Cynapsus is a clinical-stage, specialty pharmaceutical company developing a convenient and easy to use sublingual thin film strip to manage OFF episodes associated with Parkinson’s disease. Our drug candidate, APL-130277, is an easy-to-administer, fast-acting reformulation of apomorphine, which is the only approved acute drug (in the United States, Europe, Japan, and other countries) to rescue patients from OFF episodes.
Over one million people in the United States and an estimated 4 to 6 million people globally suffer from Parkinson’s disease, and its prevalence is expected to increase with the general aging of the population. Parkinson’s disease is a chronic and progressive neurodegenerative disease that impacts motor activity resulting from the gradual loss of certain neurons responsible for producing dopamine. It is characterized by symptoms including tremor at rest, rigidity and impaired movement and ability to communicate.
Based on a recent studies, it is estimated that between 25 percent and 50 percent of patients experience OFF episodes in which they have impaired movement and/or communication capabilities, with such patients having between one to six OFF episodes daily. OFF episodes are considered one of the greatest unmet medical needs facing Parkinson’s disease patients as they often result in patients’ inability to perform simply daily tasks such as eating, bathing and dressing. As Parkinson’s disease progesses, patients are often forced to leave the workforce early and become increasingly dependent on care-givers.
To date, Cynapsus has studied approximately 110 subjects / patients in five clinical studies, with the most recent result being our CTH-105 Phase 2 clinical trial, which had 16 people with Parkinson's disease who completed the dosing regimen. Out of 16 patients, 14 converted from OFF to ON with clinically meaningful improvement in motor control in as early as 10 minutes after administration of APL-130277 and lasted longer than 90 minutes. The maximum mean change from baseline UPDRS III was 18.4, which is a large clinically important difference. The CTH-105 Phase 2 clinical trial results showed the APL-130277 treatment was safe and well-tolerated, with no local irritation, no postural hypotension and a low number of nausea events.
Cynapsus expects to initiate Phase 3 clinical trials in 2015, which will be of longer duration and with larger patient numbers to confirm the efficacy and safety of APL-130277. The details of these trials will form the basis for the registration package necessary for a 505(b)(2) New Drug Application, or NDA, with the United States Food and Drug Administration, or the FDA, expected to be submitted to the FDA in 2016.
Through surveys and commercial and competitive assessments that we’ve had conducted by third-parties, we estimate APL-130277 may be an appropriate treatment for up to 1 million Parkinson’s patients worldwide, with 800,000 being located in the United States and Europe.
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 and more 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. Top-line results of the CTH-105 study were reported on November 19, 2014.
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-300 Efficacy Study. 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-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 FDA.
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 will begin the preparation of a FDA 505(b)(2) NDA in 2016.
Establishment of compelling clinical market rationale is required to justify a full-scale development program for any drug. OFF episodes in patients with Parkinson’s are disabling and represent a significant clinical problem. They limit the patient’s ability to move, his or her productivity and participation in activities of daily living and social activities. They may also cause severe anxiety and depression, the loss of a sense of self and other disabilities.
The unmet therapeutic need is great because, despite the acknowledged efficacy of the current standard of treatment, the many disadvantages and adverse effects of subcutaneous apomorphine render it inadequate and infrequently used by patients. They include needle aversion, injection pain, inflammation, panniculitis and nodule and scar formation. In addition, many patients, particularly the elderly (in the OFF state), lack the manual dexterity required to self-inject, which may be required up to three or more times daily. Significant unmet need and the many previous failed attempts to develop an alternative to subcutaneous apomorphine indicate commercial viability of APL-130277. To demonstrate that there is a commercially attractive opportunity, Cynapsus has undertaken several market studies and market estimates.
In December 2011, Cynapsus engaged a medical market research consultant to conduct a global survey of 500 practicing neurologists who treat motor fluctuations in Parkinson’s disease.
• Neurologists indicated that they would treat 15% of mild patients, 38% of moderate patients, and 49% of severe patients with APL-130277.
• It is estimated that 30% of all Parkinson’s patients are candidates for treatment with APL-130277.
The report concluded that there was a substantial unmet medical need and that prescribers would find a meaningful place for APL-130277 in Parkinson’s therapy.
In December 2013, the Corporation engaged a global pharmaceutical consulting firm to perform a commercial assessment of the US market for APL-130277. The firm carried out in-depth interviews with key opinion leaders, general neurologists, movement disorder specialists, Parkinson’s patients and payors.
• Approximately 30% of Parkinson’s patients suffer from OFF episodes at least once daily.
• It is estimated that approximately 400,000 patients will be eligible for APL-130277 therapy in 2022.
• It was found that the currently available apomorphine injection imposed a treatment burden on the patient and care giver that was in excess of the benefit of the product.
• It was determined that APL-130277 would have a much lower treatment burden than the injection.
• Parkinson’s patients would be interested in a thin film strip to treat OFF episodes.
The report concluded that APL-130277 would be offered to 10-30% of patients who suffer OFF episodes at least once daily and that 45-70% of patients would accept the treatment. In addition, it is expected that patients could use APL-130277 for 40-70% of their OFF episodes.
In December 2013, the Corporation also engaged an international drug development consulting firm to perform a competitive assessment of APL-130277. The firm identified all known drugs in development for Parkinson’s disease that may have an impact on OFF episodes and identified those that directly or indirectly compete with APL-130277. The firm also assessed the ability of the drugs identified to address the needs of patients with OFF episodes as well as assessing the probability of regulatory success of competitive products in development.
• Nineteen products in development or approved have an impact on OFF episodes.
• Three approved and two products in development are likely directly competitive with APL-130277.
• APL-130277 may be better able to meet patient needs than the three approved competitive products and the two competitive products in development.
• APL-130277 may have a higher probability of regulatory success than the two competitive products in development.
The report concluded that APL-130277 had safety, convenience and efficacy advantages over competitive products on the market and in development.
The results of this research further confirm the Corporation’s identification of unmet medical need and market opportunity for APL-130277.