Episode 14: Clinical Trials for Parkinson’s

Dan Keller (00:08)
Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller at the Parkinson's Foundation. We want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research, the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow. Over the past several decades, new treatments have been developed that can help control the symptoms of Parkinson's, but no therapies so far have been able to slow or stop its progression. Every episode of this podcast, we say the fruits of research are the treatments and techniques that will help you live a better life today and in the future. Dr. Tanya Simuni of the Parkinson's Disease and Movement Disorder Center at the Parkinson's Foundation Center of Excellence at Northwestern University Feinberg School of Medicine in Chicago describes some of the current research and why she thinks these potential new drugs are promising. However, she says the tree can only bear fruit if people with Parkinson's are willing to participate in clinical trials. Dr. Simuni discusses a couple treatments that are currently in phase three trials. This means they have already been tested for safety and are being tested in larger study groups to see how well they work. One she mentions is the drug isradipine, which is already approved as a blood pressure medication. The other is inosine. While there are many treatments to reduce the impact of Parkinson's symptoms, the hope is that these new therapies might slow disease progression.

Dr. Tanya Simuni (02:07)
Parkinson's, compared to other neurodegenerative diseases, compared to Alzheimer's disease, is really, on the one hand, privileged, because we have a larger armamentarium of medications that treat the symptoms. We can improve functionality of the patients. We can improve their functional capacity. However, what remains the holy grail of Parkinson's is finding the intervention that would slow and ultimately stop the progression of the disease, and that has been the hottest area of research for years. And specifically now

Dan Keller (02:47)
You carry out trials, you coordinate them, you design them. What's coming along?

Dr. Tanya Simuni (02:52)
So this is an exciting time in Parkinson's experimental therapeutics, and I will position the studies in the phases of the development. Phase three are the studies that were vetted out in the earlier phases of the development and the studies that are asking the ultimate question: is the intervention efficacious? So as of today, there are two disease modification studies being carried out. One of them, with a full disclaimer, I'm fortunate to spearhead, is the drug called isradipine. It is actually a drug that has been approved for management of elevated blood pressure for years and has been found in the lab and in the animal models of Parkinson's to be neuroprotective against development of Parkinsonian features. The mechanism of neuroprotection has nothing to do with reduction of the blood pressure, but has to do with the presence of unique channels present, largely on the cells that are susceptible to Parkinson's pathology, and reducing the activity of those channels translated in a neuroprotective effect in animal models without causing negative implications. That is the data that led to the launch of the early phase studies. We completed a phase two study that demonstrated that the drug had the parameters sufficient for safety to move on to the phase three study. And the phase three study now is in the third year of its development, and we will have the readout of the data in two years. It remains to be seen. The other phase three study is spearheaded by Dr. Schwarzschild from Mass General, and the drug that is being tested is inosine, based on the observation in large epidemiological studies that people with high levels of urate—and urate is one of the most potent antioxidant chemicals in the body—have both lower risk of development of Parkinson's, and if they develop Parkinson's, less of the rate of the progression of the disease. So the team led by Dr. Schwarzschild also conducted earlier phase studies, a phase two study demonstrating acceptable safety of moving on with the study into phase three, and that study just started recruitment of the participants a couple months ago. So as a clinical trialist and as a clinician treating a lot of patients with Parkinson's disease, I cannot resist putting a pitch into the fact that people with Parkinson's should participate in clinical trials. That's the only way for us to find better therapeutic options and ultimately, hopefully, the cure for the disease. So these are the phase two studies, moving on into the earlier phases of the development and jumping all the way into the phase one studies. Probably the most exciting target for the development are the molecules that are approaching the abnormal protein associated with Parkinson's disease. So some of the listeners probably have heard about synuclein-targeted therapies. Synuclein is that protein that is present in every person, but in the Parkinsonian state, it gets clumped, it gets misfolded, and it is believed that that misfolding of the protein and cells having trouble clearing that protein from the cells contributes to the mechanism of the development of Parkinson's and progression of the disease. So there are a couple companies around the world that are developing vaccines—immunization, simplistically saying—against that synuclein. These are early phase development studies, but definitely the studies that are targeting the underlying biology of the disease. All of us are certainly very hopeful that they will be ultimately successful.

Dan Keller (07:11)
In the later-stage trials that you just described with the urate pathway and isradipine, what are the primary endpoints? What's the outcome you're looking for—limiting progression, fixing symptoms?

Dr. Tanya Simuni (07:25)
So these are the studies to slow progression of the disease. So that's the primary readout. That's the primary objective of the study. How do you read out progression of Parkinson's disease? You use what we call validated, reproducible clinical scales in the field of Parkinson's. As of 2016, we do not have objective measures in the form of blood sugar level or cholesterol level to apply an objective variable for the progression, so we use clinical outcome measures, and those will be the readouts of both of the studies.

Dan Keller (08:04)
So you're really looking at the severity of the disease or the clinical symptoms.

Dr. Tanya Simuni (08:10)
Ideally, you want to have the happy marriage of both. Obviously, for the phase three studies, in order for any regulatory agency to approve the molecule, you need to have a readout that is clinically meaningful. So the clinical outcome—the role of biomarkers, and that is an extremely hot word in neuroscience in general, and Parkinson's is an example of that—is that they provide the biological readout whether the clinical improvement was triggered by and linked to underlying improvement of the biology, or whether we are improving compensatory mechanisms of the body, which is no less significant for the clinical outcomes but gives us the other part of the story. The other significance of biomarkers is that they're very important in early phase clinical development because they allow us to separate the winners from the losers much faster than tracking the clinical outcomes that take time.

Dan Keller (09:13)
How long does it take, say, in one of these phase three trials, to accumulate enough symptoms or on a rating scale to see a difference, to know whether the drug is working or not? It seems like a long study.

Dr. Tanya Simuni (09:26)
Again, disease modification studies are looking not at the immediate improvement of the symptoms, but rather at slowing progression of disability. And obviously, in a disease that spans a decade plus, an immediate readout three months from initiation is not going to give us the answer to the story. So the majority of disease modification studies in Parkinson's disease span at least a year, some of them two years. The study of isradipine actually is the longest to be conducted study of disease modification in newly diagnosed people with Parkinson's disease. The duration of that is three years of exposure for every participant. And the reason why we've done that is because it's important for us, if the molecule shows benefit, to have at least a readout over a three-year period of time. We understand that it's not 10, but that if there is a benefit, it is sustainable.

Dan Keller (10:32)
How encouraged are you at this point, from what you see in clinical trials, various pathways, various approaches, that you're going to see really meaningful improvements in therapy, say, within five, six, even 10 years?

Dr. Tanya Simuni (10:46)
You know, if you asked me that question five years ago, I would have said I am cautiously optimistic but will not promise you the timeline. The field has changed remarkably in the last couple of years. A number of pharma companies are coming into the field. There is really exciting research. There is common understanding that Parkinson's is not one disease, but an umbrella under which there are kinds of different ethnicity, different behaviors, so to say, and that we really need to start thinking of personalizing our interventions to different members of the constituency. And there are companies that are stepping into that arena. So really optimistic—cautiously, but really optimistic.

Dan Keller (11:42)
Anything we've missed—interesting to add, important?

Dr. Tanya Simuni (11:46)
Again, I would strongly encourage people affected by the disease to take an active role in management of their disease, meaning a positive outlook, meaning participation in clinical trials, meaning a healthy lifestyle. Everyone with Parkinson's has heard about the role of exercise, should hear about the role of exercise, and really should make that part of daily living. If we're talking about disease modification, animal studies are very convincing on the role of physical activity. In humans, it's more difficult to prove it, but common sense always prevails—you will be in better shape, you will be able to sustain the disability related to the disease better.

Dan Keller (12:35)
Great. Thank you.

Dr. Tanya Simuni (12:46)
If you would like to find out more about what's in development for Parkinson's, or if you want information about finding and participating in a clinical trial, call our toll-free helpline at 1-800-4PD-INFO. Many clinical trials involve medical centers around the country, so there may be opportunities near you. Dr. Simuni mentioned early phase studies that target the protein alpha-synuclein, which is known to be involved in Parkinson's. We talked about these so-called Parkinson's immunizations with Dr. Mark Gutman, so check out our podcast episode of vaccine for Parkinson's. If you have any questions about the topics discussed today, or if you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. We'll respond to some questions in future episodes. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series twice a month like this one. Our next couple of episodes will focus on research, what's new in clinical trials, and why it's important for you to get involved. Till then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-473-4636. Thank you for listening.

Tanya Simuni, MD, is an Arthur C. Nielsen Jr. Professor of Neurology and Director of the Parkinson’s Disease and Movement Disorders Center at Northwestern University Feinberg School of Medicine in Chicago, Illinois. She also serves as Residency Program Director in the Department of Neurology.

Dr. Simuni graduated with her medical degree from Leningrad Medical School and completed an internship in medicine in Leningrad, Russia. She subsequently completed an internship in internal medicine at Albert Einstein Medical Center and a neurology residency and a clinical neurophysiology fellowship at Temple University in Philadelphia. She remained in Philadelphia to pursue a movement disorders fellowship at the University of Pennsylvania, where she served on the clinical faculty for three years and was Medical Co-Director of the Parkinson’s Disease and Movement Disorders surgical program. She is board certified in neurology and clinical neurophysiology.

Dr. Simuni joined the faculty of the Northwestern University in 2000 to build and lead a multidisciplinary movement disorders center that is now a Parkinson’s Foundation Center of Excellence and serves as a training model in the region. She is currently the investigator of more than a dozen PD clinical trials, one of which is a multicenter, phase 3 clinical trial to evaluate isradipine as a potential disease-modifying agent in early PD. Her works have been widely published in peer-reviewed scientific journals and she has lectured nationally on PD and other movement disorders.

Dr. Simuni is an active member of the American Academy of Neurology, American Neurological Association, Movement Disorders Society, Parkinson’s Study Group, Restless Legs Syndrome Study group, and REM Behavior Disorders Study Group.