LAS VEGAS—An oral extended-release agent composed of carbidopa–levodopa microbeads that was shown, in clinical studies, to improve symptoms in patients with early or advanced Parkinson’s disease is one of several promising new therapies for this neurodegenerative disorder, according to a presentation at the American Academy of Neurology’s Fall 2016 Conference.
In addition to extended-release carbidopa–levodopa (Rytary), these therapies include drugs recently approved by the FDA for orthostatic hypotension (droxidopa) and psychosis (pimavanserin) in Parkinson’s disease and investigational agents such as an inhaled levodopa (CVT-301) and a leukemia drug (nilotinib) currently in clinical trials for use in patients with Parkinson’s disease. “These are things that patients are going to be talking to you about and that you all can use in taking care of patients with Parkinson’s disease,” said Jeff A. Kraakevik, MD, Associate Professor of Neurology at Oregon Health & Science University in Portland.
Jeff A. Kraakevik, MD
Expanding the Armamentarium
Dr. Kraakevik presented data on two new deep brain stimulation systems—Vercise from Boston Scientific, which has not yet been approved by the FDA, and Infinity from St. Jude Medical, which has been FDA approved—and a third surgical device from Medtronic, which is not new, but now has new FDA labeling regarding broader MRI compatibility for limited body scans. He also reported on a randomized trial of focused ultrasound for essential tremor that has led to FDA approval and touched on a clinical trial of a specific gene therapy for Huntington’s disease that is now enrolling patients. However, the bulk of his presentation focused on pharmacologic therapy.
Extended-Release Carbidopa–Levodopa (Rytary)
Citing a 2016 review of cumulative data by Dhall and Kreitzman that included five randomized controlled trials, Dr. Kraakevik indicated that Rytary is a superior formulation of carbidopa–levodopa, compared with a prior controlled-release formulation—largely owing to factors related to gut absorption, such as the slow rate at which the extended-release component of the latter formulation goes through the stomach. “Parkinson’s patients are often constipated, so there is a variable gut transport, as well as a protein competing with the carbidopa–levodopa as it [gets absorbed],” he said. “All those things led to this being a fairly unpredictable [process]. If you talk to patients about it, they usually are rather unhappy with the controlled-release formulation, especially as the disease progresses.”
The extended-release formulation of Rytary can entail what essentially amounts to a dosing-related trial period for some patients started on it; but, in Dr. Kraakevik’s experience, patients who stick it out usually are glad that they did. For one, the combination of immediate-release and sustained-release beads in each capsule makes the formulation much more predictable than controlled release. “The patients I’ve been able to get through the transition period have really, really liked it,” he said. “We tell people we are going to have … maybe at least a couple of weeks to a month of trying to figure out what the best dose of Rytary is.”
He also commented on the high cost of the drug. “The company has a support desk that patients can call; but, even with that, every time I’ve had to do a dose adjustment and change the pill I’ve had to do another prior authorization, which then sets it back,” said Dr. Kraakevik. “That also has been a barrier for some of my patients to get started on Rytary. That being said, especially for later-onset … motor fluctuations, it is a very good formulation.”
Droxidopa (Northera)
In terms of treating orthostatic hypotension in Parkinson’s disease, prior agents include midodrine, fludrocortisone, and pyridostigmine. They all work relatively well, according to Dr. Kraakevik; however, if one looks at the studies on midodrine, for example, the data are somewhat equivocal. “It is nice that we have this additional therapeutic in our armamentarium,” he said of droxidopa (Northera). “It is a precursor to norepinephrine, so it has a different mechanism of action than [any] of the medications we have to treat orthostasis.”
Symptom and symptom-impact composite scores from the trial that resulted in FDA approval for droxidopa show a statistically significant difference versus placebo. In his practice, Dr. Kraakevik talks to his patients a lot more about whether they are fainting or feeling lightheaded and a lot less about listing all their orthostatic blood pressure readings over the previous several weeks. Most of his patients have been seeing primary care physicians who, for years, have been telling them that their blood pressure should not exceed 140/90 and that, if it does, they should call their doctor and, if it is more than 180 or 185, they should go to the emergency room.
“I get a lot of phone calls because these medications are going to make these people have blood pressures that are going to be above those ranges,” said Dr. Kraakevik. “It is probably going to be up there for only about five, 10 minutes, and then it is going to come back down. So that is why I do not tell people to focus on the numbers, but more on symptoms. You can see [in the aforementioned trial] that for dizziness/lightheadedness, visual disturbances … [droxidopa] has a nice effect. Looking at symptoms [such as] when they are standing for a long time, standing for a short time, all these things—except for walking for a long time—symptoms were significantly reduced with use of droxidopa.”
Pimavanserin (Nuplazid)
Pimavanserin (Nuplazid) has recently been FDA approved for treatment of hallucinations in Parkinson’s disease. It is a 5-HT2A inverse agonist. Pimavanserin blocks the serotonergic receptor and reduces the stimulation effect, causing a decrease in the ability to create hallucinations to the striatal limit. In a 2014 trial, pimavanserin was shown to significantly decrease hallucinations over 43 days. “It is an effective medication … not much in the way of side effects at this point,” said Dr. Kraakevik. “It does have that QT prolongation possibility, so you need to be a little careful in patients who have some cardiac abnormalities or rhythm abnormalities when you use this medication. But otherwise it is relatively well tolerated.”
Therapeutics on the Horizon
Medications in the pipeline include an inhaled carbidopa–levodopa agent (CVT-301). In a randomized controlled trial of 86 subjects, investigators found it to be effective in rapidly reversing “off” symptoms, Dr. Kraakevik reported. “Most of the patients who were in this trial had reversal of their symptoms within about 10 minutes,” he said, adding that CVT-301 should be in phase III studies soon and coming up for approval within the next two years.
Nilotinib was approved by the FDA in 2010 as a treatment for adult patients with a form of chronic myeloid leukemia. Given its mechanism of action as a tyrosine kinase inhibitor, researchers hypothesize that it could be applicable to Parkinson’s disease. In a phase I study involving 12 subjects, investigators found that all of the patients who received nilotinib had a reversible decrease in their Unified Parkinson’s Disease Rating Scale score while also scoring “much better on their Mini-Mental State Examination,” according to Dr. Kraakevik.
“It reversed when the medication was taken away,” he emphasized. “This led to a lot of press and a lot of questions in my clinic, where we are asked … why is not every [therapy] able to do this? And my response to patients is, ‘Right now we have 12 people in an open-label study. We need more data.’”
Such data could come from a double-blind, placebo-controlled clinical trial currently in the planning stages, “but there have allegedly been some disagreements between the key entities about the best way to proceed, and this has slowed the process significantly.”
—Fred Balzac
Suggested Reading
Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540.
Dhall R, Kreitzman DL. Advances in levodopa therapy for Parkinson disease: review of RYTARY (carbidopa and levodopa) clinical efficacy and safety. Neurology. 2016;86(14 suppl 1):S13-S24.
Fox SH. Pimavanserin as treatment for Parkinson’s disease psychosis. Lancet. 2014;383(9916):494-496.
Kaufmann H, Freeman R, Biaggioni I, et al for the NOH301 Investigators. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014;83(4):328-335.
LeWitt PA, Hauser RA, Grosset DG, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356-1365.
Pagan F, Hebron M, Valadez EH, et al. Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503-517.