Combining Existing Drugs Introduced New Parkinson’s Disease Treatment
Researchers at Pharma Two B combined two existing Parkinson’s disease drugs to introduce a new treatment, a drug called P2B001.
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- The National Institute of Neurological Disorders and Stroke, a subset of the NIH, estimates that nearly one million people in the United States have Parkinson’s disease. Considering the ever-aging population and the increased risk of Parkinson’s disease with age, neurologists are constantly looking for effective treatment methods. Researchers have recently studied P2B001, a new drug that combines low doses of existing drugs to develop a new treatment method.
PharmaNewsIntelligence interviewed C. Warren Olanow, MD, Professor of Neurology and Neuroscience at the Mount Sinai School of Medicine in New York and CEO of Clintrex LLC, who worked on the study to understand better the drug’s impact on Parkinson’s disease care.
Background
To start, Olanow explained the current issues in treating Parkinson’s disease (PD). He began by explaining that there are multiple treatment methods available to neurologists.
“Neurologists have some pretty good treatments for the early management of Parkinson's disease — not so much for later but pretty good early. However, there isn't universal agreement as to the best way to treat PD patients,” he shared.
Olanow explained that different neurologists have their preferred treatment methods, noting that even he has his own prejudices. That said, “guidelines were released by the American Academy of Neurology recently where they talked about the strengths and weaknesses of currently available therapies.”
Currently Available Medications
Olanow shared some currently available and widely used treatment methods, outlining their benefits and shortcomings. Levodopa — sometimes shortened to L Dopa — is a more commonly used PD drug.
“Levodopa is the most effective drug we have. But using levodopa starts the clock for developing motor complications such as wearing off phenomena and dyskinesia,” he noted. “Those can become severe and disabling and are the primary reason people undergo surgical interventions such as deep brain stimulation. L Dopa is a very effective drug, but has, potentially, severe side effects.”
Another common interventional approach for PD patients is dopamine agonists. According to Olanow, these drugs, while not quite as effective as levodopa, are still very effective in treating PD. Despite their efficacy, these drugs have their own side effects.
“Patients using this interventional approach get a lot of dopaminergic side effects — nausea, vomiting, orthostatic hypertension, and hallucinations. The more serious side effects have been sleep-related problems. There are examples of patients who become so sleepy that they fall asleep without warning. That can happen while driving a car or operating heavy machinery,” continued Olanow.
Beyond levodopa and dopamine agonists, Olanow highlighted issues with MAO-B inhibitors and other interventional approaches.
“The dilemma a doctor has is which to start with. The American Academy of Neurology committee recommended that clinicians start with levodopa, recognizing it carries the risk of motor complications,” reported Olanow.
Pharm Two B
Considering the current limitations of PD treatment, Pharm Two B (P2B) set out to develop a new solution that is equally as effective with a lower risk of side effects.
Hypothesis
“Researchers at P2B asked what happens if we take very low doses of these agents, namely, a MAP-B inhibitor and dopamine agonist pramipexole, make them in dose levels that are not available commercially, combine them, and put them in extended-release formulations?” he inquired.
Olanow hypothesized that “because they're in low concentrations, these drugs might have an excellent side effect profile as most side effects are dose-related. On the other hand, because they act through two different mechanisms, the dopamine agonist acts directly on the dopamine receptors, and the MAO-B inhibitors block the breakdown of dopamine, there may be a synergistic — or at least additive — effect with enhanced benefits in comparison to either one alone.”
Current Study Design
The combined drug design was called P2B001. “The current study was designed to test P2B001 in a dose of 0.6 milligrams pramipexole and 0.75 milligrams rasagiline, both doses lower than what's used in the real world. And in addition, there was an additional arm which was a titrated pharmacologic marketed dose of pramipexole to see how P2B001 compared to optimal doses of pramipexole in terms of safety and efficacy,” recalled Olanow.
Recruitment
According to Olanow, the study recruited over 500 participants who either received P2B001 or the titrated pramipexole. To recruit patients, the scientists had to confirm a PD diagnosis. Olanow shared that many patients with a PD diagnosis do not actually have PD. A publication in the American Journal of Managed Care suggests that nearly 26% of patients diagnosed with PD are misdiagnosed.
Beyond having an accurate diagnosis, Olanow states, “they must be untreated because the team was testing a new way of treating. If patients are already on some other medicine, it would be difficult to see how good this drug was or if another drug was improving symptoms. Additionally, if they got side effects, there would be no way to determine which drug was causing the side effects.”
Study Outcomes
Olanow explained that the study’s primary endpoint was the total Unified Parkinson’s Disease Rating Scale (UPDRS) change. He revealed that “the results showed that indeed P2B001 was superior to either of the individual components and the differences were quite meaningful.” He explains that the superiority was present overall and in individual factors such as daily living and motor skills.
Beyond comparing the combined drug with its individual components, Olanow and other researchers also compared P2B001 to the second arm of the study.
“When the researchers and I looked at how P2B did with respect to marketed doses of pramipexole, we found that, with respect to all of those endpoints previously described, P2B was comparable to pramipexole. They were virtually identical. Additionally, post-hoc non-inferiority studies show that it was not inferior,” asserted Olanow.
In addition to the primary endpoints, Olanow explained that the secondary endpoint was the effect on the Epworth sleepiness scale. Compared to pramipexole, P2B001 was significantly less likely to yield a higher sleepiness score.
Looking Forward
PharmaNewsIntelligence asked Olanow what he thought the next steps were for P2B001. “No two neurologists think exactly the same. Arguments can be made for all the different therapies available today, and for individual patients, there are pluses and minuses,” he responded.
That said, Olanow encourages neurologists to discuss and compare this treatment as they do with all other kinds of treatment. During the conversation, he suggested hosting more conferences where providers and experts can debate the benefits and uses of these drugs, among other PD treatments.
“It is important to have information shared. My experience with clinicians is they love to have information shared in a way with a debate, where they can ask questions and have a live discussion,” he claimed.
As the drug advances in the FDA approval process, neurologists and healthcare professionals will share their opinions or recommended regimens.
“This is a straightforward invention. This low-dose combination has the benefit of high-dose pramipexole. It avoids the side effects to a large degree. It's once a day; it has no titration. It should be considered an initial treatment for Parkinson's patients,” recommends Olanow.
