20 µg dose shows favorable safety, tolerability and
encouraging therapeutic signal on top of standard of care
Novel mechanism of action shown preclinically to promote
synaptogenesis
NEW YORK, July 19, 2017 /PRNewswire/ -- Neurotrope,
Inc. (NASDAQ: NTRP) today presented clinical results from its
recently completed Phase 2 trial demonstrating that
moderate-to-severe Alzheimer's disease (AD) patients treated with
20 µg bryostatin-1 showed preliminary evidence of sustained
improvement in cognition compared to placebo. The data and
comprehensive statistical analysis were presented in the
Developing Topics: Clinical Trials oral session, "Effect of
Bryostatin-1 on Cognition and Daily Living Tasks in Moderate to
Severe Alzheimer's disease Preliminary Report of a Phase 2 Study"
at the Alzheimer's Association International Conference 2017 in
London.
"In this exploratory study evaluating a novel mechanism of
action, we see an encouraging therapeutic signal in late stage AD
patients with the 20 µg group, which was maintained across time
points with relatively minimal toxicity and good tolerability,"
said Martin R. Farlow, MD, Vice
Chairman for Research in the Department of Neurology, Indiana University School of Medicine, Indiana
Alzheimer Disease Center, who presented the data. "This study has
shown a real and sustained increase in SIB over and above standard
of care in a difficult to treat population. It is important now to
determine if these effects can be maintained and enhanced over a
longer period of time."
The 13-week, randomized, double-blind, placebo-controlled study
evaluated the safety, tolerability and efficacy of bryostatin-1 in
147 moderate-to-severe AD patients across three treatment arms (20
µg, 40 µg, placebo). This is the first placebo-controlled, AD trial
of a protein kinase C epsilon (PKCɛ) activator, which in
preclinical studies induced the growth of new synapses and
prevented neuronal death. This represents a new therapeutic
strategy for AD that directly addresses the emerging consensus that
synaptic loss has a major impact on cognitive deficits of AD.
The improvements in the primary cognitive endpoint, the Severe
Impairment Battery (SIB), were observed in the study's 20 µg
treatment arm as early as week five, and were maintained throughout
the 13-week study (Table1). The scores for the secondary functional
endpoint, the ADCS-ADL-SIV (Alzheimer's Disease Cooperative Study
Activities of Daily Living Inventory Severe Impairment Version) for
the 20 µg treatment arm showed improvement at week 13. Unlike the
20 µg dose, there was no therapeutic signal observed with the 40 µg
dose. This contrast between the signal observed with the 20 µg dose
versus the 40 µg dose was reinforced by the results of a Cohen's D
analysis, part of an in-depth statistical evaluation of the study
data that found a consistent signal of benefit in SIB and
ADCS-ADL-SIV for the 20 µg dose at the end of the trial.
"Although the study was not powered for statistical significance
at a = 0.05, the clinical effects in the 20 µg group compared to
placebo were consistent in magnitude for cognition and function,
and hold up under multiple sensitivity analyses," said Suzanne Hendrix, PhD of Pentara Corporation, a
leading expert in statistical analysis of AD clinical trial
results. "Standardized effect sizes were small for the sensitivity
analyses for the 20 µg group. Using a standardized effect size such
as Cohen's D allows comparison of effects between different scales
in a way that is independent of the sample size."
Patients dosed with 20 µg had a dropout rate similar to placebo,
while patients dosed at 40 µg experienced poorer safety and
tolerability, and had a higher dropout rate. Treatment
emergent adverse events (TEAEs) were mostly mild or moderate in
severity. TEAEs, including serious adverse events, were more common
in the 40 µg group, as compared to the 20 µg and placebo groups.
These data reinforce the safety and tolerability of the 20 µg
dose.
The lack of signal at the higher 40 µg dose is not entirely
unexpected based on the in vitro dose response features of
bryostatin-induced PKCɛ activation. As seen with the 40 µg dose,
the obligatory downregulation phase appears to override the initial
activation phase, thereby mitigating the desired clinical
effect.
"The persistent improvement seen in the 20 µg group versus the
outcomes seen in the 40 µg treatment arm help define an optimal
dosing range to potentially sustain clinical benefit with minimal
side effects," remarked Daniel
Alkon, MD, President and Chief Scientific Officer at
Neurotrope. "These findings are consistent with preclinical
research on bryostatin-1 and affirm the viability of its mechanism
of action. We are well positioned to move forward with our clinical
development program."
Table 1: SIB Results, MMRM Change from Baseline versus
Placebo
|
SIB Change Score
Difference Compared with Placebo
|
|
Week
5
|
Week
9
|
Week
13
|
20 µg mITT
|
3.0
p=0.056
|
1.0
NS
|
1.9
NS
|
20 µg
completer
|
4.0
p=0.016
|
1.9
NS
|
2.6
p=0.07
|
40 µg mITT
|
0.6
NS
|
-0.6
NS
|
0.8
NS
|
40 µg
completer
|
2.1
NS
|
0.1
NS
|
1.5
NS
|
NS = not statistically significant; pre-specified (per
statistical analysis plan) p <0.1, 1-tailed
The prospective analysis defined two primary patient
populations: the modified intent-to-treat (mITT) population (135
subjects received study drug and had at least one efficacy/safety
evaluation), and the completer population (the 113 subjects in mITT
that completed the 13-week assessment).
The full presentation from the oral session is available at:
http://www.neurotropebioscience.com/Welcome_to_Neurotrope_BioScience/HomePage-Forms/AAICF.pdf
About Bryostatin
Bryostatin-1 is a protein kinase C epsilon (PKCɛ) activator that
works through synaptic growth factors, as well as anti-amyloid and
anti-tangle signaling pathways in the brain. It has been shown in
preclinical efficacy studies to induce the growth of mature
synapses in the brain and prevent neuronal death. Thus,
Bryostatin-1 introduces a fundamentally different biological
mechanism of action with the potential for longer lasting effects
than the other currently available therapies. Bryostatin-1 is the
first PKCε modulator to be tested in a phase 2 clinical study
for patients suffering from moderate to severe AD — a difficult to
treat population.
The rationale for researching this novel mechanism in AD results
from in vitro and in vivo models of AD demonstrating
that modulation of PKCε by Bryostatin-1 enhances synaptogenesis and
prevents neuronal death. As synaptic loss is tightly
correlated with cognitive impairment in AD, this attribute of the
molecule made bryostatin an intriguing candidate for additional
investigation in dementia. Furthermore, preclinical studies also
demonstrated bryostatin reduces toxic Aß levels, prevents plaque
formation, inhibits tau phosphorylation, and enhances
cognition. Thus, the multimodal effects of this first PKCε
modulator offer a potential new mechanism to study in AD with the
ultimate goal to slow or prevent the progression of
disease.
The maximum dose chosen for this study, if normalized to a
standard body surface area (BSA) of 1.73 m2, is similar
to the 25 µg/m2 dose studied in oncology patients and
shown to be relatively safe.
About Neurotrope
Neurotrope is at the forefront of developing a new approach to
combatting AD and other neurodegenerative diseases. The
Company's world-class science offers the potential to realize a
paradigm shift to overcome one of today's most challenging clinical
problems — finding a way to slow or even prevent the progression of
AD.
In addition to the Company's Phase 2 trial of bryostatin-1 in
moderate to severe AD, Neurotrope has also conducted preclinical
studies of bryostatin as a potential treatment for Fragile X
Syndrome, Niemann-Pick Type C disease and Rett Syndrome—three rare
genetic diseases for which only symptomatic treatments are
currently available. The FDA has granted Orphan Drug Designation to
Neurotrope for Bryostatin-1 as a treatment for Fragile X
Syndrome. Bryostatin-1 has already undergone testing in more
than 1,500 people in cancer studies, thus creating a large safety
data base that will further inform clinical trial designs in
AD.
Forward-Looking Statements
Any statements contained in this press release that do not
describe historical facts may constitute forward-looking
statements. These forward-looking statements include statements
regarding the Phase 2 study and further studies, and continued
development of use of Bryostatin-1 for Alzheimer's dementia and
other cognitive diseases. Such forward-looking statements are
subject to risks and uncertainties and other influences, many of
which the Company has no control over. These statements are subject
to the risk that further analyses of the Phase 2 data may lead to
different interpretations of the data than the analyses conducted
to date and/or may identify important implications of the Phase 2
data that are not reflected in these statements. Clinical
trial data are subject to differing interpretations, and regulatory
agencies, medical and scientific experts and others may not share
the Company's views of the Phase 2 data. There can be no
assurance that the clinical program for Bryostatin-1 will be
successful in demonstrating safety and/or efficacy that we will not
encounter problems or delays in clinical development, or that
Bryostatin-1 will ever receive regulatory approval or be
successfully commercialized. Actual results and the timing of
certain events and circumstances may differ materially from those
described by the forward-looking statements as a result of these
risks and uncertainties. Additional factors that may influence or
cause actual results to differ materially from expected or desired
results may include, without limitation, the Company's inability to
obtain adequate financing, the significant length of time
associated with drug development and related insufficient cash
flows and resulting illiquidity, the Company's patent portfolio,
the Company's inability to expand the Company's business,
significant government regulation of pharmaceuticals and the
healthcare industry, lack of product diversification, availability
of the Company's raw materials, existing or increased
competition, stock volatility and illiquidity, and the
Company's failure to implement the Company's business plans or
strategies. These and other factors are identified and described in
more detail in the Company's filings with the SEC, including the
Company's Annual Report on Form 10-K for the year ended
December 31, 2016 and on Form 10-Q
for the quarter ending March 31,
2017. The Company does not undertake to update these
forward-looking statements.
Please visit www.neurotropebioscience.com for further
information.
Contact information:
Investors
Jeffrey Benison, Director of Corporate Communications
Neurotrope Bioscience, Inc.
973.242.0005 Ext. 101
jbenison@neurotropebioscience.com
Media
James Heins
Senior Vice President
ICR Healthcare
203.856.2121
james.heins@icrinc.com