and uncertainties should also be
considered in evaluating forward-looking statements and undue
reliance should not be placed on such statements.
CONTACT: Investor and Media Contact:
Jenene Thomas
Jenene Thomas Communications, LLC
Investor Relations and Corporate Communications Advisor
T: (US) 908.938.1475
E: jenene@jenenethomascommunications.com
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