Episode 115: Repurposing Medications to Slow Progression of PD

Dan Keller 0:02 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.

In the modern era, the standard method of developing a medication for a disease has been to understand the faulty mechanism underlying the disease, and then invent and test a chemical compound for it. Another way, lately gaining more traction, is to rationally sift through the vast array of currently developed medications to choose ones to test for a different disease or indication. This is the approach of the International Linked Clinical Trials for Parkinson's disease program. So far it has focused on 16 potentially useful drugs, some of which have gone into clinical trials.

I spoke with Dr. Patrick Brundin, Director of the Parkinson's Disease Center at Van Andel Institute in Grand Rapids, Michigan, and member of the program, to learn how a basic understanding of Parkinson's disease leads to the choice of drugs for testing, including the actual process of narrowing down the thousands of potential drugs to test a workable few in terms of finding disease-modifying drugs. How are researchers trying to understand the causes of PD, and what sort of things are they using to be able to understand it?

Dr. Patrick Brundin 2:06 Well, first of all, it is important to understand the causes, but also the actual disease process to be able to develop therapies that modify it and slow it down. So that's it. It's a very pertinent question. I think research in this area is being done in a variety of ways. Epidemiology tells us who's more prone to get the disease. Genetics tells us what the gene influences are, and then one can work with cells and experimental animals in the laboratory to try to understand the molecular processes we think are involved. Brain samples from patients who passed away, or doing imaging on the brain or other parts of the body, is important.

Dan Keller 2:46 Is more basic research needed in the biology of Parkinson's, or do you think you have a pretty good grasp of what's going on?

Dr. Patrick Brundin 2:55 No, unfortunately, we need more basic research. We now understand that there is a genetic component, but it's actually not that big. If you go back 30 or 40 years ago, people would say Parkinson's disease is not genetic, it's totally environmental. Now we think if you look at the whole cause of the disease, maybe some 25% is related to genetic risk, but the remaining 75% is still an enigma. We need to understand what are the causes and what are the processes that they trigger, so we can stop them.

Dan Keller 3:27 What are some of the current thoughts on the main areas of molecular changes underlying the disease process?

Dr. Patrick Brundin 3:35 We learned a lot from genetics, because if we look at the relatively rare genetic causes—it's about 5% of all people have an inherited form of disease—we can understand what kinds of cell processes are they affecting, and that might be relevant to the more common garden variety of Parkinson's disease.

And if I were to summarize it in a very big picture, I'd say the three major areas: one is that there's a problem with proteins clumping up, it's called protein aggregation, it's a specific protein that forms clumps, it's called alpha-synuclein. Another major area is that there might be a problem with energy supply in cells, and the energy factories called mitochondria seem to fail in some types of disease. Finally, and perhaps something that's gained more traction in the last five years or so, is that there might be a strong, or there is a strong immune component to Parkinson's. Exactly the nature of that we don't understand, and what starts this inflammatory immune response that seems to be going on.

Dan Keller 4:40 You mentioned alpha-synuclein. Do you think it's causal or could it be a result, and it's just something you can see and measure, so people have sort of decided to attack it?

Dr. Patrick Brundin 4:53 Well, that is a great question. We know that in very rare forms of disease, where there are genetic mutations in the gene of alpha-synuclein, it has to be causal. I mean, this is the problem. There might be one amino acid that has changed, and these families will get a very similar disease to Parkinson's, so they might have an extra copy, actually, of the alpha-synuclein gene, so they make too much of it.

So, in those cases, we can say it's causal. In the other forms, I mean, the 95% that remain, we can't be sure if it's a sign that the disease is ongoing and it's a parallel phenomenon, or whether this clumping could be a response to disease that is trying to rescue cells that are being stressed. But if I had to put my money on something, I would think that alpha-synuclein plays an important role in, if not the very first steps, so, certainly, as the patients get worse over the years, I think those clumps play a role.

Dan Keller 5:57 Are all patients with Parkinson's similar? Do they have a similar disease process, or could there be a final common pathway you see, but sort of like many streams flowing into a river, would you have to dam up each stream separately, or could you dam up the river?

Dr. Patrick Brundin 6:18 Also a great question. I would say that we used to think that all Parkinson's patients were sort of similar, the age of onset might differ, but once again we've learned tremendous amounts about this disease, and it's clear that patients are not all similar. People have tried to group them with mixed results, trying to say, "Here's a cluster that has this particular feature, here's a cluster that has that particular feature," and probably every patient is to some extent unique, and that's a little bit troubling, right? If you're trying to develop a therapy, it might turn out to be very difficult.

Now, on the upside, even though each patient is unique in its details, I do think there are common pathways, and just to take an example, the inflammation that I mentioned, it seems to be present in all patients, more or less in some way, so that might be something one could attack when trying to develop new therapies. Similarly, these clumps of protein, they're present in over 90%—some people say 100%—of people who don't have an inherited form of Parkinson's, so the classical form. So those are certainly two areas where there might be a common pathway that it converges on.

Dan Keller 7:38 You've been looking at repurposing current drugs or compounds to modify the course of the disease. First of all, how do those come to light? And can you tell me about the International Linked Clinical Trials Program?

Dr. Patrick Brundin 7:54 Sure, so drug repurposing means we take a drug that's being used for another disease and we test it in Parkinson's disease. It means that one could cut short the drug development process because that drug has already been tested, hopefully in many patients with this other disease, and proven safe.

And the International Linked Clinical Trials initiative is currently the largest such drug repurposing effort in Parkinson's. It's a collaboration between the Van Andel Institute, where I work, and Cure Parkinson's, which is a patient-initiated foundation in London, UK, and it also has collaborators in Australia, where there's a Parkinson's Foundation also sponsoring this. And the way it works is we have a group of experts—a group of about 15 people meet for a couple of days every year to review new candidates that might be repurposed, and we look in detail at each one of these drugs and think, "Could this be a good one, and how would we test it?" And if we agree on a few every year, two or three every year, we try to move them forward and get them funded by government agencies, industry, and philanthropy.

Dan Keller 9:04 And the International Linked Clinical Trials Program has committees that reviewed what might be good candidate drugs.

Dr. Patrick Brundin 9:14 That's correct. So, we have a scientific committee with people from many of the major research institutions across the world, so people are experts in different things. Some are experts on drugs and drug metabolism, or some are experts on the clinical features of the disease, or the design of clinical trials, and several experts on the molecular mechanisms. So, combined, I think that committee has a reasonably good way of trying to figure out what might work.

Of course, it's still ultimately guesswork, because we don't have a final answer, but we have at least 10 drugs that are in trials at the moment across the world, and the very first one that was tested, now going back about eight years ago, it's called Bydureon. It met its endpoint, its primary endpoint in the first trial, and Bydureon is an anti-diabetic agent used in type 2 diabetes. And in that first trial it was safe, but it also had a hint that it might be slowing up the disease or even improving the symptoms acutely. That means that now there's been interest from the government in the UK, so currently it's going into phase 3, and it'll be tested in six centers, 200 patients over two years, so we'll then get a definitive answer whether this can slow progression and whether maybe there are certain subgroups of patients who are more responsive than others.

Dan Keller 10:46 You can thank those Gila monsters. It came from Gila monster saliva, I think another example of good basic research, where it leads.

Dr. Patrick Brundin 10:55 It is, it is. And it's also an example, sort of, of some degree of serendipity, right? People are looking for something, and maybe find something else, and we go back to the discovery of penicillin by Alexander Fleming, and that's a beautiful example of that too. So, lots of basic research going on. Eventually, basic scientists may stumble upon something profound while they're looking for something else, and that doesn't mean they shouldn't be pursuing what they think is important to begin with, but always have an open mind, always look for the unexpected, and try to understand the unexpected observations.

Dan Keller 11:34 I think Louis Pasteur said that more than a century ago, "Chance favors only the prepared mind." Has anything come out of the ILCT, besides Bydureon, that looks like you should follow it?

Dr. Patrick Brundin 11:50 So, there is another drug that has shown some interesting results. It's a drug called Ambroxol. It's a drug that's been used for decades as a mucolytic drug in respiratory diseases, and by chance it was found that this drug could improve some of the garbage disposal system in cells. And a number of Parkinson's patients have mutations in a protein that is involved in this garbage disposal system, and it looks like our Ambroxol, at least in culture dishes and in mice, can somewhat correct this deficit if you have a problem with this garbage disposal.

And this has now been tested in a trial, a small trial in London, as was the case with Bydureon, and this first trial was successful. It's a small trial, so one can only say it's worth moving ahead. We can't say it's a treatment yet. And they're now looking to move ahead and make a larger trial. And here it's possible to do something which is called precision medicine, or personalized medicine, because here it would be possible to screen patients and select those that have this mutation, or what's actually not a mutation, it's a genetic variant in the garbage disposal system, and say, "Hey, you might be the most suitable ones, because here we have a drug that particularly can target that mechanism."

So I think that's another wonderful, exciting development. Every time I say it's exciting, we should remember we don't have a success yet, right? We don't have a single drug today that will slow progression of Parkinson's disease, so the bar is pretty high in some ways, or not, the bar is low, I guess. If we get anything that works, it's amazing, but it's proven to be very difficult. So, we have to be humble with this task, and not think everything will work. That's one thing we're sure of.

Dan Keller 13:53 I think one implication of what you just said about testing people and saying, "This is a drug that could work for you because you have this variant or you have this metabolic difference," also could muddy the waters when doing clinical trials. If 10% of the people would be amenable to treatment with such a drug or some other drug, and you give it to 100 people, it's not going to look like you're getting much of a signal.

Dr. Patrick Brundin 14:19 You're absolutely right, it's the issue. So that's why, if we come back to what we discussed earlier, it'll be important to understand what are the differences between the different people with Parkinson's, and perhaps then already stratify the patients before the trial and test certain drugs in one group of people, other drugs in another group of people.

But I think this has to be an iterative process. We continuously learn, because we can also go back and look at the trials that have been done, and we can say, "Oh, here were some individuals that seemed to show some remarkable effects. How did they differ? What can we measure or understand in these people, and perhaps get clues?" Then, in the next trial, select for that particular type of patient.

Dan Keller 15:04 Right. Some subgroup analysis, slicing and dicing your results.

Dr. Patrick Brundin 15:10 Yeah, eventually one has to do that.

Dan Keller 15:13 Is there anything interesting or important to add on the topic of repurposing drugs or finding ways to modify the course of the disease?

Dr. Patrick Brundin 15:23 Well, first of all, I think it is exciting that this drug repurposing is also stimulating the formal drug industry. They're saying, "Oh, interesting, you have a signal here in a drug repurposing trial," and they may have a very similar drug that is now unique, so they can patent it, and therefore they can invest lots of money. And it means that with small efforts and small trials funded by small government funds or by philanthropy, one might stimulate the juggernauts of the drug industry, who obviously have motivation of eventually making money, but have lots of investors behind them, stimulate them to go back and do more research in areas that perhaps they would have neglected otherwise. That's a very interesting and positive development of this, and it's—it's actually happening right now with several of these types of drugs that have been tested as repurposed drugs.

Dan Keller 16:18 Very good. I appreciate it. It sounds like it's a worthwhile avenue to pursue. Other times people have looked at rational drug design—they looked at the target, and then they decided to design a drug. It seems like you could speed up the process by taking off-the-shelf drugs and see if they do work.

Thank you. For more information, search our website at parkinson.org for clinical trials. There's information on the value of participating in a clinical trial, how to find ones that are recruiting, and what to consider before enrolling in one. Also, you can find two previous podcasts of interest, titled The Skinny on Clinical Trials in PD and The Golden Year for Testing Disease Modifying Drugs. You can search for drug repurposing on parkinson.org to find out more about this approach to applying current drugs to the problem of PD progression.

If you have questions about today's topic or anything else having to do with Parkinson's, our information specialists can provide answers in English or Spanish. You can reach them at 1-800-4PD-INFO. News and updates about future events and resources are available by joining our email list at the bottom of our website's homepage.

If you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. If you enjoyed this podcast, be sure to subscribe and rate and review the series on Apple Podcasts, or wherever you get your podcasts. 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 every other week. Till next time, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO. That's 1-800-473-4636. Thank you for listening.

Deputy Chief Scientific Officer, Van Andel Institute, Director, Center for Parkinson’s Disease, Grand Rapids, MI, USA

Patrik Brundin earned his PhD in 1988 and MD in 1992, both from Lund University, Sweden, and joined the Van Andel Institute in 2012. He is highly cited in neuroscience with more than 400 publications on Parkinson’s disease and related topics. His research focuses on pathogenic mechanisms of Parkinson’s and development of therapies that slow or stop disease progression or that repair damaged brain circuits. He is a member of the World Parkinson Coalition Board of Directors and The Michael J Fox Foundation for Parkinson’s Research Executive Scientific Advisory Board. He also serves as co-editor-in-chief of the Journal of Parkinson’s Disease and chair of the Linked Clinical Trials scientific committee.