Expert Briefing: The Latest Advances in Parkinson’s Research and Treatment

Dr. James Beck 00:00:00
Hello everyone, and welcome to the Parkinson's Foundation Expert Briefings. I'm Dr. James Beck, Chief Scientific Officer of the Parkinson's Foundation, and it's a pleasure to have you with us today. In today's briefing, we'll have an in-depth look at the latest advancements in Parkinson's disease research and emerging treatments. Here, we will cover the current medication pipeline and highlight new therapies and their potential impact on symptom management. Thank you for joining us.

Before we begin, I'd like to do as we always do and just get a sense of who's here joining us today. A poll should have appeared on your screen, and here's an opportunity to let us know your connection to Parkinson's disease.

Are you a person with Parkinson's, a spouse or partner, a healthcare professional, physician, clinician, you name it, on that list? Let's find out who you are. It's part of the process. If you're joining us on Facebook Live, you can put your affiliation with Parkinson's disease, your connection, right there in the comment section. We will see where we are.

Okay. Not surprising. A lot of people with a direct connection to Parkinson's, either living with the disease or care partners, have joined us, as well as some other individuals. Welcome, everyone, to today's expert briefing. Thank you for sharing your connection with Parkinson's disease.

Before we begin our formal briefing, I'd like to take a moment to introduce the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit organization dedicated to improving the lives of those living with Parkinson's by enhancing care and advancing research. Our efforts are deeply rooted in collaboration with the Parkinson's community, as you'll see today, and ensuring that everything we do aligns with your needs and priorities.

Dr. James Beck 00:01:34
Today's program, as I said, is an example of how we're working with you to meet those goals. The Parkinson's Foundation has invested more than $440 million in research and care to improve the diagnosis and treatment of Parkinson's and push scientific breakthroughs forward. One of our key initiatives is PD GENEration. PD GENEration is an opportunity to have free genetic testing and counseling.

If you live with Parkinson's disease, by participating you can learn about your genetic connection to Parkinson's and contribute to the research effort that is underway to better understand the genetic architecture of the disease and, hopefully, drive new treatments and one day a cure. We encourage you to share this opportunity with your community if you've already done it, and I believe together we can make a difference in Parkinson's disease.

Just a reminder that we are recording this expert briefing, so there's no need to worry that if you've missed something, you'll be able to watch it again. By registering, we will send you an email to give you information when that link is available, so you can watch it again and share it with others who may have missed what I think will be a fantastic expert briefing.

I also would like to highlight that our PD Health @ Home series is presented by the Light of Day Foundation, whose generosity has made this programming possible. I'd like to extend our thanks to the Light of Day. Also, thanks to our expert briefing sponsor today, BioVie Pharmaceuticals. For more information on their clinical trials, you can scan that QR code on the screen and pick up some information about their trial to see if that's of interest to you.

Dr. James Beck 00:03:16
Next, I'd like to welcome Dr. Kevin McFarthing as our speaker today. He originally trained as a PhD biochemist, and he held leadership roles in research and development across life sciences, diagnostics and consumer healthcare businesses, with companies that include Amersham, Serono and Reckitt. He currently serves as joint editor of the Clinical Trial Highlights section in the Journal of Parkinson's Disease and as a member of the research committee at Cure Parkinson's, a nonprofit based in the UK. He's also the lead author of an annual review on the clinical trial pipeline in Parkinson's, with the most recent update published in 2024.

Dr. McFarthing curates the Parkinson's Hope List, which is an online global database of therapies in research and clinical development, and chairs the patient and public involvement group for the Edmond J. Safra Accelerating Clinical Trials program. Dr. McFarthing was diagnosed with Parkinson's in 2012 at age 55, and he brings both professional expertise and personal insight into his work in this field. Please join me in welcoming Dr. Kevin McFarthing.

Dr. McFarthing?

Dr. Kevin McFarthing 00:04:30
Can you hear me?

Crista Ellis 00:04:32
Yes, we can hear you.

Dr. Kevin McFarthing 00:04:35
Good. Right. I'm delighted to be here to talk about advances in Parkinson's research and treatment. Many thanks to Jim and Crista for the invitation.

I'll start with some disclosures: none.

Just to clarify what we're trying to do today, we hope to deliver some insights into some breakthroughs in Parkinson's research, learn about upcoming medications and the potential impact on managing these symptoms, talk about emerging therapies and their potential influence on patient care and quality of life, and find out how to participate in clinical trials.

The way I'll do that is to provide some context to the research and development activities in Parkinson's, talk about some options for symptom relief, some options for disease-modifying therapies and, finally, talk about some new trial designs that are coming down the pipeline to increase throughput of agents in clinical trials.

Crista Ellis 00:05:38
Dr. McFarthing, would you share your slides for us, please?

Dr. Kevin McFarthing 00:05:43
Sorry, I thought it was.

Crista Ellis 00:05:45
It happens.

There they are. Thank you so much for sharing.

Dr. Kevin McFarthing 00:06:14
Let's skip back a bit. Learning objectives: getting insights into Parkinson's research and promoting new treatments, learning about new medications coming down the track, seeing how emerging therapies can influence care and quality of life, and how to participate in clinical trials.

As I mentioned, this is the agenda, with the aim to meet those learning objectives.

First of all, it's important to be clear that nothing I say today is intended to be medical advice or any kind of recommendation. If you are inspired to do something to help manage your own Parkinson's, please don't do anything without consulting the appropriate healthcare professional.

Jim's already been through this background. I'll just add one thing. I was diagnosed at 4 p.m. on the 10th of December 2012. I mean, many people remember the day and the time and the context, and the neurologist who did it as well.

Right. It's a tough game trying to develop drugs for the central nervous system. The Tufts Center for the Study of Drug Development in Boston did a study in 2019 that showed that to get one drug out of the end of the pipeline, you need to put $2.6 billion in. That doesn't mean to say it costs $2.6 billion per medicine. This is to have to start off with a very large number of potential medicines. Then they whittle down through various stages of research and whittle down through various stages of clinical trials, but it costs $2.6 billion for the failures as well.

It takes longer than average compared to other disease indications. It's less likely to succeed. It takes longer to get regulatory approval. The FDA priority review is used much less often.

In that context, you could imagine that pharmaceutical companies are not interested in Parkinson's. However, there are some characteristics to the Parkinson's market and world that make it more interesting. The prevalence is increasing. These are figures from 2018 from Dorsey and Bloem, and a recent paper looking in more detail predicted that by 2050 there would be 25 million people around the world living with Parkinson's.

It's a chronic condition. It's not like a throat infection where you could take two weeks' worth of antibiotics and you're cured. For Parkinson's, there is currently no cure, which means there's a big opportunity for the people who deliver that cure.

Dr. Kevin McFarthing 00:09:27
I put cure in inverted commas because that means different things to different people. We probably all have our own individual views of what a cure might mean. It could be anything from a magic bullet that resolves all symptoms and restores abilities back to where we were before it started. I think that's highly unlikely.

For somebody who might be approaching the end of their life, if there's a drug that gives them another 10 years of symptom-free life and they continue to live a natural course, that could be seen to be a cure as well. So there's a full spectrum of potential meaning behind the word cure.

Each year, a company called Pharmaprojects, which is part of the Citeline group, does a study on the state of the pharmaceutical research and development world. They look at the top 25 diseases or indications that are being targeted. We find Parkinson's at number 16, which is a respectable position, but 15 of the 25 indications are cancer. If you take those out, because they dominate, Parkinson's is at number three behind type 2 diabetes and Alzheimer's. It is ahead of rheumatoid arthritis and ahead of obesity. So that's a pretty respectable position to be in.

I started doing my own assembly of what was going on in the research and development world for Parkinson's in about 2013 or 2014, a couple of years after I was diagnosed, looking to produce my own list. It started with a simple Excel list, then expanded and expanded, and it reached something that let's call the Parkinson's Hope List.

That has a list of 355 projects, both for symptom relief and for disease modifying. I put down there at least, because those are the ones that I've been able to find. There are probably more out there that I haven't found yet, and new ones arise almost every week. That's in the research stage, when you're trying to discover molecules, all the way through to clinical Phase 3, where people are trying to get the last piece of data before applying for registration.

The other thing to mention here is that there are 355 projects all being funded by somebody. So not only is there a massive amount of work going on, there's a phenomenal amount of investment going into Parkinson's research and development, and the majority of those 355 are commercial entities.

When we think about the purpose of these potential therapies, they're either going to relieve symptoms, slow down the progress of the disease, stop the progression of the disease or renew what's been lost. The last three are what's called disease modifying, because almost exclusively they try to modify the underlying biology of Parkinson's to stop the bad things happening and, hopefully, get some good things happening with biology.

Dr. Kevin McFarthing 00:13:21
When we look at how this splits the numbers, there are 102 projects looking to relieve symptoms and 253 looking to modify the course of the disease.

The renewal angle is a tough one, because once it's gone, it's gone. You can't get it back. I think that's probably most likely, but there are other ways that quality of life can be improved and some functionality restored.

This is a summary. I won't go into it in great detail, but this is how the data is cut. On the research side, we can find out what's in discovery and preclinical. On the clinical side, we can see which phase a project is in. In both research and clinical, we can look at whether the target of the project is symptom relief or to modify disease.

We can also look at whether something is a new chemical or biological entity, whether it's a reformulation of an existing active, for example, turning levodopa into a nasal spray, or repurposing, which is where you take an existing drug that's been used for a different indication and apply it to the treatment of Parkinson's. It's interesting to note that of the 153 projects in clinical phases, 47, almost a third, are looking to repurpose existing molecules. We have cells and gene therapy.

Each year for the past five years, together with some colleagues from the U.S. and UK, we've written a review of the therapeutics in the clinical trial pipeline. There's a U.S. government website called ClinicalTrials.gov, which acts as the database for almost every clinical trial that's going. You have to register with ClinicalTrials.gov, and it's a fantastic database to analyze active trials.

Sue Brophy is involved with this because her husband has Parkinson's. Gary and Ken have Parkinson's as well. Brian is from the Michael J. Fox Foundation, and the rest of the team is from Cure Parkinson's. We usually end up with about 136 to 140 active trials ongoing. This paper is also open access, so anybody can go along and read it. You can look at the different categories and targets that the clinical trials were aimed at, and lots of interesting information and data in that publication.

Let's look at some things that are going on to relieve symptoms.

This is the Parkinson's iceberg, which some of you may be familiar with. It splits what people see, such as tremor, rigidity, gait problems and slowness of movement, from what people don't see: constipation, panic, loss of smell, hallucinations, depression, pain and bladder problems.

Parkinson's affects each of us in many different ways. I'm sure you've heard the phrase, if you see one person with Parkinson's, you've seen one person with Parkinson's. It's the heterogeneous nature of the disease that makes it challenging to actually do studies on the disease.

What we're finding now is that a lot of projects are being started looking at specific symptoms rather than saying, there's some levodopa, and that's it. That's your medicine. It's exclusively dopaminergic, with dopamine agonists and even more of the treatments like that, to looking at different targets.

Let's first of all just give you some numbers. As you can see, the biggest one is still general symptom relief, primarily dopaminergic. Also, the number of specific symptom relief projects is approaching the number of general symptom relief projects.

To give you an example of some of the things that are going on, just taking some of the projects that are in process for targeting dyskinesia: in Poland, Celon Pharma's CPL'36 has just done a very impressive Phase 2. Also, IRLAB in Sweden has mesdopetam, which is a dopamine receptor antagonist as opposed to agonist, and that has also successfully passed Phase 2 with good efficacy and good tolerance. Vistagen is targeting the NMDA system for a variety of symptoms, including dyskinesia.

The thing that strikes me about these three is that they're all looking at different biological targets. So not just dopamine, not just serotonin, but phosphodiesterase inhibitors, dopamine D3, all different routes to the same objective, which is to relieve the symptoms of dyskinesia. Looking further ahead, Sinopia Biosciences, based in Chicago, has a preclinical candidate for dyskinesia that they're aiming to get into clinical trials fairly soon.

Dr. Kevin McFarthing 00:20:13
Many of us experience dyskinesia and wearing-off periods, but it all comes back to the therapeutic window for L-dopa. When we start taking L-dopa with mild symptoms, the therapeutic window is wide. You can take levodopa, the level goes up in the blood and comes down again, and at the very top or the very bottom, we might experience motor symptoms.

As the disease progresses, this therapeutic window narrows, primarily due to the underlying neurodegeneration and progressive nature of the disease, so that you get more time with potential dyskinesia and more time with potential off periods, and that gets worse as time progresses. What we need is a lesson from Goldilocks. If you go through the therapeutic window, always try to keep in the middle. Not too much, not too little, but just right.

This is the principle that's being used for the launch of a new product called Vyalev, also known as Produodopa in Europe. This is a very smart piece of work by AbbVie, because one of the problems previously with levodopa pumps, and the concept is not original and it's not Nobel Prize-winning, is that the dosages of levodopa that we tend to take, and carbidopa as well, are such that the volume you need to deliver under the skin would be very large.

What they found is that by using the phosphate-substituted levodopa, so levodopa with a phosphate group attached, that is much more soluble than standard carbidopa and levodopa. They're able to use much less volume while still using the same ingredients. It's got a smart device with a pump inside, with a syringe slowly delivering through the tube underneath the skin.

This is a snapshot of some of the levels in the blood. The y-axis is the concentration of levodopa, and on the x-axis you have time. Here, you see the standard oral carbidopa-levodopa going up and down, and here is the Vyalev, taking a lesson from Goldilocks: not too much, not too little, just right.

This chart is from a paper from Professor Ray Chaudhuri's group at King's College London, which was published last year on the new Vyalev product. They found good decreases in off periods. The efficacy was maintained over the 52 weeks of the study. It improved nocturia, so that's not getting up in the night to go to the bathroom as much. It improved freezing of gait. It was monotherapy in approximately 30% of people, so that 30% of people on Vyalev weren't taking any other Parkinson's medicines. There were decreased tremors and dyskinesia, improved sleep and decreased early morning off periods.

It's not without its problems, because some people find skin reactions at the injection sites. So that has to be watched very closely.

Tavapadon is a dopamine agonist that acts on two of the five dopamine receptors, with the aim to reduce common side effects, for example impulse control disorders that are associated with dopamine agonists, and also to deliver better efficacy than the existing agonists. It has done very well in the Phase 3 studies.

They've done three successful trials, one with a fixed dose therapy on its own, a second with a flexible dosing regime, but just on its own, and thirdly, in addition to levodopa. The results from all of them showed good tolerance and good efficacy. Adverse events were low or moderate, and we have an extension Phase 3 on the way. Hopefully, they'll be submitting a dossier to the FDA this year.

It's an interesting story because Cerevel, the company that developed this, was formed out of Pfizer's neuroscience intellectual property, and Bain Capital put about $400 million into this joint venture. Last year, AbbVie paid $7 billion to acquire Cerevel and its clinical pipeline, which includes tavapadon. So from a situation where people were very disappointed and sad that Pfizer were pulling out of neuroscience, to a situation where a potentially new symptom-relieving drug is on the way.

Dr. Kevin McFarthing 00:27:17
Stem cells. It's a tough game to do studies in stem cells because each data point involves brain surgery, and it takes time for the effect on symptoms to become apparent following the implantation of cells. The results have been quite variable despite the work from people like Aspen, the TRANSEURO study and others, but we haven't yet gone beyond Phase 2 with a cell replacement therapy. Until now.

BlueRock Therapeutics, a subsidiary of Bayer, has recently completed a Phase 1/2 trial, primarily looking at safety. I think it was about 17 people, and the new therapy called bemdaneprocel has, toward the end of last year, been approved as a regenerative medicine advanced therapy by the FDA. They're allowing BlueRock to go directly to Phase 3, which they plan to do with about 80 people. This will be very exciting, the first Phase 3 for cell therapy, and good numbers as well.

Let's move to stopping or slowing progression.

This is the Gila monster, and it's an interesting story on GLP-1 agonists. These Gila monsters, by the way, live in the southwestern United States. The bad news is it's venomous to humans. The good news is its maximum speed is one mile per hour. So even with Crocs, we should be able to escape them.

About 20-odd years ago, a molecule called exendin-4 was discovered in the saliva of the Gila monster. This acted with properties like glucagon, which is important in diabetes. Since then, they've grown massively. So Wegovy and Ozempic, names that you might see appearing in the news, are GLP-1 agonists. GLP stands for glucagon-like peptide-1.

They've made a big splash in diabetes and obesity, but they've also been very interesting in Parkinson's because, to cut a long story short, they are neuroprotective. They protect nerves from damage, and that's what we desperately need.

One of the GLP-1 agonists, lixisenatide, was studied in a trial in France that was published last year. This was about 80 people per group with 12 months' worth of treatment. The primary measure was something called the UPDRS, the Unified Parkinson's Disease Rating Scale, Part III, which is the motor examination. This is a summary of the results.

Moving to the left is improvement. Moving to the right is getting worse. The difference between placebo and lixisenatide was about three points, which is similar to the decline that we would expect in normal life. The placebo was declining similarly to patients who would decline anyway, but lixisenatide didn't move, which is very encouraging.

Then there was a Phase 3 for exenatide, one of the earlier GLP-1 agonists, done in London, which was two years' worth of treatment, with UPDRS Part III being the main measure. This was building on a successful Phase 2 and some good preclinical work led by Tom Foltynie at UCL in London. We were expecting more than we got, because what happened was this:

Placebo and exenatide had a very similar outcome. In all of the substudies as well, there was no difference.

There was another GLP-1 agonist trial, liraglutide, with 42 people in the active group and 21 in placebo. There was no difference in motor symptoms, but there was a significant improvement in some key non-motor symptoms.

NLY01, a modified exenatide, had two groups, active and placebo, and there was no difference between the two groups. There are two studies still to report. One is an imaging study in Stockholm, Sweden, and the other is semaglutide, which is Wegovy and Ozempic.

One theory behind why exenatide did not work is that it is an earlier GLP-1 agonist, with not as high an affinity for the receptor as semaglutide has. Now, that will tell us something when the results come out. This is a classic example of the development of drugs. You win some, you lose some.

It does not mean that GLP-1 agonists are dead. Far, far from it. In fact, looking back at the development of levodopa in the 1960s, some of the trials done on levodopa were also negative. We all know today how effective that drug is.

Gene therapy: if you cannot deliver a molecule to the right part of the brain without complicated plumbing, then one option you have is to deliver a gene, which will then produce the protein that you want to have. GDNF, glial cell-derived neurotrophic factor, has been associated with a lot of studies over the years. Now AskBio, also associated with Bayer, is looking to deliver gene therapy for GDNF. That is in phase one at the moment.

Dr. Kevin McFarthing 00:35:26
Some other disease-modifying prospects: inflammation is one of the key things that goes wrong in Parkinson's. A key checkpoint in the process of inflammation is the construction of the inflammasome, and NLRP3 is a molecule that is a key part of the inflammasome. Inhibiting that is a very interesting target. Over the last two years, seven NLRP3 inhibitors have entered clinical trials at the early stage, phase one, with even more being lined up in preclinical.

GBA and LRRK2 are genes that are strongly associated with Parkinson's. People with variants in these genes can produce the wrong kind of GCase, which is the enzyme produced by GBA, or the wrong kind of LRRK2. What we need to do with GCase is increase its activity because it has declined. With LRRK2, we want to inhibit the activity because that gets too active.

Not only have GBA and LRRK2 genes taught us an awful lot about the biology of Parkinson's, but they are also interesting targets for potential therapies. We will go into a bit more detail when we run out of slide time.

Alpha-synuclein is widely thought to be the baddy, the key baddy, in Parkinson's, although there is a theory that the loss of soluble alpha-synuclein is the problem. Most people think targeting alpha-synuclein aggregation is of great interest. This is not just trying to remove alpha-synuclein that has already aggregated and blocked nerves, but preventing that aggregation from happening in the first place. There is a lot of effort focused on alpha-synuclein.

Nicotinamide riboside is a precursor molecule for nicotinamide adenine dinucleotide, NAD, which is a cofactor in many different biochemical reactions in the body. It is felt that by boosting NAD, which can decrease, and making sure that NAD levels, particularly in mitochondria, are normal, that could help slow or stop the progress of Parkinson's. There is an interesting trial underway on nicotinamide riboside.

Growth factors are proteins that help or stimulate nerves to grow. I have already mentioned GDNF. CDNF is cerebral dopamine neurotrophic factor. BDNF is brain-derived neurotrophic factor. There is a lot of work going on, particularly in Finland, on the potential of these molecules as disease-modifying therapies.

Dr. Kevin McFarthing 00:39:20
This is just a simple list of the companies that are working on GBA targets and LRRK2 targets. GBA and LRRK2 together probably account for between 10 and 15% of Parkinson's cases, with the rest of them being either small genetic variants like PINK1 and Parkin, or idiopathic, which is what the majority of us have. There are seven trials going on with ambroxol. I'll tell you more about ambroxol in a few slides' time. There is a lot going on with the genetic target and genetic rationale.

Two potential therapies have been going for some time now, with a lot of effort going into them. Prasinezumab is an antibody against alpha-synuclein. It has gone through two phase two studies now, and in neither one did it meet its primary objective. But there are signals in the data that Roche believes are positive, and so they are carrying on with the project.

Buntanetap from Annovis Bio reduces the production of alpha-synuclein. It did a phase three study that did not meet its primary objective. Again, Annovis believes there were signals in the data that mean they want to carry on trying to dissect out the reasons for success or failure and revisit the clinical development of buntanetap.

We have a challenge in phase three. This is a diagram from the Journal of Parkinson's Disease paper I mentioned earlier. I will not be testing you on your memory for all of these drug agents, so I will only make one point.

The white line going across the middle separates disease-modifying therapies on the top and symptomatic-relief therapies on the bottom. Within each half, you have a repeated slice of phase one studies, a repeated slice of phase two, and a very narrow phase three slice, which includes exenatide and a small project on lactobacillus.

Phase three is the last stage before a company applies to the FDA for approval. As you can see, we have a dearth of phase three disease-modifying therapies in the pipeline at the moment. We need the phase two ones to rapidly get through, hopefully be successful in phase two, and get into phase three. That is the big challenge for today's treatment, which leads me to ways to address that challenge.

Dr. Kevin McFarthing 00:42:54
Edmond J. Safra was a U.S. financier who died with Parkinson's and left behind a tremendous legacy of investment in new initiatives for Parkinson's. As well as funding research, the Edmond J. Safra Foundation funds clinical fellows and a variety of other ways to enhance the life of people with Parkinson's. They funded an initiative to design a new way of doing clinical trials, which is the EJS ACT-PD, ACT being Accelerating Clinical Trials in Parkinson's Disease.

Jim mentioned that I chair the public and patient inclusion and engagement team within the project.

The standard way of doing clinical trials is to go through phases one, two and three, where one has to deal with the issue of testing one active against one placebo, building the infrastructure, including people, and dismantling it once the trial is finished. When it comes to the next phase, it is rinse and repeat. Unless you have lots of money, you end up with long gaps between phases.

The MAMS way of doing it, MAMS meaning multi-arm, multi-stage, is that once you know that a drug is safe enough to go into people, you start with a phase three design. You do not start with phase two. You have interim reviews, meaning any arms that are not showing efficacy can be stopped. You test more than one active against a single placebo and keep the infrastructure because you will have a queue of drugs ready to be tested.

The design would look something like this: start with placebo. Go through year one, year two, year three, year four. That does not change. Treatment one, in this theoretical scenario, passes the interim review there, carries on, passes the interim review there, and is reviewed at the end of five years for phase three interim. The treatment time for the EJS ACT-PD is three years. It takes time to build, to recruit enough people and then to analyze the data, so that is why we think it will be five years.

Meanwhile, treatment two did not pass the interim analysis because there was no sign of efficacy. Treatment three, likewise. You create two spaces there, which can be filled by treatment four and treatment five. Again, they did not work either. Treatment six then comes in, and it is looking good. Treatment seven likewise fails. We expect to get more failures than successes because of the nature of what we are trying to do, but we believe that something will come out of this.

Part of the reason we are quite confident about this is because of the three landmark studies for multiple sclerosis, prostate cancer and motor neuron disease, also known as amyotrophic lateral sclerosis or ALS. They have all produced successful additions to the medicine's armory using this landmark study design.

There are three active drugs starting off: telmisartan, which is used to treat high blood pressure; terazosin, which is used to treat enlarged prostate; and UDCA, which is used for a liver disease called primary biliary cholangitis. We are expecting 480 patients per arm, 1,600 total, and the first one of those are expected to be taking the drugs by early summer.

Dr. Kevin McFarthing 00:47:28
There are some other Parkinson's-related studies underway as well. The HYDRA trial is a phase three trial in Norway. SLEIPNIR, which is also in Norway, aims to be a triage center for phase two studies before accelerating into phase three, with a French version being developed. The Australian Parkinson's Mission has already evaluated three drugs in the Australian Parkinson's Mission Part One, and they are now planning phase two with three more drugs to be tested.

Interestingly, in the second phase, they are looking to test a combination, which is a little different. The P2P trial in the U.S. is the Path to Prevention.

Ambroxol, which I mentioned before, is one of the drugs being used in the combination for the Australian Parkinson's Mission Part Two. There is doxycycline, an antibiotic. It is an old cough medicine that has been used for many years in Central Europe, Germany, Poland and Belgium. Screening of more than 1,600 existing molecules found that ambroxol increased the activity of GCase in models of Parkinson's. GCase is the enzyme produced by the GBA gene.

They did a phase two, which was funded by Cure Parkinson's, in people with Parkinson's who were taking tablets. It was shown to increase the activity of GCase in people as well. Phase three is about to start, and it is particularly important for people who have that GBA gene variant. It is looking at two years of treatment, and 350 people have been recruited.

How do you find your study? Clinical trials are nothing without participants. There are people with the desire and courage, and at times thinking, to join in the study.

The Parkinson's Foundation has a section on the website where you can find and join studies, as does the Michael J. Fox Foundation's Fox Trial Finder. I mentioned ClinicalTrials.gov earlier. That also is a way of finding out what studies are ongoing. The ClinicalTrials.gov data is packaged into a much more easily readable form by Sue Brophy's PD Trial Tracker, and again, you can see what studies might be going on in your local area.

To summarize, Parkinson's is attractive to drug developers for a variety of reasons. There are promising options for symptom relief and for slowing progress. Disease-modifying clinical trials are tough, and we need multi-study ones. But new clinical trial designs will improve the outlook. With that, thank you very much for your attention.

Dr. James Beck 00:51:15
Thank you very much, Dr. McFarthing. I appreciate you sharing that. It was really interesting. I think it is really great to see the context. That is a question I'm sure you've heard, and I know our audience has thought as well: why aren't there new therapies that have come to market? I think it is clear that you have shown it is not for want of trying that there are not new therapies. It is really fantastic to see that there are so many who are trying and spending tremendous amounts of funding in order to advance them, especially those that might stop or even halt Parkinson's disease. I think that is great to see.

Thank you for being able to do that and put that in context. Some of the questions that have come through, I think, have been interesting. When we talk about the different phases of research, phase one is that very early stage, really about safety. Sometimes it is with healthy volunteers, sometimes it is with people who have the disease. Then phase two is a larger study. I guess in Parkinson's, it could be 100 to 200 or so people. Again, safety is a primary concern, but they are looking for a sense of efficacy.

Then that phase three study is really the critical one, where they are looking to see whether this potential therapy can work or not. A question that has come through, I think, is interesting. I am just curious about your thoughts on it. Why are we seeing so many failures in this last step, whether it is with the FDA or the European counterpart, the EMA, as part of that process? What are your thoughts, especially as you talked about that GLP-1 study?

Dr. Kevin McFarthing 00:52:54
It is a difficult and frustrating situation. One issue is the heterogeneity of Parkinson's, because we are all different. Our processes might have started in different ways and might be progressing in different ways. It is much different from those other diseases that do not have the same level of difference.

I think the assessment methods are not ideal either. UPDRS can have variability. There are potentially ways around it, but that is still an issue. There does not seem to be a consensus on the best measure for disease-modifying studies.

Also, we still do not know what exactly causes Parkinson's. We have strong associations with pesticides. We know there is genetic risk, but we do not know what the trigger is to set off the pathology. We do not know whether the pathology is the cause or the consequence of the disease. I think also, because it is a relatively slowly progressing disease, it takes a lot of time to open up any difference between placebo and active. Some of the studies really do not give it enough time.

Dr. James Beck 00:54:41
Why do you think they do not give it enough time? I think you and I both know, but it is good to articulate it for our audience, what one of those barriers is.

Dr. Kevin McFarthing 00:54:51
Money is one thing.

Dr. James Beck 00:54:53
Yeah.

Dr. Kevin McFarthing 00:54:54
There are probably some other reasons. Keeping the interest going for a much longer time is a big challenge. The longest treatment time I can remember is something like the isradipine trial, which was done by Tanya Simuni in Chicago. That was over a period of three years.

Also, it might be the uncomfortable conclusion that if everything else is right, some of these drugs still would not work. Phase three failure is not unique to Parkinson's.

Dr. James Beck 00:55:40
For sure. I think that remains an issue, and that is really one of the reasons why we look to these phase three studies to be, as I say, pivotal in our understanding of whether they are going to work or not as part of the process.

One of the things I think is interesting is that we talked about these novel dopamine agonists that are hopefully going to be coming to the market, tavapadon, which you brought up from AbbVie. Why do you think there is an interest in pursuing these agonists versus conventional levodopa-carbidopa? What would an agonist, in theory, be beneficial for a person with Parkinson's?

Dr. Kevin McFarthing 00:56:27
I guess it is the same principle that we use to add other adjuvants to levodopa, like entacapone or opicapone, for example. It is about extending. It is also a different tool, which approaches the receptor in a different way. I am fairly pragmatic. If it helps me live better for longer by relieving symptoms, then I am interested.

Dr. James Beck 00:57:02
I think it is also one time a day, too, which I think has an advantage over conventional levodopa-carbidopa. Even with some of the extended release, you have to take it multiple times a day as part of that process. Perhaps that is a different dosing because there is a real burden with having to take oodles of pills on a regular basis as part of the process.

You mentioned GLP-1 agonists, and we have not yet seen success on that. I just came from Vienna last week for a meeting on Alzheimer's and Parkinson's disease. It was interesting to hear some of the original researchers in semaglutide talking about how they are looking to push that into Alzheimer's disease, too. Sometimes we have heard, and this was maybe said in jest, that Alzheimer's and Parkinson's disease are type three diabetes.

There has always been hope to be able to apply some of these medications that have been used for type two diabetes to Parkinson's disease. What do you think it is about these GLP-1 agonists that might actually provide the benefit? Is it something direct in helping with bioenergetics, or do you think it could be inflammation that it could help reduce as part of its impact on the brain for people with Parkinson's? Do you have any thoughts on that? I do not know if you have been thinking about that.

Dr. Kevin McFarthing 00:58:37
The risk is this being above my scientific pay grade. I think there is also another potential thing, which is that I think they reduce the aggregation of alpha-synuclein.

Dr. James Beck 00:58:52
Okay.

Dr. Kevin McFarthing 00:58:53
I think there is also glucose intolerance, so insulin resistance, which is happening in the brain as well. I think the GLP-1 agonists can help get over that.

Dr. James Beck 00:59:08
Yeah. I think so, too. I am hopeful that, as you point out, the latest generation might actually show some effect with people with Parkinson's. I was really excited to see this other novel class, which is targeting the NLRP3 medications that can really target brain inflammation. Hopefully, we might see some benefit there, too, because of the issues that are occurring in Parkinson's disease as part of the process.

I know we are coming up toward the end of the time, but if you are listening in the audience, I think Dr. McFarthing has really put forth, and I think made a strong case, that there are a lot of medications that are coming to fruition. They are in clinical trials, but it really depends upon our audience to participate in these trials. ClinicalTrials.gov is one way, as are our own Foundation website and the Fox Trial Finder.

Those are ways, I know, that several questions have come in about looking to participate in clinical trials and without having to wait for your doctor to advise you on it. Those are good ways to do that as part of the process.

Dr. McFarthing, I want to thank you for your time today and presenting the Expert Briefings, the latest advances on Parkinson's research. I would like to thank everyone who has joined us today as part of the process.

We had a lot of questions come in. I'm sorry we did not get a chance to get to them all, but we are doing our best. If your question was not answered, I encourage you to call our Helpline at 1-800-4PD-INFO.

What we are expecting to come next in May is an exciting opportunity, Managing Nighttime Interruptions in Parkinson's Disease, which will be our last expert briefing for the spring. We will take a pause, a hiatus over the summer, and begin again in September with Parkinson's Medications 101 as part of the process.

Needless to say, I should mention that we have a number of resources available to you. In addition to our expert briefing today, we have our PD Health @ Home with our weekly virtual programs as part of the process, and that is something to consider. There is a QR code you can hold your phone up to the screen to register if you are interested, or you can do it the old-fashioned way and type in Parkinson.org/PDHealth.

I would also like to thank again our sponsor BioVie Pharmaceuticals, which has a clinical trial focused on Parkinson's disease. If you are interested in that, you can again pull out your phone, Google BioVie for their website, or go to our Join a Study page where we have a link there as well, if you are interested in that potential recruitment opportunity.

Dr. James Beck 01:01:58
As always, we are here for you as part of the Parkinson's Foundation, either through our website, our Helpline, 1-800-4PD-INFO, or by sending an email our way at Helpline@Parkinson.org. As this webinar comes to an end, the screen may go black, but what should pop up is a little brief survey. We utilize this information to share with our presenters and to think internally about how we can always improve what we are presenting to our community. Please take a moment to fill out that survey. Until then, I look forward to talking to you again in May. Take care.