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.
An international survey of 500 practicing neurologists assessed the need for off-episode rescue therapy. From their practical experience, neurologists and movement disorder specialists indicated that 49% of severe, 38% of moderate, and 15% of mild patients suffer at least one off-episode daily -- all potential candidates for rescue therapy. Nevertheless, demand for injectable apomorphine remains extremely low for reasons outlined above. According to the survey and a US commercial assessment by a global consultancy, practitioners believe that up to 30% of Parkinson’s patients might be candidates for treatment with APL-130277 for off-episodes with the number of doses varying from 1 to 2 per day in mild disease to 4 per day in severe disease.
Approximately 75% of surveyed physicians considered APL-130277 a useful means of achieving fast “on” in morning mobilization of patients with PD. A similar majority of surveyed physicians reported that APL-130277 could provide further clinical benefit by allowing patients to reduce daily levodopa consumption thereby forestalling dyskinesias.
Up to 5% of Parkinson’s patients could be using APL-130277 in the fifth full year after launch in each of the US, EU and Japan with a minimal sales and marketing effort. With moderate sales, marketing and training efforts, 10% of patients could be using the drug in the fifth full year of sales.
With a substantial investment in sales, marketing, training and re-imbursement support, it is estimated up to 18% of patients could be using APL-130277 in the fifth full year of sales.
The unique attributes of apomorphine to provide off-episode rescue in PD and the demonstrated activity of Apokyn have led to numerous failed attempts by other firms to reformulate apomorphine for oral, nasal, rectal, buccal, and inhaled routes of administration. APL-130277 is a sublingually administered film strip that dissolves quickly, incorporating a buffer to neutralize the acidity of the apomorphine hydrochloride salt and a permeation enhancer to increase the rate of absorption. Upon sublingual application, the buffer reduces local irritation otherwise caused by dissolution of apomorphine hydrochloride; the permeation enhancers facilitate capillary uptake of apomorphine. The presentation and composition of APL-130277 promote ease of patient use and therapeutic concentrations of apomorphine with a Tmax similar to the Referenced Listed Drug in the US, Apokyn.
The 505(b)2 regulation in the US allows for an NDA to be filed incorporating data from a Reference Listed Drug (RLD). This regulation allows a sponsor’s reformulation of an approved drug to be considered based on a limited set of clinical trials that reduce time and expense to marketing approval. Approval will be sought on the basis of efficacy studies designed to demonstrate clinical benefit of APL-130277 similar to Apokyn, the RLD.
APL-130277 clinical development has occurred in incremental steps after verification of a US NDA strategy.
CTH-101 demonstrated that apomorphine could be delivered in human subjects by a sublingual strip. A drug load (3mg) was used because bioavailability in human subjects was uncertain at the time.
CTH-102 demonstrated that a therapeutic dose of apomorphine could be delivered. An 8 mg API load achieved therapeutic blood levels of apomorphine greater than 3ng/mL in human subjects.
CTH-103 (funded by the Michael J Fox Foundation) demonstrated dose proportionality in preparation for registration studies in Parkinson’s patients. Subjects in CTH-103 were crossed between the APL-130277 film strip and subcutaneous apomorphine. In addition to achieving therapeutic blood levels, there were fewer total adverse events, fewer moderate adverse events and no serious adverse events with the strip formulation.
A bioavailability trial (CTH200) is planned to confirm data from CTH-103 demonstrating that a therapeutic dose range of apomorphine comparable to the RLD can be delivered with APL-130277. In addition, two efficacy studies in apomorphine naïve (CTH300a) and apomorphine experienced patients (CTH300b) are expected to demonstrate similar efficacy to apomorphine injection. A larger clinical trial assessing safety is expected to demonstrate safety, including topical effects of the thin film strip in the sublingual space.