It represents a potentially significant respite for Parkinson’s Disease sufferers – the development of a new medication that lasts longer and requires fewer doses to treat the debilitating symptoms of the disease. And it seems only fitting that the man reporting this possible advance, Robert Hauser, MD, director of USF’s Parkinson’s Disease & Movement Disorders Center, displays a video-conference background image that makes it appear as if he’s an explorer inside a space capsule.
The fact is, Dr. Hauser has been at the helm of Parkinson’s discovery for several decades now, charting a bold course into the unknown of an incurable condition – through research, innovation and seeking enhanced treatments. They include the widely used Hauser Diary for tracking patients’ daily responses and now, evaluation of a newly developed drug – IPX203 – that promises to be more effective in helping patients experiencing movement difficulties.
The findings by Dr. Hauser and colleagues were recently published in JAMA Neurology, a monthly peer-reviewed medical journal of the American Medical Association. At the core is a novel method of boosting decreased dopamine levels with an extended-release formulation of the existing medication – carbidopa-levodopa.
That medication has long been the standard of treatment, yet it has limitations. IPX203 is an extended-release formulation of carbidopa-levodopa being developed by Amneal Pharmaceuticals, and currently awaiting approval by the Food and Drug Administration. To understand how the new medication works and benefits patients, it’s essential to know what carbidopa-levodopa’s strengths and weaknesses are. Here’s how Dr. Hauser explained it:
“In Parkinson’s Disease, people are losing neurons in the brain that make dopamine,” said the professor of Neurology in the USF Health Morsani College of Medicine. “Once they’ve lost 50 percent of those neurons and the chemical dopamine is reduced by half, they develop motor signs of Parkinson’s – slow and small movements, stiffness and tremors.”
That’s why many treatments to control Parkinson’s symptoms are focused on boosting dopamine levels while causing the fewest possible side effects.
“Because we can’t get dopamine directly into the brain, we give a precursor to it called levodopa,” he said. “Levodopa doesn’t get absorbed in the stomach. It has to get past the stomach into the small intestine, where it goes into the blood, gets into the brain and is absorbed by remaining dopamine neurons. It’s then converted to dopamine and is released over time to provide relief from slowness, stiffness and tremors.”
Sounds good. But there is a problem.
Levodopa has a short half-life in the bloodstream – lasting roughly 90 minutes to two hours. It is commonly given in conjunction with a companion drug, carbidopa, to prevent nausea and vomiting. For patients with early Parkinson’s disease, the standard carbidopa-levodopa protocol is to take the medication three times daily, spreading the doses about five hours apart throughout the day and evening.
Unfortunately, over time, Parkinson’s patients continue to lose dopamine neurons and the ability to store and release dopamine is diminished. Consequently, the carbidopa-levodopa benefit starts to wear off more quickly – lasting only four hours instead of five. On top of that, because the drug takes 30 minutes to work, patients often suffer stiffness, slowness and tremors for some 90 minutes between doses. And this problem worsens over time.
“This is the problem, the duration of benefit from each dose gets shorter and shorter,” he said. “Patients tell me, ‘Hey doc, it only lasts four hours and wears off, and then my slowness, stiffness and tremors return.’ And eventually, it may wear off in three hours or even less.”
This pattern is complicated by a related symptom called dyskinesia – marked by involuntary, writhing movements of parts of the body, rapid jerking or twisting, turning movements. When patients develop a sensitivity to levodopa, dyskinesia is the result. Years ago, Dr. Hauser coined the broadly used term for the extreme form of the condition: “troublesome dyskinesia.”
“Dyskinesia can be so bad that you can’t even sit in a chair; it will throw you right out of it,” he said. “We want people to get good benefit from medication – without troublesome dyskinesia – for as much of the day as possible. But the problem is that carbidopa-levodopa in its standard immediate release formulation is lasting a shorter and shorter amount of time, and patients are going up and down in terms of dopamine in the brain and in their physical response.”
Against that complex backdrop, Dr. Hauser and colleagues compared IPX203 to standard carbidopa-levodopa in Parkinson’s disease patients who were experiencing these types of response fluctuations. “The goal is to have a form of levodopa that will last as long as possible without worsening dyskinesia,” Hauser said. And IPX203 appears to have succeeded, pending FDA approval, as a drug that produces better results with fewer doses.
The explanation of results involves two other terms: “on” for periods when patients are getting the benefit of medication and “off” for when they are not. These words are part of the Parkinson’s lexicon and key components of the Hauser Diary. The diary has proven extremely valuable in providing a reflection of clinical status over a period of time.
In evaluating the new drug, Hauser and colleagues found that patients enjoyed significantly more daily “on” time – without troublesome dyskinesia – and required, on average, only three daily doses as opposed to the usual five.
“We found that each dose of IPX203 lasted, on average, 1.55 hours longer than the standard carbidopa-levodopa formulation,” he said. “A lot of people might not understand how much that is, but if you’re trying to live your life in three-hour chunks that’s pretty tough. If you can get it up to 4.5 hours, that makes a big difference for people.”
How does it work?
“It doesn’t start any quicker than the standard formulation,” Dr. Hauser explained. “But the new formulation involves extended-release beads that are manufactured to slowly release medication. In addition, the real key is a muco-adhesive polymer that keeps it attached to the area in the small intestine where it gets absorbed for a longer time. The problem with existing levodopa formulations is that levodopa is only absorbed in the small bowel and since it moves past that area quickly, there is limited time for absorption. IPX203 keeps levodopa in the small bowel longer.”
Dr. Hauser said the FDA has requested more information and that he believes the outlook for eventual approval “appears promising.”
Still, a stark reality exists for Parkinson’s patients. Medications that replace dopamine are effective for five to seven years. Between five and 10 years, sufferers experience greater ups and downs, with more dyskinesia. “And the bigger problem is 10 years and beyond,” Dr. Hauser said. “The disease spreads beyond the dopamine system, and that’s when many people experience balance and cognitive problems.”
No effective symptom treatments have been developed for that stage, which is why the heavy focus is on early detection and slowing the disease down.
“If we can slow it down 50 percent, the people running into problems after 10-12 years might not experience those problems until 20-30 years,” he said. “And since the average onset for Parkinson’s is 60, that would help a lot of people.”