APL-130277 is a unique and patented apomorphine delivery system offering ease of use and pharmacokinetic properties suitable as a rescue therapy to treat motor fluctuations (off-episodes) in patients with Parkinson’s disease (PD). APL-130277 is a sublingual, thin film strip containing apomorphine, buffer and absorption enhancers which rapidly dissolves when placed under the tongue. APL-130277 quickly produces blood levels in normal volunteers that in patients with PD are known to restore relatively normal motor function and may persist longer than the injectable apomorphine hydrochloride sold under the trade names APO-go, Apokyn, and Apomine for management of “off” episodes in PD. Apomorphine is highly lipid soluble, allowing it to quickly cross mucous membranes and the blood brain barrier. Because apomorphine is a mixed D1 D2 agonist, restoration of motor function does not change with disease progression as occurs with other dopamine agonists.
Up to 50% of patients with PD experience daily fluctuations in performing motor activities. These off-episodes range from end of dose, wearing off symptom control, latency to onset of baseline medication benefit for symptom control, or unpredictable inability to control motor activity despite “adequate” baseline medication.
Off-episode market experience with injectable apomorphine illustrates that few PD patients or caregivers elect this treatment option due to fear of injections -- less than 1% of all PD patients even try the injectable rescue therapy in the US. Injections are difficult for patients, inconvenient for caregivers and, for approximately 50% of those who elect subcutaneous apomorphine, injection site reactions are common. For patients, caregivers, and prescribers, APL-130277 has the potential to be more convenient and acceptable than an injection.
The US FDA confirmed that APL-130277 qualifies for the 505(b)2 approval pathway with Apokyn® (apomorphine hydrochloride injection) as the Reference Listed Drug (RLD). The company is seeking FDA guidance for an efficacy approach to the 505(b)2 NDA.
Parkinson’s Disease & Off-Episodes
Parkinson’s disease is the second most common degenerative brain disease. One percent of 60 year olds and 4% of 80 year olds have PD. Dysfunction and loss of dopamine neurons throughout the brain, particularly in the substantia nigra, cause the cardinal symptoms of tremor, difficulty moving, shuffling gait, and postural instability. Disease symptoms manifest only after 60-80% of dopamine neurons in the substantia nigra have died; diagnosis most commonly occurs in the sixth or seventh decade of life. An estimated 4 to 6 million people worldwide have PD (about 1 million in the US alone) a number expected to reach 8.7 million by 2030.
The cornerstone of symptom management in PD is dopaminergic replacement. Initially, patients may be treated with inhibitors of dopamine degradation or dopamine agonists. Eventually, these therapies become insufficient to control motor function as disease progresses. Patients are transitioned to levodopa, often combined with enzyme inhibitors and dopamine agonists. Levodopa is a substrate that is readily synthesized to dopamine by remaining dopamine neurons. Too much levodopa results in excessive brain dopamine which induces dyskinesias - painful cramps or flailing movements. With disease progression, dysfunction and loss of remaining dopamine neurons reduce the brain’s ability to synthesize, store and transport dopamine. The clinical result is patients increasingly cycle rapidly between “off” episodes and dyskinesias with a limited time in normal motor function.
Off-episodes are thought to occur when brain dopamine levels fall below a critical threshold to sustain relatively normal motor function (“on”). Off-episodes may result from: End of dose wearing off (levodopa levels fall ahead of the patient’s next dose), Latency to “on” (a dose of levodopa is not absorbed in the usual timeframe with failure to achieve expected “on”), or Sudden off-episodes or no-“on” (excess utilization of dopamine results in a temporal deficit of brain dopamine).
Off-episodes may occur at any point after onset of symptomatic PD. By the fifth year from diagnosis, half of all PD patients suffer at least one off-episode daily; by the tenth year from diagnosis, virtually all patients suffer at least one off-episode daily. Fear of off-episodes promotes social isolation because patients are embarrassed by off-episodes while in public. A patient’s first awareness of off-episodes most commonly occurs in the morning when the previous day’s doses of levodopa have worn off. The patient is awake and aware but unable to initiate or continue normal morning activities.
APL-130277 Regulatory Plan
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 US 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. The CTH-105 study is expected to begin in mid-2014 subsequent to the acceptance of an Investigational New Drug (IND) application by the FDA. CTH-105 is expected to be completed by the end of Q3 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). The CTH-200 Bridging Study is expected to begin in mid-2014 subsequent to completion of CTH-105. It is expected to be complete by end of Q3 2014 and is required under the FDA’s 505(b)(2) regulations to demonstrate comparability to the reference listed drug.
(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 Safety Study is expected to start in early 2015 and be completed by the end of 2015. 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, the Corporation 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.
Critical findings were:
• Neurologists indicated that they would treat 15% of mild patients, 38% of moderate patients, and 49% of severe patients 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.
Critical findings were:
• Approximately 30% of Parkinson’s patients suffer from “off” episodes at least once daily.
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.
Critical findings were:
• Nineteen products in development or approved have an impact on “off” episodes.
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 extensive research further confirm the Corporation’s identification of unmet medical need and market opportunity for APL-130277.