Parkinson’s Disease

Parkinson’s disease is a chronic, progressive neurodegenerative disease that results from the death of certain neurons in an area of the brain called the substantia nigra that controls movement. These neurons are responsible for producing dopamine, an essential brain signalling chemical, or neurotransmitter, that enables smooth, coordinated movements of both voluntary and involuntary muscles throughout the body. The lack of dopamine in patients with PD renders them unable to regulate motor control, producing characteristic symptoms including tremor at rest, rigidity (stiffness), slowness of movement (bradykinesia) and impaired balance and walking, as well as significant non-motor disturbances, including mood disorders, sleep impairment, fatigue, bowel and bladder dysfunction and dementia. By the time of PD diagnosis, approximately 60% to 80% of the dopamine producing cells have died. The onset of symptoms and speed of progression of disease differs for each patient afflicted with the disease. Initially, a patient may have little motor impairment; however, as the disease progresses, motor function and the severity of PD symptoms gradually worsens until a patient is no longer able to perform normal daily tasks such as eating, bathing and dressing.

While the cause of PD remains undetermined, the effects of PD have a devastating impact on the lives of patients and their families, impairing the ability of patients to work or care for themselves, leading to an increased reliance on caregivers and long-term care in their homes or in specialized facilities. More than one million people in the United States and an estimated four million to six million people globally suffer from PD with prevalence increasing with the aging of the population. The debilitating effects of PD result in a significant economic burden for patients, caregivers and the healthcare system in general.
 

Current PD Treatment Approaches and Inherent Limitations

There is no cure or disease modifying treatment currently available for PD. Current treatment strategies are focused on the management and reduction of the major symptoms of the disease and related disabilities, with treatment becoming less effective over time as the disease progresses. The standard of care regimen for the symptomatic treatment of PD is levodopa, which was the first drug approved specifically for PD nearly 50 years ago. Levodopa is mostly administered orally in combination with a peripheral dopamine decarboxylase inhibitor, usually carbidopa, in order to increase the amount of levodopa that enters the brain, and to decrease the frequency of dopamine-related side effects (namely, nausea, dizziness, orthostatic hypotension). Levodopa improves motor function as long as it produces dopamine levels in the brain that remain within an individual’s therapeutic range. Carbidopa/levodopa is initially given three times a day, but its frequency of administration increases as the disease progresses. Carbidopa/levodopa must be started at the lowest dose and titrated slowly with changes on a weekly level in order to lessen the occurrence of dopamine-related AEs.

Levodopa, however, has several limitations relating to its chemical structure, oral delivery and the motor dysfunction in PD patients:

• Levodopa has a short half-life, which decreases as the disease progresses, resulting in the need for higher and more frequent dosing;

• Levodopa must be actively absorbed, or transported, through the gastrointestinal tract into the bloodstream. The ability of levodopa to reach its specific absorption site is dependent on its ability to move reliably through the gastrointestinal tract. PD patients have slowed gastric motility and erratic emptying resulting in fluctuating and unpredictable levels of levodopa in the bloodstream; and

• Gastrointestinal transport is also frequently slowed by meals, decreasing the amount of levodopa that can be absorbed when it is given orally near mealtime. Additionally, in the specific portion of the gastrointestinal tract where this transport occurs, levodopa competes with food (specifically amino acids in food) for active transport.

As a result of these challenges, patients are unable to predictably and reliably count on existing medications or therapies to keep themselves in their therapeutic range and to treat their PD symptoms. Despite efforts by physicians to continually optimize and individualize patients’ regimens, the unreliability of oral levodopa results in episodes of unexpected and often rapid return of PD symptoms. The re-emergence of PD symptoms is referred to as an OFF episode. OFF episodes are thought to occur when brain dopamine levels fall below a critical threshold to sustain relatively normal motor function, or ON. It can be a period of time when a patient’s PD medication is not working adequately to alleviate the patient’s PD symptoms, when the medication has a delayed effect, or does not work at all. On the other hand, excessive levels of dopamine in the brain can cause dyskinesias, or extra, involuntary movements. As the graphic below depicts, as the disease progresses, a PD patient’s therapeutic window narrows and levodopa becomes less effective resulting in increased severity and duration of OFF episodes and ON time with dyskinesia.
 

OFF Episodes and Types of OFF

OFF episodes can be unpredictable or predictable and in some cases episodes may be preceded by non-motor symptoms such as pain, tingling, sweating, and anxiety, which can alert patients that motor-impairing symptoms are returning. OFF episodes are generally categorized into the following four main types, as shown in the below diagram, which illustrates one patient’s response to levodopa over the course of a day.

(1) Morning OFF Episodes. Morning OFF episodes occur after patients take their last dose of dopaminergic drugs late in the evening prior to retiring for the night. After a full night of sleep, the patient has little or no dopaminergic drug left in the brain. As a result, the patient is OFF and has only a small reserve of dopaminergic stimulation. This results in a significant delay in the response to the first morning dose of levodopa or other PD medication, which is also referred to as morning akinesia. This delayed response is unpredictable, and a PD patient cannot rely on the onset of levodopa in the morning. Impaired gastric motility and erratic gastric emptying in PD patients generally delay levodopa absorption or cause it to not occur at all. Morning OFF episodes are considered the most debilitating OFF episodes and the most difficult to treat and to convert to ON.

(2) Delayed ON, Partial ON or Dose Failure. Delayed ON occurs when a patient takes a dose of levodopa, but does not achieve ON in the usual time frame. To the patient, it appears that the dose has not worked. A partial ON occurs when a patient experiences some improvement in motor function but not enough to be able to perform their daily activities. A dose failure occurs if the patient does not experience any response to the dose of levodopa. A delayed ON, partial ON or dose failure may occur for a number of reasons. Oral delivery of levodopa requires the drug to be actively absorbed through the gastrointestinal tract into the blood stream. The gut contains dopaminergic neurons that can become depleted of dopamine. When this occurs, the gut fails to function normally, resulting in delayed, limited or no absorption of the dose. These OFF episodes are also difficult to convert to ON and do not respond to adjunctive PD medications.

(3) End of Dose Wearing OFF Episodes. End of dose wearing OFF episodes are the most common type of OFF episodes. With PD progression, levodopa’s effect decreases in duration. Eventually, levodopa is not fully effective between doses, which causes a patient to go OFF ahead of the next levodopa dose. These OFF episodes occur in a relatively predictable fashion following each dose of levodopa.

(4) Unpredictable OFF Episodes. These OFF episodes occur without warning when the patient is in the ON state and at unexpected times. The goal of levodopa therapy is to maintain a constant blood level of levodopa that is expected to result in a constant supply of levodopa to the brain and, therefore, a constant level of dopamine and dopaminergic stimulation. However, the brain does not use dopamine at a constant rate. Changes in activity level or changes in mood such as agitation or anxiety result in an increased use of dopamine. The brain then depletes the reserves of dopamine, and more time is required to rebuild that dopamine deficit. As a result, a patient in the ON state can unexpectedly and suddenly turn OFF when their normal PD medications are typically effective.

OFF episodes can have a tremendous negative impact on patients’ daily lives. The potential for unexpected loss of motor function or the unpredictable onset of benefit of one’s PD medications can result in patients’ avoidance of certain social settings and hinder performance of simple daily tasks such as eating, bathing and dressing. Further, a patient’s varying consumption of dopamine from variable “daily stresses” as well as the loss of dopaminergic cells, exacerbates the frequency, duration and severity of OFF episodes. As the disease progresses, patients are often forced to leave the workforce and become increasingly dependent on caregivers. In a survey by the German Parkinson’s Association, it was found that OFF episodes and specifically, early morning akinesia, or morning OFF episodes, were the two most significant symptoms suffered by PD patients and the only two symptoms reported as “very important” by more than half of the patients surveyed. Other studies have shown that all types of OFF episodes have a significant negative impact on health-related quality of life in PD patients.
 

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