April 24, 2014
TORONTO, CANADA - Cynapsus Therapeutics Inc. (CTH:
TSX-V) (CYNAF: OTCQX), a specialty pharmaceutical company, today
announced positive data from its recently completed CTH-104 healthy
volunteer pilot study of a single 25mg sublingual strip
(APL-130277) dose of apomorphine. APL-130277 is an
easy-to-administer, fast-acting reformulation of apomorphine, which
is the only approved drug in the United States, Europe, Japan and
other countries for the acute rescue of "off" motor symptoms of
Parkinson's disease.
Mr. Anthony Giovinazzo, President and CEO of
Cynapsus commented, "The results from the CTH-104 study in human
healthy volunteers are very important as we move forward with
testing APL-130277 in Parkinson's patients. Not only have we
demonstrated dose proportionality of the doses tested in CTH-103
(10mg and 15mg) and CTH-104 (25mg), but we have demonstrated in
CTH-104 that the 25mg dose is sustained over an extended period of
time (162 minutes) above the minimal efficacious plasma
concentration of apomorphine (approximately 3ng/ml), which is
believed to be a level demonstrating symptomatic relief of "off"
symptoms. Importantly, we believe we are closer to our goal
of being able to provide neurologists and movement disorder
specialists with a range of doses that are needed to treat their
patients experiencing "off" episodes. We look forward to
moving on to our next clinical study (CTH-105) in patients with
Parkinson's disease who are naïve to the use of apomorphine and who
experience at least one daily "off" episode."
Dr. Albert Agro, Chief Medical Officer at
Cynapsus, also commented: "The pharmacokinetic data we have
gathered to date not only supports delivery of our formulation by
the sublingual route, but also gives us confidence that our
formulation may offer several clinically important benefits.
We look forward to demonstrating the effectiveness of our drug in
Parkinson's patients."
CTH-104 Key
Findings
The CTH-104 study was a single dose, single arm,
placebo-controlled, healthy volunteer pharmacokinetic study, which
was designed to examine the pharmacokinetic profile of the 25mg
dose of APL-130277. In total, 13 subjects completed the study
(11 active and 2 placebo). The following are the key findings
of the CTH-104 study, which are also compared to the results of the
CTH-103 study (See the Corporation's January 13, 2014 Press
Release):
-
Dose
Proportionality. A higher blood concentration of
apomorphine was achieved when comparing the 25mg dose of APL-130277
used in CTH-104 to the 10mg and 15mg doses used in the CTH-103
study. Importantly, dose proportionality was achieved when
comparing the maximum concentration achieved (Cmax) and the area
under the curve (AUC). Dose proportionality allows clinicians to
know that increasing the dose of the drug will increase the
patients' exposure to the drug in a predictable way.
2.
Time to Maximum Concentration
(Tmax). The Tmax for the 25mg dose of APL-130277 was
approximately 40 minutes, which was similar for the 10mg and 15mg
doses of APL-130277. The rapid uptake of apomorphine in the
APL-130277 strips is comparable to that described in the Apokyn®
label (i.e. between 10 and 60 minutes).
3.
Maximum Concentration (Cmax). The
mean Cmax of the 25mg dose of APL-130277 was greater than the Cmax
of the 10mg and 15mg doses, as expected. The pharmacokinetic
profiles of all three doses of APL-130277 showed more rounded
curves, as compared to the sharper peaks seen following
subcutaneous injections of apomorphine.
4.
Minimum Efficacious Blood Level (Extrapolated
Time-to-On). The minimal efficacious plasma concentration
of apomorphine that demonstrates symptomatic relief of "off"
symptoms in patients with Parkinson's disease ranges from 1.5ng/ml
to 4.5ng/ml. The 25mg dose of APL-130277 achieved within 8 minutes
an average minimum threshold concentration of 3ng/ml. The
time to reach 3ng/ml in 10mg and 15mg doses of APL-130277 was
approximately 13 minutes and 10 minutes, respectively.
-
Duration Above Minimum
Efficacious Blood Level (Extrapolated Time On). The
average duration above 3ng/ml was 162 minutes for the 25mg dose of
APL-130277. This compares favourably to the 10mg and 15mg doses of
APL-130277 where the average duration above 3ng/ml was 66 minutes
and 129 minutes, respectively. The extended duration of apomorphine
plasma levels above blood concentration associated with "on" in
Parkinson's patients (approximately 3ng/ml) may provide a longer
clinical benefit to patients than following the subcutaneous
injection of apomorphine.
-
No Dose Limiting Side
Effects. The side effects observed in the CTH-104
study were mild to moderate and were not defined to be dose
limiting. The onset of adverse events was consistently
between 15 minutes and 30 minutes after dosing. The most common
adverse events were sleepiness, dizziness and nausea.
*Note: The
CTH-103 study was designed as a three-dose (10mg, 15mg and 25mg)
active comparator, placebo-controlled, randomized cross-over trial
to examine the pharmacokinetic profile of sublingual administered
APL-130277 compared to (2mg, 3mg and 4mg) subcutaneous injections
of apomorphine in healthy volunteers (See January 13, 2014 Press
Release). The 10mg and 15mg APL-130277 sublingual thin film strips
were crossed over to 2mg and 3mg subcutaneous injections, with N=15
and N=14 for the two cohorts, respectively. The intent in the
CTH-103 study for the third cohort was to compare the 25mg
sublingual thin film strip (APL-130277) to the 4mg subcutaneous
injection, but this third cohort could not be dosed due to the
dose-limiting adverse events experienced with the 3mg subcutaneous
injection. The 15mg APL-130277 side effects were mild-to-moderate
and not dose limiting. As a result, the Corporation completed the
CTH-104 study, a single arm, healthy volunteer pharmacokinetic
study to look at the 25mg APL-130277 sublingual strip (without a
crossover to the injection).
Critical Next
Steps
For development of APL-130277 in the United
States, the Corporation will follow the 505(b)(2) regulatory
pathway. Specifically, the Corporation is pursuing the
reformulation of apomorphine from a subcutaneous injection to a
convenient, tolerable and safe sublingual thin film strip. The drug
being delivered (apomorphine) is identical to the drug used in the
injection, and its use will be intended as an acute rescue therapy
for Parkinson's patients experiencing acute, intermittent
hypomobility (i.e. "off" episodes) associated with advanced
Parkinson's disease, which is the description of the use of
apomorphine in the current U.S. approved label.
The 505(b)(2) pathway will require that the
Corporation provide statistically sufficient clinical evidence that
Parkinson's patients experience management of their "off" episodes,
as a result of delivery of apomorphine via the sublingual thin film
strip route. The primary end point will be based on changes in the
Unified Parkinson's Disease Rating Scale Part III (UPDRS III)
movement score. In addition, the Corporation will be required to
provide in a separate study, statistically sufficient clinical
evidence that administering apomorphine via a sublingual thin film
route results in Parkinson's patients experiencing low to no oral
irritation as a result of multiple daily exposures to the drug for
an extended period.
To achieve this, the Corporation currently expects
to complete the following clinical studies:
-
CTH-105 Pilot
Study. A pilot study in patients with Parkinson's disease
who are naïve to the use of apomorphine and who experience at least
one daily "off" episode with a total duration of "off" in any
24-hour period of at least 2 hours. This study is planned to
examine the effect of APL-130277 on relieving "off" episodes over a
single day with a dose-titration used to determine dose strengths
necessary for future clinical development.
-
CTH-200 Bridging
Study. A single dose, crossover comparative
bioavailability and PK study in healthy volunteers. This study is
designed to provide the clinical "bridge" to the FDA's finding of
safety and efficacy for the Reference Listed Drug (s.c.
Apomorphine).
-
CTH-300a Efficacy Study in
apomorphine naïve patients. A double-blind,
placebo-controlled, parallel-design study with Parkinson's patients
who have at least one "off" episode every 24 hours, with total
"off" time of at least 2 hours. The primary end point will be the
change in the UPDRS III score.
-
CTH-300b Efficacy Study in
apomorphine experienced patients. A double blind, placebo
controlled, crossover-designed study with Parkinson's patients who
are presently controlled with the use of apomorphine. The primary
end point will be the change in the UPDRS III score. Upon
successful completion of CTH-300a and CTH-300b, the Corporation
will provide the results to the FDA and request a meeting to seek
final guidance for the design of Safety Study (CTH-301).
-
CTH-301 Safety
Study. A long-term safety study in apomorphine naïve
Parkinson's patients who have at least one "off" episode every 24
hours, with total "off" time of at least 2 hours. The study will
specifically look at the safety and tolerability of the new
delivery route over a minimum period of 16 weeks.
The above clinical development plan has been
vetted with both clinical experts and regulatory consultants who
have expertise in overseeing FDA 505(b)(2) submissions to the
Agency.
In parallel to the studies described above, the
Corporation will be performing the necessary scale-up, process
validation and stability as part of the Chemistry, Manufacturing
and Controls ("CMC") requirements for the filing of the NDA.
Accordingly, all development will be performed according to current
Good Manufacturing Practices ("cGMP") methodology.
Upon completion of the efficacy and safety
studies, as well as the CMC section, the Corporation expects to
begin preparation of a FDA 505(b)(2) NDA in 2016.
About
Apomorphine
Apomorphine, a potent dopamine agonist, is the
only drug approved specifically for the treatment of acute motor
fluctuations/hypomobility (freezing or "off" episodes) in patients
with advanced Parkinson's disease. Presently, apomorphine is
administered by intermittent subcutaneous injection usually via a
pre-filled injection pen, or, in some cases outside the United
States, by continuous infusion pump. Drawbacks associated with
subcutaneous injection therapy for patients and caregivers include
aversion to needles, the need for multiple injections, which can be
painful and are often associated with irritation and inflammation
at the injection site, and the requirement for a degree of manual
dexterity that some Parkinson's patients find difficult.
About Cynapsus
Therapeutics
Cynapsus is a specialty pharmaceutical company
developing a convenient and easy to use sublingual (oral) thin film
strip for the acute rescue of "off" motor symptoms of Parkinson's
disease. Cynapsus' drug candidate, APL-130277, is an
easy-to-administer, fast-acting reformulation of apomorphine, which
is the only approved drug (in the United States, Europe, Japan and
other countries) to rescue patients from "off" episodes. Cynapsus
is focused on maximizing the value of APL-130277 by completing
pivotal studies in advance of a New Drug Application ("NDA")
expected to be submitted in 2016.
Over one million people in the U.S. and an
estimated 4 to 6 million people globally suffer from Parkinson's
disease. Parkinson's disease is a chronic and progressive
neurodegenerative disease that impacts motor activity, and its
prevalence is increasing with the aging of the population. Based on
a recent study and the results of the Corporation's Global 500
Neurologists Survey, it is estimated that between 25 percent and 50
percent of patients experience "off" episodes in which they have
impaired movement or speaking capabilities. Current medications
only control the disease's symptoms, and most drugs become less
effective over time as the disease progresses.
More information about Cynapsus (TSX-V: CTH)
(OTCQX: CYNAF) is available at www.cynapsus.ca and at the System
for Electronic Document Analysis and Retrieval (SEDAR) at
www.sedar.com.
Contact
Information
Cynapsus Therapeutics
Anthony Giovinazzo
President and CEO
(416) 703-2449 x225
ajg@cynapsus.ca
Andrew Williams
COO & CFO
(416) 703-2449 x253
awilliams@cynapsus.ca
Forward Looking
Statements
This announcement contains "forward-looking
statements" within the meaning of applicable securities laws.
Generally, these forward-looking statements can be identified by
the use of forward-looking terminology such as "plans", "expects"
or "does not expect", "is expected", "budget", "scheduled",
"estimates", "forecasts", "intends", "anticipates" or "does not
anticipate", or "believes" or variations of such words and phrases
or state that certain actions, events or results "may", "could",
"would", "might" or "will be taken", "occur" or "be achieved".
Forward-looking statements are subject to known and unknown risks,
uncertainties and other factors that may cause the actual results,
level of activity, performance or achievements of Cynapsus to be
materially different from those expressed or implied by such
forward-looking statements, including but not limited to those
risks and uncertainties relating to Cynapsus' business disclosed
under the heading "Risk Factors" in its March 26, 2014, Annual
Information Form and its other filings with the various Canadian
securities regulators which are available online at www.sedar.com.
Although Cynapsus has attempted to identify important factors that
could cause actual results to differ materially from those
contained in forward-looking statements, there may be other factors
that cause results not to be as anticipated, estimated or intended.
There can be no assurance that such statements will prove to be
accurate, as actual results and future events could differ
materially from those anticipated in such statements. Accordingly,
readers should not place undue reliance on forward-looking
statements. Cynapsus does not undertake to update any
forward-looking statements, except in accordance with applicable
securities laws.
Neither the TSX Venture Exchange nor the OTCQX
International has passed upon the merits of the Offering or
approved or disapproved the contents of this press
release.
--30--
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responsible for the content, accuracy and originality of the
information contained therein.
Source: Cynapsus Therapeutics Inc. via Globenewswire
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