Cynapsus' product candidate, APL-130277, is an easy-to-administer, sublingual thin film formulation of apomorphine. It is a “turning ON” medication designed to rapidly, safely and reliably convert a patient from the OFF to the ON state and treat all types of OFF episodes, including morning OFF episodes. Our unique packaging is specifically designed to allow most patients, even while OFF, to open the packaging and self-administer the thin film. When patients are OFF or begin to experience the onset of an OFF episode, they simply peel open the packaging, remove the thin film and place it under their tongue, as illustrated in the figure below. The thin film dissolves over the course of a few minutes, allowing the apomorphine to enter into the bloodstream quickly.
We believe APL-130277 has the following advantages:
• as a “turning ON medication” that has demonstrated a clinically meaningful improvement in motor function as early as 10 minutes and converted patients to full ON in 15 minutes;
• it has a demonstrated durable effect lasting through 90 minutes, the last point measured;
• it is designed to address all types of OFF episodes, including morning OFF episodes, at all stages of the disease;
• it delivers apomorphine, the only approved fast-acting dopamine agonist for the on-demand treatment of OFF episodes for PD patients;
• as a thin film, it is designed to be easily administered and used anytime and anywhere with little or no assistance;
• our unique packaging is specifically designed to allow patients, even while OFF, to open the packaging and self-administer the thin film;
• our sublingual delivery method provides a plasma concentration profile of apomorphine that reduces the severity and frequency of dopaminergic AEs seen with injectable delivery of apomorphine, while maintaining efficacy and also avoiding local irritation; and
• it was demonstrated to be safe and well-tolerated in our trials.
Our target market consists of PD patients who suffer at least one OFF episode per day. A 2014 paper by A. Rizos, et al found that approximately 60% of PD patients suffer morning OFF episodes. We believe that nearly all patients that suffer morning OFF episodes suffer other types of OFF episodes. However, not all patients that suffer OFF episodes suffer OFF episodes daily. Therefore, we further estimate that two-thirds of the approximately 600,000 patients that experience OFF episodes suffer at least one OFF episode every day, resulting in an addressable population of approximately 400,000 patients.
Based on academic research and third-party surveys conducted on our behalf, we believe that of these 400,000 patients in the United States, approximately 20% are mild (experiencing one OFF episode per day), approximately 55% are moderate (experiencing two OFF episodes per day), and approximately 25% are advanced (experiencing three or more OFF episodes per day).
A number of other academic papers and research cite data that suggests OFF episodes may be significantly more prevalent. A recent MJFF survey of 3,000 patients with PD found that 90% suffer OFF episodes, 65% suffer at least two hours OFF daily, and 22% experience over four daily hours of OFF time.
APL-130277 Clinical and Regulatory Plan
On February 4, 2015, Cynapsus held an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (“FDA”). For development of APL-130277 in the United States, the Company will follow Section 505(b)(2) of the Food, Drug and Cosmetic Act. The drug substance (apomorphine) in APL-130277 is identical to the active pharmaceutical ingredient in the FDA approved subcutaneous injection, Apokyn®, and APL-130277 is designed for similar usage.
The Section 505(b)(2) regulatory pathway will require the Company to provide statistically significant clinical evidence that PD patients experience improvement in their motor function as a result of delivery of apomorphine via the sublingual thin film route.
To achieve this, the Company currently plan to complete the following clinical studies:
• CTH-200 Bridging Study. A single-dose, crossover comparative bioavailability and pharmacokinetic study in healthy volunteers. This study is designed to allow the Company to use the safety and efficacy data for Apokyn® in its NDA submission to the FDA. This study is planned to commence in the second quarter of 2015.
• CTH-300 Efficacy Study. A double-blind, placebo-controlled, parallel-design study with an estimated 126 PD patients who have at least one OFF episode every 24 hours, with total OFF time of at least two hours per day. The objective is to evaluate the efficacy and safety of APL-130277 versus placebo in patients with PD. Sites will recruit patients over several months. The 126 patients will each be observed for 12 weeks, with dosing at home and in clinic. Patients will be evaluated every four weeks in clinic. The primary end point will be measured at week 12 in clinic. The primary endpoint will be the mean change in the MDS-UPDRS Part III score at 30 minutes after dosing. This study was initiated in the second quarter of 2015.
• CTH-301 Safety Study. A long-term open-label, single arm safety study in PD patients who have at least one OFF episode every 24 hours, with total OFF time of at least two hours per day. The objective is to evaluate the safety and tolerability of APL-130277 in patients with PD over 6 months of treatment. Sites will recruit patients over several months, with each patient being evaluated for six months. An estimated 226 patients will be enrolled, including up to 126 who had been enrolled in the CTH-300 efficacy study and rolled over to this study, plus an additional 100 new patients. The CTH-301 protocol has a built-in adaptive component potentially allowing the open label titration procedure to be modified to at-home titration. This change will be based upon the safety assessment completed by a Drug Safety Monitoring Board in the CTH 300 study. This study is planned to commence in the third quarter of 2015.
In parallel, the Company will continue to perform the necessary development activities, including process validation and stability studies as part of the chemistry, manufacturing and controls, or CMC, requirements for the filing of the NDA. The Company expects that all development will be performed according to current Good Manufacturing Practices methodology.
Additionally, the Company plans to apply for regulatory approval in Europe. The Company expects to use the United Kingdom as the reference country. Management is working with regulatory consultants and apomorphine key opinion leaders in the United Kingdom.