What New Therapies for Parkinson’s Disease Are on the Horizon?
HILTON HEAD, SC—Many new treatments for Parkinson’s disease are in the pipeline, according to a lecture given at the 40th Annual Contemporary Clinical Neurology Symposium. Researchers are examining potential symptomatic therapies and neuroprotective agents.
A “Niche Therapy” Emerges
Rapidly acting abortive agents have emerged as “a niche therapy” for Parkinson’s disease, said Thomas L. Davis, MD, Professor of Neurology at Vanderbilt University in Nashville. The purpose of these drugs is to reduce motor fluctuations and unpredictable off periods that sometimes limit patients’ social activities. The only approved treatment of this kind is an autoinjector that delivers apomorphine subcutaneously. The device allows the patient to adjust the dose and delivers it reliably. Many patients dislike giving themselves injections, however.
Several other rapidly acting abortive agents under investigation may soon become available. A sublingual formulation of apomorphine is currently in phase III trials. These self-dissolving strips avoid the potential inconvenience of self-injection, but one challenge is the possibility that patients may swallow the strips before they dissolve fully. These formulations also do not permit fine control of the dose. The phase III trials are almost complete, and this drug could be available in the near future, said Dr. Davis.
Studies of an inhalable formulation of levodopa also are nearing completion. This formulation has a quicker onset of action than an oral formulation. Delivering a consistent dose over various administrations can be challenging for inhaled formulations, said Dr. Davis. A patient in an off period might have trouble breathing deeply enough to get an adequate dose, he added. The therapy has shown promise, however, and may come to market soon.
In addition, researchers are studying two pumps designed to provide continuous dopaminergic stimulation throughout the day. One device delivers apomorphine through a subcutaneous pump and has been available in Europe for several years. The other pump delivers a solubilized form of levodopa methylester salt subcutaneously. A pump provides continuous administration and allows for control over the dose. The volume of medication that a pump can deliver is limited, however, and pumps sometimes irritate the skin.
Downstream Therapies Heighten Levodopa’s Effects
Levodopa acts on the striatum, but investigators also are studying drugs that act at points further downstream in the CNS. Adenosine A2A inhibitors are one potential class of downstream therapies. They heighten the downstream effects of levodopa and may increase on time without causing dyskinesia. They also may reduce freezing of gait. Current symptomatic therapies for Parkinson’s disease lower blood pressure and cause somnolence. Adenosine A2A inhibitors, however, increase blood pressure and act as stimulants.
Caffeine, istradefylline, and tozadenant all inhibit adenosine A2A receptors. Istradefylline has regulatory approval in Japan for the treatment of motor fluctuations and freezing of gait, but study results in the United States did not convince the FDA that the drug was effective. Tozadenant is currently under investigation in the US.
Anecdotal evidence suggests that marijuana reduces tremor, but “it is not really hard to stop tremor if you do not mind making somebody high,” said Dr. Davis. “The problem is that your balance gets worse and your cognition gets worse.” Data indicate that nabilone, a cannabinoid receptor agonist, might decrease dyskinesia, but trials of other cannabinoid receptor agonists and antagonists have been negative. In short, evidence that marijuana is beneficial in Parkinson’s disease is lacking, said Dr. Davis.
Researchers Seek Neuroprotective Agents
Other research in Parkinson’s disease aims to find neuroprotective therapies that could slow disease progression. One obstacle is the lack of a biomarker of disease progression. In a sampling study, investigators are measuring alpha synuclein in various tissues to determine whether synuclein levels could be a biomarker of disease progression.
Structural MRI based on voxel-based morphometric analysis may emerge as a reliable biomarker, said Dr. Davis. Atrophy of certain brain regions over time may be the most sensitive means of observing disease progression. “The resolution of MRI has increased to the point that with computer calculations, you can detect relatively small changes in volume reliably,” he added. Researchers also are studying SPECT ligands, PET ligands, and ultrasound of the midbrain as potential biomarkers.
Despite the lack of a validated biomarker, the NIH Exploratory Trials in Parkinson Disease (NET-PD) program has screened and tested various potential neuroprotective agents. The program has examined creatine, minocycline, CoQ10, nicotine, and pioglitazone, but all of these drugs failed to slow disease progression.
The NET-PD program recently completed recruitment for a study of inosine. The study follows an epidemiologic observation that patients with a higher level of urate, a natural antioxidant and free-radical scavenger, had slower progression of Parkinson’s disease. Because inosine increases the level of urate, the program is studying the drug in a phase III trial.
