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2014-04-24

Cynapsus Therapeutics Inc. : Cynapsus Announces Positive Results of CTH-104 Clinical Study of APL-130277 for Parkinson's Disease

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):
1 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.

1 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.

1 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:
1 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.

1 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).

1 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.

1 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).

1 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...

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