Prions, the Pipeline, and the Latest in Parkinson Disease

Bret S. Stetka, MD; Maurizio Facheris, MD, MSc


May 08, 2015

Editorial Collaboration

Medscape &

Editor's Note: While onsite at the 67th American Academy of Neurology Annual Meeting, Medscape sat down with Maurizio Facheris, MD, MSc, senior associate director of research programs at the Michael J. Fox Foundation for Parkinson's Research, to discuss advances in Parkinson disease (PD).

Medscape: Let's start with treatments. What areas of therapeutic research in PD are you most excited about at the moment?

Dr Facheris: Two Fridays ago, the news was released that Adamas Pharmaceuticals received orphan drug status by the US Food and Drug Administration (FDA) for extended-release amantadine, a drug they're developing to treat levodopa-induced dyskinesia in patients with PD. I truly think this is great news and will help speed up development of dyskinesia-specific drugs.

I do wonder where the FDA came up with the cut-off that for a condition to be considered a rare disease, it must affect fewer than 200,000 people in the United States. We did an assessment, and out of the roughly 1 million people in the US with PD, about 38% have some form of dyskinesia, so that's already 380,000 people.

A lot of companies with investigational drugs are looking at improving levodopa delivery. NeuroDerm has developed liquid formulations of levodopa/carbidopa delivered via belt pumps or patch pumps that allow continuous administration and maintain steady blood levels of the drugs. There is also the inhaled levodopa formulation developed by Civitas Therapeutics, now acquired by Acorda Therapeutics.

The Canadian company Cynapsus Therapeutics is developing a sublingual formulation of apomorphine (a dopamine agonist), and IntecPharma is implementing an accordion pill of levodopa/carbidopa that would release the drug for about 8 hours and allow more controlled absorption by the duodenum. Finally, both Impax Rytary® and AbbVie Duopa® (levodopa /carbidopa intestinal gel) are now available in the United States.

The goal of improving levodopa delivery and other dopaminergic strategies is to reduce motor fluctuations and potentially prevent the onset of dyskinesia. So, maybe the FDA is taking these novel developments into account when considering the prevalence of dyskinesia. Regardless, this is truly great news!

The Adamas extended-release compound I mentioned, as well as Acadia's pimavanserin, a drug to reduce psychosis, are the only potential new drugs for PD-related issues that are not just different formulations of classic dopaminergic drugs.

Medscape: You probably saw the data[1] released this week on aducanumab, the first monoclonal antibodies targeting amyloid-beta in people with Alzheimer disease to demonstrate positive results. Are monoclonals against alpha-synuclein being looked at in PD?

Dr Facheris: Yes, that was huge news! As soon as that came out, our CEO wrote us, saying, "This is enormous." And yes, people are looking at immune-based therapies in PD.

There are two approaches: One is active immunotherapy, in which you inject a small fraction of a synthetic alpha-synuclein, causing the body to produce antibodies against synuclein. This is the approach that AFFiRiS is taking. They have PD01A and PD03A in parallel development. AFFiRiS is testing both "vaccines" in two different disease populations that have a high load of alpha-synuclein pathology—namely, PD and multisystem atrophy.

So far, PD01A has been shown to be safe and well tolerated in PD, but AFFiRiS is waiting to see the results from PD03A and the exploratory data on the antibody response for this compound before selecting the best candidate to test in a phase 2 clinical trial (efficacy).

And then you have passive immunotherapy, which Prothena Corporation is pursuing. In this case, they inject monoclonal antibodies directly rather than induce production. The advantage of passive immunotherapy is that you know the specificity of the antibody you created and the amount of antibody that you inject in a person, but you cannot anticipate whether the body will tolerate the antibody (potential immunogenic response). With active immunotherapy, it is difficult to predict the response of someone's body to generate antibodies against a specific target—but the advantage is that it should be safer, because it's the body's natural response against the toxic protein.

It's not all simple, though. The disadvantage with either approach is whether the antibodies can truly enter the brain and bind to the toxic synuclein clumps.


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