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.

Thomas L. Davis, MD

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 A_2A 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 A_2A inhibitors, however, increase blood pressure and act as stimulants.

Caffeine, istradefylline, and tozadenant all inhibit adenosine A_2A 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.

Alpha Synuclein Receives Renewed Attention

The past year has witnessed a renewed interest in alpha synuclein, said Dr. Davis. In Parkinson’s disease, the protein forms abnormal polymers and accumulates in Lewy bodies. Removing abnormal or dysfunctional alpha synuclein might reduce symptoms or modify the disease course. One way to effect this removal is to increase autophagy, the body’s mechanism for clearing dysfunctional proteins.

Nilotinib, a tyrosine kinase inhibitor approved for the treatment of Philadelphia-positive chronic myelocytic leukemia, increases autophagy clearance of alpha synuclein in rodent models. In 2016, researchers randomized 12 patients with either Parkinson’s disease dementia or dementia with Lewy bodies to 150 mg/day or 300 mg/day of nilotinib for 24 weeks. The drug appeared to be safe and well tolerated, and the results suggested possible motor and cognitive benefits of treatment. CSF levels of homovanillic acid, the end metabolite of dopamine, were significantly increased at week 24, compared with baseline, suggesting an increase in dopamine production. The trial was open label.

Other research is examining whether active immunization would produce antibodies and help clear misfolded alpha synuclein. Initial trials of this strategy included 28 participants, most of whom developed antibodies. The antibodies were short-lived, and the researchers administered booster shots at one year. The method appeared to be safe, and the vaccine is scheduled to enter phase II trials. One potential problem with active immunization is that it would be delivered mainly to older individuals, whose immune response likely would be less vigorous than that of younger people, said Dr. Davis. In addition, physicians would have little control over the magnitude of the immune response, and an excessive response could cause encephalitis.

An alternative technique is passive immunity, which entails the delivery of humanized monoclonal antibodies against alpha synuclein. Investigators studied this strategy in a phase Ib trial of 80 participants with Parkinson’s disease. The treatment was safe and well tolerated, and levels of free serum alpha synuclein decreased by as much as 97% with vaccination. The challenge with humanized monoclonal antibodies is that less than 1% of the therapy crosses the blood–brain barrier, said Dr. Davis. “The hope is that you can give so much systemically that even that small amount would be therapeutic.” Further trials of this strategy are under way.

Exercise May Improve Outcomes

Researchers continue to find evidence that exercise is helpful in Parkinson’s disease. Exercise induces the production of neurotrophic factors, reduces oxidative stress, decreases neuroinflammation, and improves cerebral blood flow. For these reasons, exercise might provide neuroprotection.

Improvements in activity-monitoring technology have made tracking activity easier and data collection quicker. Also, sample sizes required for exercise studies have decreased.

The National Parkinson’s Foundation is sponsoring the Parkinson’s Outcome Project, a longitudinal registry that collects outcomes data on 9,000 international participants annually. “Early in the course of this [project], it became clear that patients who exercised did better,” said Dr. Davis. Whether exercise caused improved outcomes was uncertain, however. Physicians have begun encouraging the sedentary study participants to exercise, and the rate of decline has slowed for the patients who began exercising.

“We do not have enough information now to give people exercise prescriptions,” said Dr. Davis. “But activity in general is so much better than inactivity that we just tell patients to find something that they like and do it.”

—Erik Greb

Suggested Reading

Alkadhi KA. Exercise as a positive modulator of brain function. Mol Neurobiol. 2017 May 2 [Epub ahead of print].

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.

Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.