Recognizing Parkinson Disease and Developing Better Treatments

January 2, 2019

The associate professor of neurology and the director of clinical trials at the University of Florida’s Center for Movement Disorders and Neurorestoration spoke about what’s being developed in the Parkinson disease pipeline.

Adolfo Ramirez-Zamora, MD

Parkinson disease is most commonly recognized by the tremors it causes in a large population of patients who have the condition, however, not all patients will have issues with shaking.

For Adolfo Ramirez-Zamora, MD, the need to understand this is critical to the early recognition of the disease. The associate professor of neurology and the director of clinical trials at the University of Florida’s Center for Movement Disorders and Neurorestoration noted that the detection of slowed movements is perhaps the most important thing for him in the early diagnosis of the disease.

And while early detection is incredibly important, developing better therapies and add-on treatments to address the wearing off of levodopa is another essential area of concern for Ramirez-Zamora. To speak more to what’s being developed, as well as share some insight into the recognition of the disease, he talked with NeurologyLive in an interview.

NeurologyLive: In the Parkinson disease pipeline, is there anything particularly exciting that's stuck out to you?

Adolfo Ramirez-Zamora, MD: The most exciting thing is that they are actively recruiting studies looking at potential disease modification, slowing down disease progression, which is the holy grail of treatment of Parkinson disease. Can we slow down this progression? Currently, there are a couple of studies that are going to have results next year, and there is a new group of potential therapeutic strategies have been established.

For the first time ever, we're starting to see studies that are specific to the patient. Now, for the longest time, we’ve recognized that Parkinson is not a single disease and there are different mechanisms that are probably causing the disease in a specific patient. In the past few years, 2 studies have been specifically designed to target people that have a specific genetic makeup—people that have LARRK2 mutations or mutations in the GABA gene. Now, there is a specific treatment that is looking at a group of people that are defined not only by having Parkinson disease, they're defined by the genetic makeup that may have a specific mechanism causing the disease. I think our chances of finding a better treatment for slowing down disease progression are much better now that we can really target the specific mechanisms that may be afflicting the patient.

That's really exciting, that we're moving from putting all these people in Parkinson in the same umbrella and give them vitamin D or E, and now we're separating them based on the genetic makeup and trying to look for better treatments.

Are there any recommendations you have for your peers in terms of how to look out for Parkinson disease?

The main thing is that it will be good to put out there that not everybody shakes. Not every patient with Parkinson disease has tremors. Parkinson disease is defined by slowness of movements, reduced amplitude and frequency of movements, rather than tremors. Patients that have Parkinson and tremors are much easier to be identified as having Parkinson disease, and for patients that don't, it's a little bit harder. You should look for possible Parkinson disease when somebody's moving very slowly. That should be the main thing when it comes down to considering the diagnosis.

For systemic therapies, we're very good at treating some of the motor symptoms of Parkinson, at least early in the disease. Levodopa and some of these related drugs are very effective. We have advanced therapies for complications like motor fluctuations—deep brain stimulation, levodopa intestinal gel—they do a really good job treating that. We need better treatments for the nonmotor symptoms of Parkinson, like psychosis, cognitive impairment, posture instability, depression, and anxiety. We definitely need better treatments for that.

It's exciting that there are new upcoming formulations of levodopa, there's very active research looking at different ways to deliver the drug—extended release preparations, infusion of levodopa subcutaneously using an infusion pump. There's quite a bit of interest and all these new strategies to help with symptom management, but the biggest gap is in the nonmotor symptoms.

Is there anything in development for those nonmotor symptoms that holds promise in your eyes?

There are a variety of medications looking at potential freezing of gait by modulating other neurotransmitters. I think that a big message should be that Parkinson disease is not only a problem with dopamine. Other neurotransmitters are affected. Serotonin and norepinephrine, they're also affected, and they may actually cause some of the most debilitating symptoms later in the disease. There are small trials looking at some of these medications to help cognition. There are variety of drugs that’re trying to modulate dopamine and serotonin to maybe help with some of these nonmotor symptoms and balance problems, but those are much more complex than tremor, which you can measure quickly in clinic.

What's been the biggest improvement in terms of off time management? What’s still needed?

The widespread application of advanced therapies has been very helpful for people to have off times. Deep brain stimulation, Duopa (carbidopa/levodopa enteral suspension), and even apomorphine infusions are better than best medical treatment, consistently. The difference is significant. Advanced therapies have been tremendous in helping to reduce wearing off and motor complications in the past few years. The wide acceptance of this and targeting patients earlier in the disease rather than later, when there is nothing else to offer, has really helped. This is probably the biggest breakthrough to try to help with the motor fluctuations

Developing new formulations of levodopa that can provide a stable concentration and control of the symptoms is very exciting. We don't have a drug that has been better than levodopa, so the focus continues to be optimizing levodopa. Unfortunately, all these other drugs have been tested, but nothing is better, so the biggest breakthrough in wearing off has been in maximizing the use of levodopa. There is excitement that there may be a new subcutaneous infusion that may be helpful. There are some new drugs that are delivered differently, these gastro-retentive devices that stay in your stomach and then slowly deliver levodopa to reduce off time, there are also rescue medications that are becoming available that are not injectable. Apomorphine sublingual film seems to be effective, intraoral levodopa maybe also very helpful for off times. There are a variety of drugs that are becoming available to help with the off times. But the biggest breakthrough has been the use of advanced therapies, like levodopa intestinal gel and deep brain stimulation.

Sometimes it’s useful to think about the therapies when the movement, wearing off, and dyskinesia are the main source of disability for patients. We used to think that these therapies were the last resort, but we want to use these therapies at the mid-levels of the disease because that's when you can have the biggest impact in quality of life.

What’re your thoughts on the COMT inhibitor class, with treatments like opicapone?

There was there was a need for better tolerated and efficient once-a-day inhibitors. We have another COMT inhibitor that's really good, but nobody uses it because you have to monitor liver enzymes. That's called tolcapone. Opicapone is fairly equivalent to some other drugs that we have here. The effectiveness opicapone was similar to entacapone and rasagiline, so about an extra hour of on time with once a day dosing, and it was fairly well tolerated. It seems like it's another drug that's going to add to the treatment of Parkinson disease. It's not going to drastically change the effectiveness of how we treat it. It’s going to be an add-on medication to levodopa for patients when they have wearing off, making it more convenient and probably better tolerated.

There's always a need for medications that help with the wearing off in different categories, and it seems like the data of opicapone in 2 big trials in Europe is fairly robust and consistent of providing a clear benefit over placebo.

Transcript edited for clarity.