Marketwired, 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.
5. 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.
6. 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.
2. 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).
3. 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.
4. 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).
5. 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.
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.
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.
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