Advancing Parkinson Disease Treatment By Building On What Works

Peter LeWitt, MD

For a treatment that has otherwise been extremely irregular in its absorption, levodopa has still been the best available option for patients with Parkinson disease.

As new methods for delivery, such as inhaled, rapid onset formulations and longer-acting formulations are developed physicians have improved their control of the treatment. Peter A. LeWitt, MD, the director of Parkinson’s Disease and Movement Disorders Program at Henry Ford Hospital, told NeurologyLive that the developments in deep brain stimulation and gene therapies have also increased the excitement about addressing needs in Parkinson.

In an interview, LeWitt discussed this pipeline of therapies and the enhancement of the clinical understanding of the disease.

NeurologyLive: Is there anything interventional that you have your eye on in the pipeline for Parkinson disease?

Peter LeWitt, MD: Well, after 50 years of levodopa being a very effective therapy—one that makes the most sense for treating a patient—we now have some improved delivery systems. We have therapies that are much longer acting and offer very high levels of continuous control without causing dyskinesias as a peak effect. In addition, rapid onset of effect with an inhaled form of levodopa is very exciting as a rescue therapy. For levodopa therapeutics, it looks like we're finally getting a level of control over a drug that otherwise is extremely irregular in its absorption.

Now, beyond levodopa, we have dopaminergic agonists, which really haven't led to much further improvements that weren't there 20 or 30 years ago, but what we are learning their role in therapy a little bit better and their adverse effects. There's far less of dopaminergic agonists as the way to control the motor fluctuating patient and more reliance on levodopa.

Nondopaminergic therapies are also quite exciting. We've seen one of the class of the nondopaminergic therapies, istradefylline, going on the market in Japan and improving motor fluctuations. Whether this will succeed in getting approved in the US and Europe remains to be seen, but the notion of going downstream from the dopamine system in Parkinson is alive and well. In fact, that's become the mainstay of advanced Parkinson therapeutics, with deep brain stimulation going beyond this pathway of dopamine replacement that can lead to control of tremors, involuntary movements, and maybe other problems including balance in Parkinson.

What are the remaining unmet needs to address in Parkinson?

There's a long list of unmet needs with Parkinson, such as cognitive impairment, hallucinations, and treating the underlying disorder itself, as well as balance problems, freezing of gait, and so on. Each of these calls for their own forms of therapeutics, and it might be that a new drug will help out with these. Certainly not dopaminergic drugs, but necessarily acting on other pathways that we know are affected in Parkinson—that seems to be the way ahead.

Deep brain stimulation or gene therapy approaches, approaches getting inside the brain, may also prove to be the keys to dealing with these long-term problems. For neuroprotection and for slowing down the disease, keeping alpha-synuclein from depositing in neurons and preventing the mechanisms that might be causing the alpha-synuclein to aggregate as the final common pathway of the disease process might be the therapies of the future.

What’s happening right now to address these concerns?

There's some exciting research ongoing right now, and although there have been more than 2 dozen clinical trials of neuroprotection that haven't been successful, there are several ongoing right now including monoclonal antibodies against alpha-synuclein that have a very strong rationale for why they should work. We hope they will be successful.

Lastly, there's just a huge industry of research—academic research, biotech research, big pharma research—that is going after the nooks and crannies of the diversity of what Parkinson is. The freezing of gait problem is a good example: there's electrical stimulation of the brain with wearable devices, as well as drugs, as well as behavioral training effects, all of which might be successful. There seem to be open boundaries for where researchers take an interest in Parkinson. The transgenic mouse and other animal models, they're also going to very much enhance our understanding of the disease better than the models of the past, to help us develop new therapies.

Has anything specifically held back the development of therapies in these areas?

For cognitive impairment, we know the problem. The defuse damage to nerve cells throughout the brain, the thinking areas of the brain, adds a dimension of challenge that is not just putting a neurotransmitter back to work—which is what a lot of Parkinson therapy is. For patients who have tremors, slowness of movement, and so on, simply placing dopamine in the synapse takes away the problems. It’s like throwing a switch. In contrast, the thinking areas of the brain are losing elements of what makes it all work, so there's a bigger challenge there. In fact, it may come down to just neuroprotection and preventing the disease. The same therapy that might prevent the dementia of Parkinson might also be the cure for the motor symptoms. That's one aspect.

For things like hallucinations—well we have a gotten new drug in the last few years that is very targeted for hallucinations. That has been very effective, but I think it's the tip of the iceberg of solving that and other cognition-related problems with targeted therapies.

With respect to prevention of dyskinesias, many patients don't develop it. Why are they so lucky? Well, we have to find out maybe there is something about the way we treat Parkinson, or certain risk factors of which we could take stock and use them as ways to prevent the disease from going into adverse responses, be they dyskinesias, be they freezing of gait, and so on. Looking at the heterogeneity of the disorder and what we treat it with, maybe there are tailored therapies based on genotyping. Or perhaps just response to medication and using that as a guide for choosing long-term therapies of Parkinson.

Balance problems are another example. Falling backward is the typical problem. It's a different part of the brain and nobody has discerned where it is, but it could be easily amenable to deep brain stimulation, as some studies have shown. Or a medication, if only we can find where that drug goes and what it's supposed to do.

Is there any advice you have for your peers in terms of how to recognize symptoms or managing these patients each day?

A few things. First of all, elsewhere in the world—in England, for example—they're fewer neurologists than there are in the state of Michigan, I've learned, so the primary care physicians and geriatricians take on the responsibility of keeping up-to-date on Parkinson because the buck stops with them. There is an evolving information database on managing Parkinson as a team effort, which calls for using ancillary help like physical therapists, and using the sleep specialists to help out and the questions of the sleepy or the fatigued patient, and using the services of, perhaps, primary care doctors who can deal better with constipation and the swallowing difficulties and the muscle cramping that are so commonly comorbidities of Parkinson.

But I think the neurologist has to step in and have a little bit more of an educational role in the community, too. Perhaps by bringing mid-level care into their practices so that they can deal with the feedback and the follow-up of patients so that the neurologist can restrict their role to being diagnosticians—if they don't have time in their community to provide Parkinson care. If you educate a primary care physician very well about the management of one patient, that information can carry over to the next who might not have to be referred as frequently.

Transcript edited for clarity.