Many of us have personally experienced or witnessed the impact of Parkinson’s disease (PD), a movement disorder that affects nearly 10 million people worldwide. This chronic, progressive neurodegenerative disorder leads to disability from motor impairments, such as tremors, rigidity, absence or slowness of movement and impaired balance, as well as from non-motor symptoms including sleep disruption, gastrointestinal issues, sexual dysfunction or loss of sense of smell or taste, to name a few.
The ideal outcome of PD clinical research would be to find a cure. But researchers are also looking at novel ways to administer proven Parkinson’s medicines in order to help people living with the disease better control their symptoms and maintain their regular, daily activities.
THE COMPLEXITY OF TREATMENT THAT EXTENDS OVER DECADES
The brain cells that die from PD are responsible for producing dopamine, a neurotransmitter involved in complex behaviors including motor coordination, addiction and motivation. As a result, treatment typically includes the use of levodopa—a medication that is converted into dopamine in the brain and relieves PD symptoms. For the first few years after diagnosis, many individuals’ symptoms are well controlled by levodopa.
The average age of onset is 60, but some people are diagnosed at 40 or even younger, potentially requiring treatment for decades. Over time, a patient’s response to levodopa changes, and the therapeutic window, or period when levodopa is effective, narrows, often leading to the prescription of additional levodopa or more frequent dosing of levodopa to manage symptoms.
As Parkinson’s disease progresses, a patient’s sensitivity to peak concentrations of levodopa increases. Physicians may prescribe more frequent doses of levodopa or a different formulation. They may also try COMT inhibitors or MAO-B inhibitors to extend the duration of activity for levodopa or add dopamine agonists to provide a constant level of dopaminergic stimulation.
Fluctuation of levodopa levels, either too low or too high, can cause side effects and the reemergence or worsening of symptoms. If levels of levodopa are too high, dyskinesia can result (abnormal, uncontrolled or involuntary movement). If the concentration of levodopa is too low, deterioration of motor functions can occur.
The periods that occur when levodopa concentration drops, and a patient’s motor function subsequently declines, are known as OFF episodes. Patients may experience different types of OFF episodes, such as early morning OFF, unpredictable OFF and end-of-dose wearing OFF.
The reappearance or worsening of PD symptoms during such OFF episodes can severely impact a PD patient’s ability to maintain independence and quality of life. OFF episodes may be characterized, in part, by tremor, stiffness or slow movements, and some patients describe them as a feeling of being “frozen.” OFF episodes can impact a person’s ability to speak, to get up from a bed or chair or to walk stably without assistance. Moreover, these episodes become more prevalent over time—about 40 to 50 percent of PD patients experience OFF episodes within two years of starting levodopa therapy. After nine years this rate grows to approximately 70 percent.
CHANGING THE PARADIGM OF TREATING OFF EPISODES
Treating OFF episodes remains a challenge. While some treatments are available, there are still opportunities to improve the options available for patients with Parkinson’s disease. Currently, there are immediate- and extended-release levodopa tablets, and an inhaled form of levodopa, as well as a surgically implanted tube connected to a pump that delivers levodopa directly to the intestine for up to 16 hours. Extended-release amantadine, taken daily, has been shown to reduce the total daily OFF time but does not convert an OFF episode into ON time.
In addition to the medication itself, it is also crucial to consider the way in which a Parkinson’s disease patient takes the medication. Not only can OFF episodes impact a patient’s ability to administer a therapy requiring complex instructions, but the disease also impacts the gastrointestinal system and can impair consistent absorption of medication taken orally.
Apomorphine is currently FDA-approved in an injectable form as a rescue therapy for OFF episodes. It is a fast-acting dopamine agonist (binds and activates dopamine receptors) that can quickly relieve motor fluctuations for a duration of time. Despite apomorphine working well to address OFF episodes, the injectable administration can be a challenge.
A novel administration of apomorphine is currently under review with the U.S. Food and Drug Administration (FDA). This dissolvable film containing apomorphine is applied under the tongue (sublingual) and could be approved by the FDA to treat OFF episodes in early 2019.
Ultimately what’s needed are effective, fast-acting, more tolerable treatments that work for all types of OFF episodes that may occur throughout the day and that patients can use when they are in an OFF state. And just like maintenance levodopa, therapy should be tailored for each patient depending on their needs.
BUILDING TOWARD THE FUTURE OF PD TREATMENT
The primary aim of PD research is a cure, and this is a goal toward which scientists and clinicians continue to strive. Medical advances rely on both small and big leaps to ensure that patients are getting what they need now and to ensure that they can be hopeful for what is to come. PD is a complex disease, and its symptoms have a very real and significant impact on everyday life. Developing medications that truly meet these needs while continuing innovation with the patient in mind is imperative.