Dr. James Beck 0:02
Hi everyone. My name is Dr. James Beck. I'm the Chief Scientific Officer of the Parkinson's Foundation. I want to welcome you to our first expert briefings of the 2023 season. This is our 14th year. And today our topic is Parkinson's and medication: what's new. Before we get started, I just want to orient you a little bit to the screen you're seeing and what these little things at the bottom mean for you to help you navigate around. The first, where the red arrow is pointing, is our chat feature. So the chats you may have noticed there could be a little red number there for some of the notices that my colleagues have put out. But this is where we're going to send information to you. So for instance, we have a PDF of Dr. Simuni's slides for our speaker today and we can make them available important links for you to click on.

Those will be made available there. Next to that is a Q&A icon and here is where you as our audience can ask questions. We get lots of questions so we may not be able to get to all of them but we do work very hard to address them all but this is where you put them in. And for those of you who may be in a loud environment or need to keep it in a quiet environment there's also a new Zoom feature called a live transcript. So it's computer generated, but it does a pretty good job of capturing what is being said so you can listen and read at the same time as part of that. But before we begin with our expert briefing, I always like to share a little bit about the Parkinson's Foundation because every time we bring new people in and want to tell them what we're doing.

The Parkinson's Foundation is a non-profit that's really focused on bettering the lives of those living with Parkinson's through improving care and advancing research. It's important to emphasize that everything we do is done in close concert for those living in our community, those who live with Parkinson's disease. So that our actions as an organization are aligned with the needs and priorities of those living with Parkinson's disease. Oops, I skipped ahead to our goal. And as part of our goal to fulfill our mission, we have three clear goals. One is improving care for those living with Parkinson's disease, advancing research towards a cure, and empowering our global community, as we're doing today through a webinar on education materials. Also just want for those of you who are new to our expert briefing series, these are recorded.

And they'll be made available at our website Parkinson.org/ExpertBriefings. If you've registered, we'll also email you a link to the recording when it's made available, as well as some other resources that may be covered in today's topic. Again, to those who've registered. The next thing I'd also like to mention again is slides are available for download today via the chat. If you click on the chat feature at the bottom, you can see the messages that are popping up from my colleague Danielle, and you can see the slides to download. On our call today, we have people from all over the globe, not surprisingly, who are tuning in. I think it is a fantastic topic that we have today. And we welcome everyone who is tuning in and we also want to welcome those who are tuning in via Facebook Live. Welcome to each and every one.

Dr. James Beck 3:08
And as part of that, we just want to get a better sense of who you are. What we're going to do is post a poll for those who are joining us via Zoom, you can just click on the link and identify yourself as a person with Parkinson's, a spouse, someone who has a family member with PD, whether you're a nurse, a physician, a clinician, scientist or other healthcare professional. Let us know. And if you're joining us via Facebook, you can enter that in the feedback and that allows us to capture that and we can compile that together. So, what best describes your connection to Parkinson's disease? And not surprisingly, the majority of our people here today are those living with Parkinson's disease, or are closely touched by Parkinson's disease. Welcome our healthcare professionals as well, who are joining us today.

Without further ado, I would like to move forward and begin to introduce our expert, Dr. Tanya Simuni. Dr. Simuni is an accomplished clinician, researcher, and leader in the field of Parkinson's disease. So, it's really hard to encapsulate all that she's accomplished and the significant contributions she's made in advancing care for people with Parkinson's. Therefore, at her request, I'm going to keep it brief. Dr. Simuni joined the faculty of Northwestern University Feinberg School of Medicine in 2000 to build a multidisciplinary movement disorders center that is recognized by the Parkinson's Foundation, the Huntington's Disease Society of America, and the Wilson Foundation, each as a center of excellence, and serves as a training model for clinicians and other healthcare professionals in the region. Dr. Simuni is an active member of the American Academy of Neurology, the American Neurological Association, the Movement Disorder Society, as well as the Parkinson Study Group. She's a lead investigator of several clinical trials and directly involved in several others, including the foundation's PD Generation Initiative. And all of this is to say that she's very well positioned to speak to our topic today of what's new in Parkinson's medications. Dr. Simuni, welcome and thank you for sharing your time and knowledge with us today. Pass the mic to you.

Dr. Tanya Simuni 5:31
Jim, really appreciate the introduction. I'm always honored and privileged to speak at the PF programs. And again, as you have indicated, our center has been Parkinson's Foundation Center of Excellence since 2001, essentially since inception, and we are proudly carrying the name. And I cannot speak more to the contribution of the foundation to improving the lives of people living with the disease and their affected family members. To that effect, let's get to my talk. I am a clinical trialist. I'm a clinician and the topic is therapeutic pipeline March 8th, 2023. These are my disclosures. As a clinical trialist, I am engaged with a number of entities and some of those will be covered in my presentation. The objectives of the talk, what's new in 2023, those are listed on the slide.

I will briefly go over new symptomatic therapies in the pipeline. Current state of treatment of early PD will be mentioned but not extensively discussed because that's not the scope. I will spend a fair amount of time on discussing experimental therapies to slow disease progression because it always is an area of great interest, legitimately and appropriately so, and that is my area of expertise. And within that scope and that angle, we'll talk about the genetic studies. All of that within about 40 minutes, so we have a lot to cover because definitely Dr. Beck and I want to set aside enough time for the questions. I don't need to tell this audience that Parkinson's is a common disease. The number of people affected by the disease is growing around the world.

It is the second most common and most rapidly increasing neurodegenerative disease after Alzheimer's disease. So we need to develop better therapeutics and ultimately halt slow progression of the disease. The good news is that while we don't have a curative therapy for the disease, we have quite a rich armamentarium of therapeutics that effectively treat the symptoms of the disease. And again, this is the list across different classes of agents that are approved, that have evidence that are being used by your clinicians to improve the symptoms. And when we speak about therapeutic interventions for the disease, obviously drugs are essentially important, but I don't need to tell you that the foundational aspect is multidisciplinary comprehensive approach to care that Parkinson's Foundation has always been the advocate and the pioneer.

Starting from education: what the disease is, objective information, what is the progression of the disease, both for the person and the family members. Exercise is part of therapeutic intervention. And again, I don't need to tell that audience, that is a prescription. This is not just nice to have, that is absolutely essential to do. Nutrition support services. On the right-hand side is something that I'm not covering, there are surgical options or advanced therapeutic options for the people for whom it's appropriate in more advanced stages of the disease. Some of you have probably seen the slide from the paper by Kalia et al. from 2015 that kind of puts into perspective what are the disease steps of progression and you can see that the disease is diagnosed when someone develops signs of motor dysfunction, slowness, stiffness, tremor, but there is the whole spectrum of what is called premotor manifestations or frequently referred to as prodromal features, which open the opportunity for the early intervention and we'll talk about that later. But again, as someone develops motor features, there is escalation as such. People start developing features of more advanced disease with non-motor manifestations that are listed here. So, it's important for us to approach therapeutics and look across the continuum. With that said, this slide kind of categorically summarizes what we do well.

And we have, as I've shown you on the previous slide, we have quite an armamentarium of effective therapeutic options for early motor symptoms. We have an approved drug for treatment of drug-induced involuntary movements that are referred to as dyskinesia. We have a whole class of agents that are approved for treatment of medication-related wearing off, uneven response to medications. We have some medications for treatment of non-motor symptoms like orthostatic hypotension, meaning the drop of blood pressure with a change of the position. We have drugs that are effective for management of mood dysfunction. We have a drug specifically approved for management of hallucinations. Again, we have quite significant effective strategies. On the other hand, we need to acknowledge what we need to do better.

And that is in two major categories: treatment for symptomatic management, treatment of more advanced motor symptoms, something that is called freezing of gait, that difficulty initiating the steps, balance problems in people with more advanced disease, definitely an area of urgent need. Treatment of non-motor symptoms and definitely at the top of that list is cognitive impairment for those who are affected by that. Sleep dysfunction, fatigue, and so on. What is happening in the field of drug development? This is a busy slide, but what the color coding refers to the stages of the drug development. Stage one is the earliest, first in human studies. Stage three is the stage when the drug is being reviewed by the regulatory agencies, by FDA and approved. Stage four is post-approval studies.

But what is important to take from this slide is a clear escalating curve of the number of drugs being developed across the different stages of the development in the last 20 years. Definitely the field is moving forward. It's not all inclusive of every drug in development, I will give you the sources, but I wanted to highlight the drugs that are close to the approval in the domain of symptomatic management. Specifically, drugs that are delivered by subcutaneous, under-the-skin continuous delivery. And there has been a number of years of development of such drugs. The rationale for that is very simple.

As some of you know, with the progression of the disease, levodopa, which is the prodrug of dopamine, the chemical that the person with Parkinson's disease is low on, and the chemical is centrally important for the coordination of movements and that is low in the person with the disease. Carbidopa levodopa also brand-named Sinemet is the most effective drug that we have, but it also comes with limitations. It has short half-life and especially with the progression of the disease, people notice that they need to take the medication more and more frequently. There are a number of ways to extend the duration of the effect of levodopa and a couple of drugs are coming on the market for the continuous drug delivery.

Dr. Tanya Simuni 13:28
So akin to an insulin pump, rather than taking the pill three, four, five, six times a day for some of the people, you have a continuous pump of drug delivery. Again, absolutely not for everyone. Definitely for people who do experience problems with wearing off and fluctuations. The compound that probably is the closest to the market is Levodopa Infusion Therapy developed by AbbVie Therapeutics that has been submitted to FDA, which is in public domain. Another program is being developed by NeuroDerm. Again, the data on the results of the Phase III study still to be available, but hopefully these are coming closer to the approval.

There are other classes of drugs that also can be delivered continuously and actually have been available on the European market for a long time, but hopefully will be coming on the U.S. market as well, belongs to the class of dopamine agonists. Apomorphine is a D1 agonist. It is available in the U.S. as an injectable preparation, Apokyn, that is just an on-demand injection or sublingual preparation of the drug. And again, infusion therapy, the same idea, hopefully will become available. On the right-hand side are some selected drugs again for the treatment of motor symptoms and specifically focusing on the drugs that hopefully are closer to the approval. Newly diagnosed Parkinson's, actually the drug that has been filed is low-dose pramipexole rasagiline.

Neither of them is a new drug, but the idea behind that is that if you combine the low doses of both, you reduce the side effects and achieve comparable benefit compared to the high doses. And that was shown in the clinical trials. Another compound to be considered. The drug that potentially a number of you are aware of, building on that concept of extending the half-life, the effective life of carbidopa levodopa, is the new preparation akin to Rytary. The same company is developing that. Studies are completed, the drug to be filed, or filed. Again, better from the standpoint of the drug half-life of another compound akin to Rytary. There is an interest in developing dopamine agonists with a better side effect profile. One example on the list is tavapadone that is in development but further away from the approval.

Now, the area of major need, non-motor symptoms. New therapies in development and again, I'm warning on that again and again, the area of major need is effective therapeutic strategies for management of the cognitive domain of disease-related disability. I am not going to spell out all the acronyms, but there are a couple programs that are in phase two development. Again, what is rewarding to see is that the companies are contributing their efforts and investments into developing those drugs, and those are urgently needed. So that was a very brief overview of the therapeutic development for symptomatic management of the disease. And now let's get into the area of when we will have the therapeutics to slow disease progression. And I don't have the answer when. I can tell you that the field is extremely active.

Dr. Tanya Simuni 17:56
Really the rest of my overview will be dedicated to what drugs are being developed, why those are being developed, and why we are optimistic that we finally, at some date, will get to that. Not the finish line, but the starting point of having such therapeutics to offer to people living with the disease. So, one reference that I want to highlight that if you want to know everything about drugs in development for Parkinson's disease, it is the publication to look at. The one that is on the screen is from 2021. It is in the Journal of Parkinson's Disease. It's available in public domain, open access. And what is most remarkable is that the first three authors of the paper are people living with Parkinson's disease who have incredible knowledge, commitment to maintain such a most comprehensive dossier.

Kevin McFarthing is leading that effort. The paper was updated in 2022 and there will be the next update in 2023. But super busy diagrams at the bottom of the slide reflect the therapeutic landscape across the phases of the development, across the indications. And again, you have to be impatient. You have to demand new therapies. But what this slide speaks to is that the field is very widely active. And the next slide speaks exactly to the same concept. It uses the same format that I showed you at the beginning, but this one, singles out specifically therapeutics for disease modification, slowing progression of disability. And you can see that despite the pandemic, there is an active and ever-growing landscape. Let's dive deeper into what does that mean to slow progression of the disease.

Ultimately, what that should mean is to halt progression of the disease biology. Let's get into Parkinson's biology 101. And I know that you're a very educated audience, but just to bring everyone to the same denominator. This slide summarizes the picture of the brain of a person who ultimately had a diagnosis of Parkinson's disease and specifically focuses on that area of substantia nigra pars compacta that loses dopamine-producing cells and when the pathologist looks at those cells under the microscope they see fewer cells and they see those brownish clumps that are called Lewy bodies and when we look at the constituents of the Lewy bodies the protein that accumulates in the cells is called alpha-synuclein.

While we still need to know more about the function of synuclein, it's unequivocally known that accumulation of that pathologically aggregated protein is linked to the development of the biology of the disease and ultimately to the disease symptoms. Again, synuclein does exist in the soluble form, something that is shown on this slide as native synuclein, and it's important for the function of the cell. We still need to know more about what it does, it's important for the healthy transmission from one cell to another cell. But it is when it aggregates, when it clumps, when it develops the oligomers and fibrils, when it becomes pathological. And the cartoon at the bottom from that Krainc et al. from a couple of years summarizes visually that there are a number of places in the cell and in connection of the cells that therapeutics are being developed to either reduce production of synuclein, reduce aggregation of synuclein, and then to the right of it, between the cells, is to reduce propagation of that pathologically aggregated synuclein. Again, multiple potential nodes where therapeutics can be developed. And consistent with that, another busy slide, but it's good to have such a busy slide, is the approaches of experimental therapies in development targeting synuclein. And you can see that all of these are still in early phases of development, none of them is in phase three. Some of the studies have read out and I will briefly cover them, but again, conveying the message that the field is active.

And that quantity ultimately inevitably will bring successful results. But so far, unfortunately, the two most front-running programs of alpha-synuclein-targeting therapeutics that were monoclonal antibodies targeting alpha-synuclein outside of the cell, if you remember that cartoon that I've just shown you, have been completed, have been published in the New England Journal, and unfortunately had negative results. And the data, again, busy slide summarizing, but the take-home message that there was no separation between active treatment and placebo in two separate studies, very similar design. Prasinezumab, the Pasadena study. Again, both unequivocally negative studies. But in the Roche program, in the Pasadena study, in the secondary endpoint exploratory analysis, there seemed to be separation between active treatment and placebo.

And based on that data, actually Roche is continuing the program, testing the same compound but in a slightly different population. It is still an early population, but stably treated with one Parkinson's medication. The study is ongoing, very much anticipated. And obviously, very disappointing, but let's put it in perspective. The Alzheimer's field that just recently celebrated approval of two drugs, specifically the latest one, lecanemab. It took 10-plus years to develop to have a positive result. So, this is the list of the studies that previously have been conducted and read out negatively. Again, the reason why I'm showing you that this is a long, treacherous road, but provided that there is a rationale, we need to continue and persevere.

Let's go on to some other classes of drugs and I know that I'm giving you a lot of information, my understanding is that the slides will be available, but I'm trying to just give you the bigger picture, right? A class of drugs that has attracted a lot of attention, actually are the class of drugs that are approved for management of diabetes. They belong to the class of GLP-1 compounds. GLP stands for glucagon-like peptide. Again, it impacts insulin resistance, but why diabetes and Parkinson's disease? It's a separate topic altogether of epidemiological data pointing to a relationship probably through the inflammatory cascade. But a lot of you probably have heard about the program of exenatide, which is one of the GLP compounds.

Dr. Tanya Simuni 26:51
But there is solid science behind testing these drugs, not to reduce the level of glucose, not to treat diabetes in people with Parkinson's disease, but to see whether it will effectively impact the disease biology. And this is a fairly comprehensive compendium, again from Kevin McFarthing of the drugs in that class of agents and GLP-1 agonists that are in different phases of the development around the globe. Again, hope to see all the data coming out relatively soon. The next class of agents that has been tested, I will talk about nilotinib as a specific molecule and there is a reason why I'm putting a subheading of detangling hype, hope, media spotlight, and science. So, what is nilotinib? Nilotinib is a drug that is approved for management of cancer. Why a cancer drug and Parkinson's?

Because it works through tyrosine kinase and there are solid preclinical data as you can see some of the studies summarized on this slide of that pathway being affected in Parkinson's separate and independent from the oncology indication. So that was a legitimate reason for nilotinib to be tested starting back in 2016 with an open-label small study that was supposed to look at the safety of this oncology drug, right? for people with Parkinson's disease, but unfortunately, the results of the study were quickly publicized in the media, drew a tremendous amount of attention from people living with the disease, and that's the reason for that editorial background, 2016, 2017 differentiating hype and hope. Let's fast forward. A number of studies testing nilotinib have been done since then. Both studies have been published.

I was privileged to lead one of them, and this is the conclusion: that despite the fact that nilotinib was safe and tolerable in a very carefully selected number of participants, the concentration of the drug in the brain was way below the concentration that putatively could have any benefit to improve the disease biology. So our unequivocal conclusion was that based on that, nilotinib should not be moved forward to assess the potential effect of that class of agents. On the other hand, we clearly stated that provided that another drug has the right biological properties and has the ability to get in the brain at appropriate concentrations, maintaining safety, such drugs should be tested.

And indeed, you can see another summary of the drugs belonging to that class, even novel therapeutics, some of them already approved for management of cancer, like radotinib being tested in Parkinson's disease. None of those phase two studies have read out yet, but again, the data will be coming. Next domain of the drugs that are frequently being asked, right? There is a lot of interest across the neurodegenerative diseases, specifically in Parkinson's disease, of the connection between the gut and the brain. There are very exciting data from the animal studies that actually the bacteria that live in your gut can contribute or protect against development of pathological aggregation of protein.

Dr. Tanya Simuni 30:58
There was a paper that is highly debated in the literature, pointing to the fact that potentially some of the people with Parkinson's start actually having the pathology in the gut before it gets into the brain. However, again, very much debated. But what is unequivocally important is that we need to study the effect of inflammation. How much is it contributing to the biology of the disease? That is a very new area, in Parkinson's research, but very hot, very actively being studied. And what is the effect of the gut microbe constituency, or genetic constituents of those microbes, which is called the microbiome. And again, I don't have the answers to you yet. A lot of patients ask, so which probiotic should I take? Which probiotic should I take? We don't have the answers to that.

But the studies are going on and this is again the summary of studies in different phases. Now, let's shift gears. So far we talked about Parkinson's all-inclusive, but there is a lot of interest stemming from the learnings from the other diseases that at the end of the day, every person with Parkinson's is unique. So, ultimately we want to develop therapeutics that are targeting not just disease at large, but targeting the biology of the disease in that particular individual. And that is basically a summary of what we frequently refer to as personalized medicine. And again, the cartoon on the left summarizes the concept. The slide on the right is from the paper by Pablo Sardi from a couple of years ago summarizing the genetically targeted drug development.

Genetically targeted therapeutics are not the only way to subtype people with the disease, but certainly are the most advanced, right? So, in the next couple of slides, I will briefly talk about genetically targeted therapeutics in Parkinson's disease. And again, the two genes that I will single out or gene variants are GBA, and again, it's a risk gene. People who carry two abnormal genetic alleles develop a disease called Gaucher disease, but it was noted a number of years ago that people who are family members of persons with Gaucher, so they have nothing wrong with their liver and spleen, but they have one abnormal part of the gene, the other one is normal, so they actually carry a substantially higher risk of Parkinson's disease.

And then when we started gene testing people with Parkinson's disease in the community at large, up to 10% of them carried the GBA variant. It can be high in certain ethnic communities. The other gene that I'm singling out is LRRK, leucine-rich kinase, and again, it's not common, but it's actually the most common genetic predisposition for Parkinson's disease. It affects about 1% to 3% of overall PD population, and can be substantially high again in certain ethnic communities. So, where is the drug development for LRRK targeting therapeutics, for GBA targeting therapeutics? And some of you would say, why would you be spending all the money on this subset of people who constitute about 1% to 3%? So, a legitimate question.

Dr. Tanya Simuni 34:53
The answer to that question is that while these gene carriers constitute a minority of people with Parkinson's, the biology that drives their disease can be relevant even to people who do not carry the gene variant. Think about it as a clean Petri dish test. You first test it in the most targeted population and then if it is positive and if the science is right, then you expand it to a larger patient population.

Dr. Tanya Simuni 00:35:59
Indeed, the LRRK oral small molecule inhibitor has completed phase one studies and is being co-developed by Biogen and Denali and is going into phase two and phase 2/3. You can see that actually their decision was to test, at least in one of the programs, not only people with Parkinson's disease, LRRK-positive Parkinson's disease, but in people who are not carriers. That's one of the studies. The other approach is antisense oligonucleotides.

That means that the therapy is being developed through a lumbar puncture, being in early-phase development. Again, very exciting, not ready to give you the results because we don't have such, but again, a perfect example of a targeted personalized approach to therapeutic development to slow progression of the disease.

Similarly, GBA-targeting therapeutics. I told you that up to 10% of people with Parkinson's disease might carry one of the variants of GBA. GBA has multiple gene variants under the umbrella of that big gene. One of the studies that was the most front-running, unfortunately venglustat, that was developed by Sanofi, read out as a negative study, excellently designed and executed study. Unequivocal result, but it definitely does not negate the significance of the overall approach to GBA therapeutics.

That pathway did not work, but there are other approaches to improve GBA function, to increase the level of the enzyme, and all of those are being tested. If there is so much interest for genetically targeted therapeutics, how do we know whom to recruit, right? That's the quintessential question. Is the field ready to start genetic testing for Parkinson's disease? Obviously, the Parkinson's Foundation has taken an unequivocal approach: yes, the field needs to test, and the Parkinson's Foundation has put a tremendous amount of funds into enabling that testing. We'll talk about the opportunities, and I hope that you know about PD GENEration, right? Again, it's a study.

Dr. Tanya Simuni 00:38:25
As of today, insurances largely do not cover genetic testing for Parkinson's disease, but it definitely is entering the clinic. We have more and more data that knowledge of genetic status can be important for therapeutic decision-making, for counseling of individuals on their progression of the disease, and might have implications for family. Definitely, more data need to be collected.

Again, we're at an exciting time of accumulating knowledge and communicating what we've developed in the research domain as the next step to the actual patient management, where it's appropriate.

What programs are available for genetic testing? I already introduced the Parkinson's Foundation PD GENEration, where again, the foundation has taken a very pragmatic and the right approach. We're not going to test only the younger people of certain ethnic background. We want to offer genetic testing to anyone who carries the diagnosis of Parkinson's disease, enabling us to actually really develop the data. How common is it across the PD community? That is definitely a front-running program.

There are other programs that I have listed on the slide. As a number of you probably know, there is direct-to-consumer testing, 23andMe, that you can order the kit, send it back, and will receive the result. You need to be aware that 23andMe has a limited panel. While they do test for LRRK, for GBA they test for a single variant of GBA. As anything else, you need to talk to the professionals. You need to understand what your results mean, and that's where genetic counseling involvement is essentially important. That is part of the PD GENEration study.

You've seen the slide before. I'm bringing it back again because we're quickly transitioning into the last topic of my presentation, which is discussion of what today is called prodromal Parkinson's disease, right? You see this long timeline, right? You see that square on the right-hand side. That's when we make the diagnosis of Parkinson's disease and progression along the continuum. But what about that maroon color shape on the left? This is the opportunity because if we identify people who are destined to progress along the continuum of the disease biology, can we intervene early and truly bring not only slowing but ultimately prevention of the disease, right? More data necessary.

Dr. Tanya Simuni 00:41:35
Sorry, a lot of work is being done, but we need to identify more of those people to follow them longitudinally. I could not resist to put a pitch in that there is the largest study that is recruiting those what we now call prodromal participants, the PPMI study. The study is recruiting participants at risk. The study is looking for people not carrying the diagnosis of Parkinson's, so it's not the discussion for people who are diagnosed.

It's the discussion for reaching out to family, friends, relatives, neighbors, asking them to do a simple smell test, because we know that 80% of people with Parkinson's disease report that they have lost sense of smell beforehand. Obviously, not everyone who has lost sense of smell develops Parkinson's disease, but we now have the biological tools to identify people who have lost sense of smell and the Parkinson's-relevant biology.

What this slide speaks to is spread the word, right? Actually, speaking of spreading the word, there is the QR code. As everything else since the pandemic, there is a QR code, right? People can scan it in and get to the landing page of the study. Certainly, important contribution. Again, this is for people who do not have diagnosis of Parkinson's disease. Spreading the word and collaboration across the programs is essentially important.

In my last couple slides, I've told you a lot about therapeutic development. I hope that I've instilled the sense of hope in you, but I always approach it in the clinic as what should we be telling patients with Parkinson's disease? First and foremost, be proactive. Be your own advocate. Seek expert opinion in a specialized Parkinson's center. Parkinson's is complex. The Parkinson's Foundation has a lot of educational materials. Inquire about clinical trials. If you don't participate, we will not develop better drugs.

Remember that we have potent medications to treat Parkinson's symptoms. Be your own advocate. Speak about the symptoms that you have. Exercise is not nice to hear, but absolutely need to do. Having a positive outlook is important. I've stolen this acronym from someone. I don't remember who was the first one to present it, but I liked it. MEDS stands not for the meds from the pillbox, but for meditation in this case. Pills from the pillbox are very important, but meditation, exercise, diet, sense of well-being are essential to maintain good quality of life and having quality of life living with the disease.

With that, I will close. This slide kind of summarizes it all: your opportunities, your responsibilities, well, our responsibilities, to develop better treatments for management of the disease. With this, I will close. I know that I ran a little bit over time, but we have 15 minutes to address the questions.

Dr. James Beck 00:44:54
Thank you very much. That was a really fascinating presentation. Lots of questions have been coming in about that. If I can for a moment, because we talked about a lot of new drugs and, you know, the basis of drug development are trials. Let's think about big picture if we can for a second. Why have we not discovered a new gold standard to help either with symptom management or, you know, really making a difference in disease progression? What do you think is really perhaps holding this back?

Dr. Tanya Simuni 00:45:33
That's a huge question. Let's dissect it, right? In the disease progression, we need solid understanding of biology, right? I talked a lot about synuclein. That is kind of the common funnel, but there are a lot of things that lead to that common funnel, and we need to better define them, right?

What is the trigger? Is that inflammation in one person? Is it dysfunction of the energy factory of the cell, which is called mitochondria? Is it dysfunction of the garbage clearer from the cells, which is called lysosome? Again, all these have to be clearly defined to find that gold standard of disease slowing of progression of the disease.

In the symptomatic domain, we shouldn't belittle what we have. The rest of the neurodegenerative diseases are incredibly envious. We have levodopa, which is the gold standard. We need to optimize the delivery. We need to reduce the longer-term complications of therapy. Where we are lacking is management of those more advanced stages of the disease, and again, that goes back to the biology. Levodopa does not stop working, and that's a misnomer from everyone. Sorry for taking more time answering the question. It's the rest of the pathology that is developing that we need better understanding what is the trigger and develop targeting therapy.

Dr. James Beck 00:47:19
Yeah, absolutely. It seems to me that, you know, a fundamental issue here is when we're talking about trials and new therapies, you presented that there's not a want of trying. We are still struggling to understand the biology of Parkinson's disease, but drug companies feel they have enough understanding to take the risk. But with that number of trials that you presented, I would imagine getting people to participate in trials remains a significant issue as well, as part of that. Is that your experience, or has it been easy to get people to sign up for new therapies that may or may not work?

Dr. Tanya Simuni 00:48:00
Statistics are that not a single study has closed recruitment ahead of the schedule. Monoclonal antibodies were actually the outliers, right? But every single study takes longer to recruit than that was planned, right?

I understand reluctance of the people as experimental therapy, quote unquote, are they testing something on me, right? But people need to recognize that none of the drugs, again, I don't give assurances and we certainly have learned that a safety profile can evolve as more people are exposed, but these drugs are being monitored. Experimental therapies are monitored very closely. To a certain degree, I am pragmatic to say that it is responsibility. Obviously, it's an opportunity. It's personal decision of everyone, but people need to understand if people do not participate in the studies, we will not develop therapeutics.

Dr. James Beck 00:49:02
Yeah. I think that's a fundamental issue. One of the interesting things you were talking about that I thought was, again, thinking about our gold standard, levodopa, carbidopa, is new formulations that are coming around.

I don't know if you've had experience with them as part of the trials, but it seems to me that they could help solve a number of problems. One of the questions, for instance, coming in from one of our viewers, Kathy, is just mentioning this issue around timing of meals and taking of medications. I've heard of it as the Big Mac attack, almost literally, where too much protein can really interfere with levodopa-carbidopa. Do you anticipate if these infusion forms of levodopa get approved, will it make a tremendous difference in management of Parkinson's disease?

Dr. Tanya Simuni 00:49:56
They will make a difference. Everything is a seesaw, right? It's balancing between the benefit and side effects, right? Will they make a difference? No question about it, especially for people who are taking the medications more frequently.

Whether it will eliminate the interaction with food, to a certain degree but not completely, because the drug still has to be — because again, it doesn't go through the gut, right? But still, it's a tiny protein molecule, right? Those infusions can be associated with skin irritation, skin nodules. Again, it will be very important for us to hear it in our armamentarium. It certainly is not required for everyone. It's not appropriate for everyone.

But it will be very important for us to have something for the appropriate people to say, you can do it once a day, put your infusion and kind of not think every couple hours about when your medication will stop working and you need to pop in the other one. Whether it will eliminate the need for taking oral medications in addition to that, that is not what the studies are showing. Just to be very realistic.

Dr. James Beck 00:51:17
Yeah, that's perfect. How does it compare to Duopa? It doesn't sound like it's a surgical procedure like Duopa. It sounds like it's something that's simpler.

Dr. Tanya Simuni 00:51:27
It is simpler, and again, not going into the specifics because it also has the relevant question: how much drug can we pump through under the skin, right? One of the programs has more restrictions with the dosing that can be delivered versus the other, but definitely simpler, right? It still is a pump, but a smaller pump that's under the skin rather than a gastrointestinal tube. I anticipate it will be much more accepted by people living with the disease.

Dr. James Beck 00:52:03
Yeah, absolutely. Another interesting line of medications coming around really are tackling alpha-synuclein directly, which is often at the heart of Parkinson's disease for many. What do you anticipate with that? A question comes in from one of our viewers, Kevin, asking how does alpha-synuclein interfere with dopamine? Does it block dopamine, or what might be going on there? What's the importance of tackling alpha-synuclein?

Dr. Tanya Simuni 00:52:39
Very good question, right? It doesn't interfere with dopamine per se, right? But if the cell that is producing dopamine has aggregated that abnormal synuclein, it's not functioning normally. If it's not functioning normally, it's not producing dopamine, right? Indirectly, that's the mechanism. The idea behind that, quintessential idea, is you reduce the pathology. You allow the cell to function more normally.

Dr. James Beck 00:53:12
Got it. That'll be great and hopefully potentially really make a difference in those who are struggling with PD. Likewise, we're talking about the gaps that are really missing in therapeutics, non-motor symptoms in particular. We mentioned freezing of gait is a gap. Do you see anything on the horizon that might be there to tackle freezing of gait, or does that just still remain one of those things that's still to be fully addressed?

Dr. Tanya Simuni 00:53:45
It's tough because it's a sign of more advanced disease. When someone has more advanced disease, there is likelihood not just dopamine dysfunction but other chemicals dysfunction, so it is not a purely dopamine or lack of dopamine problem. Because if it was, then it should respond to the medication. There are programs in early phases of the development that actually are testing therapeutics for gait impairment, for falls associated with Parkinson's disease, and looking beyond dopamine.

Dr. James Beck 00:54:27
Yeah, absolutely. Likewise, as we think about some other non-motor symptoms, one of our listeners, Carol, is asking about autonomic dysfunction. Particularly, she's talking about internal thermostat and dealing with hot and cold. I presume we've seen people with Parkinson's, they can have sudden sweats, these hot flashes. Are there things to help regulate that, or are there other medications perhaps that are even there? Maybe we don't need a specific medication that's a PD-specific medication. I look to you, Dr. Simuni.

Dr. Tanya Simuni 00:55:01
Definitely refrain from any specific recommendations. You’re not going to hear a drug from me because it would be, again, that has to be discussed with your specific physician.

Categorically, autonomic dysfunction, autonomic nervous system is the one that is responsible for control of our sweating, for control of our blood pressure, for control of bladder function. Bowel function is impacted by the disease pathology. Ultimately, we need the therapeutic that, returning back to if we make all these cells function in a healthier way, then we should improve the symptoms.

But in the symptomatic domain, specifically sweating, nocturnal sweating can be difficult to treat, but there are a couple pharmacological strategies, off-label, nothing approved for Parkinson's disease specifically, to talk to your specific physician.

Dr. James Beck 00:56:06
Yeah, certainly worth following up if people are dealing with these issues, to talk to their doctor about. As always when doing symptoms, there are things out there that can help. People may not realize they are part of Parkinson's or part of something else and can be treated.

You mentioned nocturnal; think about sleep. Many people with Parkinson's, and even those who don't yet have Parkinson's, sometimes wrestle with vivid dreams, as they call it. One of our listeners is asking about that. Are there things with which to address that, or is that really just part and parcel to the progression of Parkinson's? What we're really looking for is perhaps a way to manage the Parkinson's; we might be able to manage these other symptoms as well.

Dr. Tanya Simuni 00:56:56
What you're referring to, most likely the person is referring to a condition called REM behavior disorder. REM stands for rapid eye movement phase of the sleep. That is the quote, unquote, dreaming phase of the sleep. In the normal condition, when we dream, our muscles are relaxed so we cannot punch anyone, whatever dream we have. In Parkinson's, in Parkinsonian condition, there is loss of that muscle relaxation, so people can quote, unquote, act out their dreams.

It's a fascinating condition because people with REM behavior disorder with no Parkinsonian signs are, long term, at higher risk of developing Parkinson's and related conditions. That's why it's of huge interest to intervene early, and that is the population that we here, the scientific community, has accumulated quite enough of the data. But I believe that the question is, what can we do just to treat the symptoms, right? There are a couple of medications, both off-label but both widely available. That's where I will call out the medications, but will say talk to your physician: melatonin, clonazepam, right? Melatonin, the supplement, or clonazepam, a long-acting benzo drug in low doses, are being used and successfully being used. Again, talk to your physician.

Dr. James Beck 00:58:28
Yeah, absolutely. We're coming up to the top of the hour. Dr. Simuni, thank you again for your time. What do you think is, again, taking the long lens, where do you think the next advancement is going to come? We've talked about a lot of different things that are in the works. Maybe it's too hard to predict, and that's why we really need to do the clinical trials to understand it, but I don't know if you're a betting woman, where might you place your bets?

Dr. Tanya Simuni 00:58:56
I don't bet. I don't gamble, but the major breakthroughs will come from biologically targeted therapeutics. Am I promising success in the next two years? I don't know that, but the fact that we're targeting underlying disease biology, the protein synuclein, that we're targeting the genetic subtypes of the disease, we are on the right track.

Dr. James Beck 00:59:24
Yeah, I certainly hope so, for certain. Dr. Simuni, thank you again for sharing your time. I want to thank our audience for listening today. For those of you who didn't get a chance to have your question answered, please reach out to our Helpline. It's just been placed in the chat, the number there, as part of that.

This is the first of our Expert Briefing series for the year. The next one is going to be April 12, A Balancing Act, and we'll get a chance to talk a little bit more about freezing and falling of gait with Dr. Colin McKinnon. In order to do that, and we have our others lined up as well, so please go online and register for those as part of that.

We have a number of resources available for those who are interested in that, our Aware in Care kit, which is a fantastic kit for people who may be going to the hospital. We have our online library, which is fantastic. Again, Expert Briefings is part of a larger webinar series we do, which is PD Health @ Home, so that has been a fantastic resource for many people. A virtual event and allowing people to engage with resources. This is for education and wellness as part of that.

Other resources: for people who like podcasts, I know my wife listens to those as she drives to work, as people still go to work. Others just find it as a convenient way of the radio, but on demand. We have professional education as well, as what Dr. Simuni mentioned, our PD GENEration study, so encourage people to take a look at that as part of that.

Again, we're here for you, Helpline@Parkinson.org if you wanted to use email or phone number, 1-800-4PD-INFO. That's one way with which to get in touch with us.

Before you go, I just wanted to say please, when this webinar closes, the screen just goes blank, but what should pop up is an opportunity to give us feedback. Dr. Simuni would appreciate it. We would appreciate it. We base a lot of what we do as part of our Expert Briefing series on the feedback from our viewers, so please take a moment and give us feedback on what you thought and what we can do better or what we did great.

With that, thank you again, Dr. Simuni. I look forward to chatting with everyone again with our next Expert Briefing series. But until then, stay warm, stay safe.