E123: Argenx Clinical Trial on Post-COVID POTS

Episode 123 March 11, 2023 00:53:46
E123: Argenx Clinical Trial on Post-COVID POTS
The POTScast
E123: Argenx Clinical Trial on Post-COVID POTS

Mar 11 2023 | 00:53:46


Hosted By

Cathy Pederson Jill Brook

Show Notes

Registration is currently open for a clinical trial on post-COVID POTS investigating a new medication that might deplete autoantibodies and decrease POTS symptoms.This is an exciting development for the entire POTS community, as this attention to POTS may lead to a more effective treatment for many people currently living with the disorder.

If you are at least 18, had PCR confirmed COVID and then developed POTS, then learn more about this clinical trial: https://www.alphastudyforpots.com

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Episode Transcript

Argenx Clinical Trial [00:00:00] Dr. Cathy Pederson: Hello, POTS patients and lovely people who care about POTS patients. I'm Dr. Cathy Pederson, your guest host for today, and we have an episode of the POTS Matters in which we will discuss a new clinical trial for people who developed POTS after COVID. Our first guest today is Dr. Artur Fedorowski. He is the Head of Syncope and Dysautonomia Unit at the Karolinska University Hospital and Associate Professor of Cardiovascular Medicine in the Department of Clinical Sciences at the Lund University in Sweden. Dr. Fedorowski has published more than 170 scientific papers on topics such as syncope, orthostatic hypotension, and POTS. He is also a member of the taskforce group of the European Society of Cardiology for Syncope Guidelines, and a member of our very own Standing Up to POTS Medical Advisory Board. Thank you, Dr. Fedorowski, for joining us today. [00:01:02] Dr. Artur Fedorowski: Thank you, Cathy, for your kind invitation. I will be very happy to join you in discussion and to touch some of the very important topics for all participation all over the world. [00:01:14] Dr. Cathy Pederson: We are very excited to have you here and in addition, our second guest today is Dr. Joost Van Middendorp, who is a principal scientist at Argenx which is a commercial stage global immunology company. Dr. Van Middendorp is based in the Netherlands, holds a degree in medicine and a PhD, cum laude, for his thesis on spinal cord injury management. In 2018, he joined Argenx where he led the European Medical Affairs activities on several autoimmune diseases, including myasthenia gravis. Thank you, Dr. Van Middendorp for joining us here today. [00:01:57] Dr. Joost Van Middendorp: Thank you, Cathy. It's a great privilege to join you and Dr. Fedorowski today. [00:02:02] Dr. Cathy Pederson: So Dr. Van Middendorp could you give us a general overview of the clinical trial and what you're hoping to find? I think this is going to be so exciting for our listeners to hear about today. [00:02:15] Dr. Joost Van Middendorp: For sure. Yes, we are excited too. The study aims to investigate the safety and efficacy of our investigative product. It's called efgartigimod and compared this to placebo in participants with post COVID 19 postural orthostatic tachycardia syndrome, which is also being called as Post COVID POTS, or PC POTS. We believe that efgartigimod may be a viable treatment option for individuals diagnosed with post COVID POTS because it has been shown in earlier studies that it reduces immunoglobulin G, IGG, levels including autoantibodies, which is a form of immunoglobulin G. And these autoantibodies, including IgG autoantibodies, which may underlie some of the autonomic disease manifestation in individuals with post COVID POTS. So this is a phase two proof of concept study where we will study 42 subjects and they are randomly allocated to receive either efgartigimod or placebo. And we will follow up for 24 weeks. During that time, they will receive weekly infusions of either efgartigimod or placebo. [00:03:28] Dr. Cathy Pederson: Can you say just another word or two about what a phase two clinical trial might be? Is this where you're looking for safety or you're looking for proof of concept or what are you looking for in a phase two clinical trial? [00:03:43] Dr. Joost Van Middendorp: Yes, exactly. It's both. So we are looking at safety because it's the first time we will be investigating the molecule in this particular indication, post COVID POTS. At the same time, we'll be looking at efficacy. So the first signs to see is the drug doing what it's intended to do in post COVID POTS patients. And what we like to see is improvement in autonomic symptoms because as we know, the post COVID POTS has a range of autonomic symptoms in the syndrome. And we'll like to see improvement of these symptoms so we can really show it is working and then we will proceed to a phase three study where we have a bigger group of patients. The sequence of phase one: healthy volunteers. We've done that eight years ago. So we've closed that chapter. Now we are looking at a number of autoimmune indications including post COVID POTS that requires a proof of concept study. And if successful, of course, we would like to proceed to the bigger phase three studies. [00:04:51] Dr. Cathy Pederson: That is so exciting. I cannot wait for this to get underway and see what comes out of this study. That's amazing. So, Dr. Fedorowski, let me ask you, how did you get involved in this clinical trial? People who read the literature know who you are. You have published so much and how did you get involved with this company and this clinical trial? [00:05:19] Dr. Artur Fedorowski: I was approached by the company or by Joost personally more than a year ago. In the very beginning, I was very surprised when I was approached by Joost asking me whether I could talk about my hypothesis of POTS background and whether I could advise something for the company who were planning a study. So I didn't know exactly what the whole story was about in the very beginning. We had performed a few studies on involvement of autoantibodies directed to cardiovascular cell membrane receptors that are sitting on the surface of different cells or different organs. And they are just like the contact in the wall. You can switch on or switch off the light in the room, or you can start any device working in your home. So these are receptors. They are switching points or contacts on the cell surface, and they are everywhere. So our body controls different functions including cardiovascular system, the heart, and the vessels. By putting signals on these receptors and making different organs change the function. So let's say we have these receptors on the cells that build the pacing system in the heart. So if you irritate them, if you stimulate them, the heart rate increases or the heart rate may get lower. So this specific receptors maybe affected or attacked by autoantibodies. So in our previous works, we have found that there are circulating autoantibodies that can change the function of these receptors producing increased heart rate or problem with vessels. The vessels who would not dilate or would not constrict. And I guess that our previous findings made the company think that if we get rid of this circulating, hypothetical autoantibodies, then the POTS patients would feel better. So this was the whole idea behind our interactions from the very beginning. [00:07:39] Dr. Cathy Pederson: That is so interesting to think about. So it sounds like the company was out looking for scientists who had some previous background and contacted you to try to partner and figure out what a good approach might be. [00:07:57] Dr. Artur Fedorowski: Yes. This is exactly as you said. I think that the idea was that the company had an instrument, a new tool, to get rid of the bad, circulating autoantibodies based on other disease models. And the idea was whether I would believe it would work in POTS. So my answer was, Absolutely yes. Cause we have seen positive effects of such experimental treatment, just like intravenous immunoglobulins or a plasma exchange. So both of these methods actually, they target autoantibodies. What they do is plasma exchange just get rid of autoantibodies without targeting specific autoantibodies. It depletes the level of autoantibodies. Now we learn a lot about how the patients own autoantibodies just by making them vulnerable and more susceptive to be removed. So probably if you infuse external immunoglobulins, you make your own immunoglobulins vulnerable so that they can get replaced. But the immunoglobulins that were infused just for the treatment purpose. So what the company proposed that why should we infuse immunoglobulins? We can make the immunoglobulins that are already there in your body vulnerable so that they can get removed very easily. So this was the idea. I liked it. [00:09:37] Dr. Cathy Pederson: This is really exciting. As a POTS mom myself, I'm a mom on a mission, right? My daughter has been sick for a long time with POTS. This is really revolutionary thinking from a science perspective. And it sounds to me like instead of, as you say, doing monthly immunoglobulin, which is very expensive, takes a lot of time. Maybe we can go upstream a little bit and knock the system out at its knees, right? So make those autoantibodies that are there vulnerable. This is absolutely amazing. I want to say just a couple words about the company because I think this is so exciting for our community. Argenx is a global immunology company, committed to improving the lives of people suffering from severe autoimmune diseases, partnering with leading academic researchers, like Dr. Fedorowski, through its immunology innovation program. Argenx aims to translate immunology breakthroughs into a world-class portfolio of novel antibody-based medicines. Dr. Van Mittendorp, you've gotta be so excited to be involved in a project like this that I think is truly revolutionary, especially for this POTS community. And I want to get down into some nitty gritty of the clinical trial. So who would be eligible to participate? I think you're getting ready to invite participants at this point. So who would be eligible, and then what would they actually have to do to complete your protocol? [00:11:17] Dr. Joost Van Middendorp: Yes, thanks Cathy. So we are recruiting subjects who are 18 years and older. So adults who had prior COVID 19 infection confirmed by a PCR test. On top of that, orthostatic vitals consistent with the POTS International Consensus Criteria had to be present at screening and ongoing symptoms of POTS. Now to more objectified inclusion. We had a threshold of the Composite Autonomic Symptom Score 31, also known as Compass 31, and the score of at least 35 points. So this is moderate to severe dysautonomia. The subjects cannot be pregnant and should be on birth control throughout the study. And the BMI has to be lower than 35. So these are the key eligibility criteria, and there are a few more detailed criteria on top of that. Now, to complete the protocol, enrolled individuals will receive weekly infusions over 24 week period, after which they will be offered the opportunity to roll over to an extension. [00:12:24] Dr. Cathy Pederson: I think what's really important here when you're trying to recruit POTS patients is that they had to have COVID, but they also have to have the PCR test to prove it. So right now, lots of people are taking home tests - that wouldn't count. Right? So this would be someone that had their blood work sent out to the lab. Am I correct about that? [00:12:46] Dr. Joost Van Middendorp: You are totally correct about that. So this is a high bar for enrollment and that has been done on purpose. So we have a small group, 42 subjects as I indicated, which is a very small group when you compare it to the larger community that has post COVID POTS. And since this is a proof of concept study, we wanted to have more of our certainty on the COVID infection and the diagnosis thereof and POTS symptoms that developed after having that PCR confirmed infection. So it's really about having a clear sample, if you like, where we can assess the efficacy compared to placebo. [00:13:30] Dr. Cathy Pederson: And so folks may be thinking, oh man, I'm out. I didn't have that PCR test, but as a scientist, this is good science. This is what we absolutely want in a proof of concept study, that you've got a definitive marker, you know a hundred percent for sure, that this person had COVID and then they develop their symptoms after that. So I'm just saying to the community, this is actually a really good thing that you're being so careful on this phase two clinical trial. Now, let me ask you another question. I think this medication is currently FDA approved, right? For another neurological disorder. It's called generalized myasthenia gravis. Is that correct? Is this medication already FDA approved? [00:14:18] Dr. Joost Van Middendorp: Yes, that's correct. It's approved in the United States for the treatment of generalized myasthenia gravis. Indeed, in adult patients who are anti-acetylcholine receptor antibody positive. So this is the biggest subgroup within myasthenia gravis. [00:14:34] Dr. Cathy Pederson: Okay, so for people that can enroll, the good news about this is it's already been through the stringent guidelines of our Food and Drug Administration. And so that brings me to the next question then which is, what are the potential side effects of this medication? [00:14:52] Dr. Joost Van Middendorp: The most common at first reactions, and that is occurring in at least 10% of patients treated with efgartigimod. Those are respiratory tract infections, headache and urinary tract infections. [00:15:07] Dr. Cathy Pederson: Okay. One more question while I've got you in the hot seat here. And that is, how will you know if this drug worked? So you're running this clinical trial, people come in, they get infusions for a set amount of time. How do you know if people are actually better at the end of the clinical trial? [00:15:29] Dr. Joost Van Middendorp: Yes, that was the big question. We were also asking ourselves when designing the study. So we are running a proof of concept study as we said. But what does it mean? Proof of concept study? It's really also to learn a lot during the study and reading the results of the study. So then it's about capturing dry data elements and also understand how immunomodulatory treatments impact the signs and symptoms in POTS. So for that reason, we will be taking a range of outcome measures in the study, and those include the Composite Autonomic Symptoms Score that I mentioned earlier. So it's the COMPASS 31, but also the Malmo POTS symptoms score. We will probably talk about that later on a little bit more because we've got Dr. Fedorowski on the call who, with his colleagues, introduced this really important outcome. Other outcomes we'll be assessing is the Patient Global Impression of Severity and Change, and a few other outcomes including the PROMIS fatigue scale and also the PROMIS cognitive function because we know brain fog is a issue. And so we've been looking for the measure of how can we capture that within the context of the clinical trial. And on top of that, we'll be looking at the pharmacodynamics and pharmacokinetics as well as the immunogenicity of efgartigimod. [00:16:52] Dr. Cathy Pederson: It sounds like you're looking at a lot of different factors. Some of them are self-report surveys that people filled out probably before they started the treatment, and then they fill it out again at the end of treatment. We're hoping that those scores improve, but it sounds like you're also looking at a lot of what's going on in the body, blood tests to measure those autoantibodies as people go through the study. So very comprehensive, which is what you would expect in a big clinical trial like this. [00:17:26] Dr. Joost Van Middendorp: Yes. And on top of that we will be also looking at biomarkers so that circulating in the body will be drawing blood samples and learn whether those biomarkers correlate with the symptoms that we will be taking questionnaires for. And yes, as I said, understanding what is happening in post COVID POTS and what is happening if you deplete the autoantibodies and do we see that signal emerging in the biomarkers and the signs and symptoms? That is what we really are after. [00:18:01] Dr. Cathy Pederson: I can't wait to read these papers. I think this could be really revolutionary for POTS treatment. At least I hope it will be. So, Dr. Fedorowski, let me turn to you as the POTS expert in the room and ask you why this clinical trial might be important to the POTS community in general. So, as Dr. Van Mittendorp said, they're really looking for a very small group of POTS patients right now. But is there a possibility that over time the findings of this study might generalize to POTS patients who developed the disorder after other infections? Our listeners know that my daughter developed it after mono. Many people have developed POTS after Lyme disease, the flu, a variety of other infections as well. Do you think there's a greater benefit eventually to this study? [00:18:58] Dr. Artur Fedorowski: Yes, of course. Let me start by saying that we are talking about well-designed, well-controlled proof of concept study. So we are not talking about some doctors treating the patients with some drug that we call a repurposed drug, meaning that it works in some disease. Then we think that the other disease has the same background. Then we just move from one disease to another disease, from myasthenia to POTS and we just treat patients and see what happens. No, this is not the case here. We're talking about well-designed proof of concept study where all such factors just like placebo effect are well controlled, taken care of. So that the doctors looking at the study results can be sure that they are decent and they are real. The effects are biologically real. Now our hypothesis is that POTS may have some genetic background as it is in the case with Ehlers-Danlos for instance, some patients may have POTS propensity and it'll develop sooner or later in their life. But majority of patients, as we believe, may be autoimmune or inflammatory, meaning that this is something that can start after viral infection. Just like in case of COVID 19, which created a huge amount of new onset POTS patients. However, not only historically, POTS has been reported to appear after other viral infections. You named a few of them, but even bacterial infections may promote it. And you know that the first study that used the term postural orthostatic tachycardia syndrome actually idiopathic postural orthostatic tachycardia syndrome. This group reported that as far as I remember, half of, or even majority of patients developed POTS in direct temporal association with viral infection. There were different viral infections, gastrointestinal meaning that your stomach was affected, or respiratory tract infections, different infections, but the outcome was almost the same. So it makes us feel pretty sure that different viral infections have different propensity to start the disease, but many different viral infection can produce POTS in the end, just like Epstein Barr virus can lead to POTS. Just like other respiratory tract viruses can produce POTS whose susceptible individual, but this is not strictly genetically the timing. As we can see, that in the same family one daughter can get POTS and another daughter is absolutely entirely free from POTS or from symptoms. So there are different aspects. We call them epigenetic, meaning that you have some genetic background that makes susceptible to disease, and then there comes the trigger or another factor. If we can identify this subtype of autoimmune POTS, this could be a very good target for this type of treatment if this is confirmed by this proof of concept study. [00:22:38] Dr. Cathy Pederson: So this is really, I think, very exciting in the fact that it potentially could generalize and I'm going to be a little bit selfish here, since I've got Dr. Fedorowski here. My daughter's been sick for a decade and many, many of our listeners have also been sick for a decade. Our normal host Jill, has been sick for almost two decades. Is there hope even in the long-term POTS patients for improvement, potentially, from a treatment like this, do you think? [00:23:11] Dr. Artur Fedorowski: Absolutely there is hope for everybody. If you have symptoms, especially if you feel exacerbation periods, meaning that you have your symptoms. They just persist over a longer period of time than you just happen to have another viral infection. You feel worse after this infection. What it means for me is that the process is there in the background. It gets worse through different triggers. It gets inflamed and you will get worse. So it means that if you get rid of the propensity of the underlying problem, you will get better wherever you are with your disease at the moment. So there is hope for everybody. Of course there might be some darker cloud in it, meaning that if you have had it for a very long time, there might be some subtle changes that we cannot see with our naked eye or we cannot see with our contemporary instruments. But we have been talking for a long time about neuropathy, small fiber neuropathy, changes that are very subtle but may have come over the longer period of disease duration. This is something that we cannot exclude, but if the disease is inflammatory and if this is mediated by circulating autoantibodies who are just creating chaos in your body, probably if we will get rid of them, you may create a space for better breathing for your body, and maybe this creates an opportunity that you can feel better. So there is hope for everybody. Absolutely. [00:25:01] Dr. Cathy Pederson: That's really exciting to hear. And even if they can't return to normal, quote unquote normal, I'm not sure there is such a thing. Any improvement in symptoms would be a good thing. So it sounds to me like there is hope that this clinical trial could help lots of folks potentially. [00:25:20] Dr. Artur Fedorowski: I would like to directly comment upon what you just said. Can you imagine a scale from 0 to 100? So if you just move from having like 80, 85 points of your disease burden and you move down to 50 40, so maybe if you look from the perspective of one who has zero, you're still sick, but if you are sick at the level of 100 or 80 points and you move to 40 50, it's a huge change in your life. You can walk maybe a few hundred meters more. You can get to the shop nearby. You can take care of you in a better way, and suddenly your life has changed. So this might be a huge step for even the sickest patient. [00:26:09] Dr. Cathy Pederson: Very well said. and Standing Up to POTS is thrilled to be involved, even peripherally, with this study. So Dr. Van Mittendorp, let me come back to you here for a minute. What are some of the challenges of running a clinical trial for post COVID POTS patients in the United States? [00:26:30] Dr. Joost Van Middendorp: Yeah. So one overarching challenge, which you are probably very aware of, is the lack of awareness and the recognition of POTS across the medical community. So hearing testimonials about how debilitating symptoms such as fatigue, brain fog and anxiety are being minimized by uneducated doctors that really sends shivers down my spine. So there's a lot of room to win there. And that's not only for the benefit of the medical community, but also for conducting clinical trials. I mean, it's quite remarkable that with the daily needed support that devoted doctors and patient organizations like Dysautonomia International, they made the introduction of the international diagnostic code for POTS happen, and that has only been introduced about six months ago. So there's a lot of room to win there. On the positive side, I noticed that the mainstream media as increasingly picking up the societal burden of long COVID as well as the high prevalence of associated autonomic sequelae, including postural tachycardia. So the awareness, it's not optimal yet. And when it comes down to challenges in running a clinical trial, I could think of three more specific challenges. So first, there are no regulatory precedents in POTS. This means that we will have to pave our own way to success, if you like. So along with the community, patient organizations like yourself, and POTS experts like Dr. Fedorowski and we are deeply committed to the POTS community and hope that our smallest contribution will aid in the recognition and awareness of this debilitating syndrome. The second challenge is that as of today, there are no validated endpoints. Given that POTS can manifest itself through many different symptoms, it is paramount to measure the most impactful symptoms and be able to track changes over time. So we were very pleased to learn that Dr. Fedorowski and his colleagues have been working on a novel outcome measure and the Malmo POTS symptoms score. Personally, I believe it has the potential to become a standard of assessing the efficacy of new interventions in future randomized clinical trials. Great progress. And we are making progress as we speak. But also there is a long way to go to have this all comprehensive package of endpoints that we can measure the impact of new treatments. And lastly, there's a limited number of centers of excellence in the world with established autonomic testing capabilities. So in order to gain a deeper understanding about the physiology and prognostic factors in POTS, increased setting capacity is really desirable. So we are grateful for collaborating with established centers like Stanford, Harvard and Johns Hopkins University. So step by step we are addressing these challenges as well as other challenges that come our way. So, experience from working in other autoimmune disorders has taught us that multi-stakeholder collaboration is the key to success. And therefore we are grateful in joining you in Standing Up together to POTS. [00:29:58] Dr. Cathy Pederson: I love that. Let me just clarify for our listeners. When you mentioned these centers of excellence across the country, does that mean you'll be recruiting post COVID POTS participants into these various centers? So you mentioned Stanford, Johns Hopkins, Harvard, I think Case Western is on that list. Texas Institute of Cardiology. So you're recruiting patients from across the United States that live close to those centers. Is that the idea here? [00:30:30] Dr. Joost Van Middendorp: Yes. So participants are welcome and invited from across the United States. And given the number of visits that are required to the study sites, it makes all the sense to have some geographic proximity to the sites. You are correct. It's a US based study and the centers of excellence are spread across the country. [00:30:55] Dr. Cathy Pederson: And how often would they need to go? So if you're going once a week to these centers, you might want to live close. If you're going twice a year, maybe you fly in. How often are you expecting participants to come to these centers? [00:31:12] Dr. Joost Van Middendorp: Yes, there's no specific set of site visits in the study. What I can say, we have home nursing arrangements included in the study, so that means that home nurses can administer the study drug at home. So it's not the case that participants would need to visit the study sites every single week in order to get the IV intravenous drug administrated. So that's not the case, but it will be assessed on an individual basis to see what the best visit schedule will look like. [00:31:49] Dr. Cathy Pederson: Okay. So it's a work in progress is what I hear there. I want to jump back to Dr. Fedorowski. We have mentioned a couple of times this Malmo POTS symptoms score and I just used that as part of the survey. Very excited about that. Dr. Van Mittendorp has mentioned it a couple of times that you're using this survey as part of the clinical trial to assess POTS symptoms. I'd love to hear a little bit about the survey, how you came up with it. I know you validated it and I think it's going to be used widely in the POTS community. I'd love to just hear your thoughts on that, Dr. Fedorowski. [00:32:29] Dr. Artur Fedorowski: So a couple of years ago, just before the COVID 19 era, we were sitting down and thinking about creating a questionnaire with score system for POTS symptoms. And we realized that there were no good such tools on the market. We searched the literature, we couldn't find anything. COMPASS 31 was too large and covered too many aspects and we wanted to focus upon POTS patients. So what we did, we just look at one of the biggest surveys on POTS, the Big POTS survey, and we selected 12 most common symptoms. The threshold level was 75% of participants should have reported it on in the survey. And then it's quite a funny because we selected 12 different items to 12 different symptom domains. And then we look at the list and we asked ourselves, is it correct? Is it how we feel it when we meet this patient? We went through the list and it fitted perfectly. Then we went to the lab and while performing new examination on POTS patients, We just ask them, oh, we prepared such a list of different symptoms. What do you think about it? We just go through all your symptoms. But this is done in a more systematic way. What do you think? And we just tested it on five patients or all of them said, oh, this is perfect. This is exactly how I feel. You just hit the major points. We don't mention all of these symptoms while meeting doctors because we do not believe it is very important. We do not believe that they are going to believe us, but you got it. So then we check it against the background of health conscious age and sex match. And then when we saw the results, it was very good discrimination. Of course, this is not a symptom score to diagnose POTS. You do it in the lab, you do it by performing active standing tests, looking at the orthostatic vitals and so on. This is to estimate the symptom burden for an individual patient so that you can place how sick he or she is. And then to see the progress... getting better or getting worse, and to avoid missing different symptoms, different domains, different organ ailments. So this is designed for this specific purpose. And I think that scientists or clinicians all over the world, they start appreciating it. They start using it now. We are open to modifying it if someone can come up with a better idea. [00:35:18] Dr. Cathy Pederson: Well, I, love it and it's something that is very easy. It's a quick assessment, and I think you've put it out there for free. Is that true? [00:35:28] Dr. Artur Fedorowski: This is our gift to POTS community. And I must just while sitting here and having Joost on board, I would like to add something else. So Joost was the first person that made it even better just by classifying different subgroups, by dividing into different subgroups. So this is a perfect example of joining forces by very smart, ambitious people from industry joining forces with very worried clinicians. I'm a romantic, idealistic person, so I like sharing knowledge. I like sharing my ideas, and I like working in team. So I think that this support that I got from Joost created a bond between us. We could understand each other. Joost, without seeing the patients, he understood how sick they were, just by looking at the numbers in the score. Joost, maybe you could add something here. [00:36:27] Dr. Joost Van Middendorp: Well, yes. I can only add to that in a sense that we have to make sense of all the symptoms that patients report back to you and then take it to the best of our capabilities to show, okay, is this going to the right direction in terms of improvement, or is there any deterioration? And how often do we need to assess those variations. And that reminds me of the waxing and waning that we hear from POTS patients, which is a real big issue to capture also in a clinical trial context. Coming from the neuromuscular autoimmune space, having worked in myasthenia gravis, this is a theme that we see a lot in other autoimmune disorders as well. The waxing and waning. So that comes with a number of challenges. Are we measuring at the right time and at the right interval? And how are we going to bring that forward to the regulators at some point? So we need to have those dialogues with the community. And I mean with the patients, with the doctors, and ultimately also the regulators to bring the most meaningful data package forward. [00:37:46] Dr. Cathy Pederson: This is really amazing, and again, helping to push this whole POTS community forward, I think. So, Dr. Fedorowski, I'm going to put you on the spot. Would you allow Standing Up to POTS to post this on our website so that physicians can find it, so that patients can see what we're talking about here? [00:38:04] Dr. Artur Fedorowski: Oh yeah. Definitely. Absolutely. [00:38:07] Dr. Cathy Pederson: That's what we like to hear. So folks, you'll be able to find the Malmo POTS Symptom Score instrument on our website and can use that as you see fit. Take it into your physicians, help them to see what's going on in POTS. [00:38:22] Dr. Artur Fedorowski: If you're going to use it, please tell us if something is wrong. If you feel there is some potential for improvement, we are very open to it. Of course, this is the prototype, the first one, but the prototype still. [00:38:36] Dr. Cathy Pederson: Wonderful. Absolutely wonderful. Do you mind if I change direction a little bit? So, Dr. Fedorowski, I'd like to come back to you again and ask about this autoimmune angle. We've been talking about this clinical trial, and I think we've taken for granted the autoimmune angle that really is important in the POTS community. And I wonder if you could just outline briefly how autoimmunity might relate to POTS itself and then some of the major comorbidities that we often see with POTS. [00:39:13] Dr. Artur Fedorowski: Let just start by saying that we have to realize that there is no causal therapy against POTS at the moment. This is a huge frustrating factor for the medical community, for healthcare workers, and for patients and their families. And anybody who has connection to this issue. So if I can make a joke here, we would like to have an antibiotic against POTS. So then probably there are no bacteria. There are no viruses. There's some theory about persistent virus in the body. But we would like to have an antibiotic against what's causing POTS, and let us imagine that circulating autoantibodies, wrong autoantibodies, dysfunctional antibodies are doing it. So giving these patients antibiotic or a medicine that can get rid of it or dampen the effect of these circulating autoantibodies could change the game completely. So everybody knows that acting against autoantibodies is not an easy match. They are there for some reason, they're helping us. They protect us from infections, for instance. But this concept is worth exploring just as we do with intravenous immunoglobins or plasma exchange in different places all over the world. We decided to test it just for the same reason. So if we decided to test the other options, so why not to test this option, which seems to be very promising in my opinion. [00:40:52] Dr. Cathy Pederson: Yeah, that's really exciting. And the idea of this particular clinical trial is not that it's going after one autoantibody. And I know you have published on several autoantibodies that are found in POTS, but rather that it's, again, going upstream a little bit and knocking out a variety of autoantibodies, some that may not even have been identified as important in POTS at this point. And so there's huge potential, I think, for this trial and for this medication eventually to really help improve symptoms for a lot of POTS patients. So Dr. Van Mittendorp, how soon will we know if this works? When would you possibly see it come into the clinical trial stage three? When might medications actually be available that doctors could prescribe? We're probably getting ahead of ourselves, but what does the future potentially look like? [00:41:53] Dr. Joost Van Middendorp: Yes, it's a matter of containing excitement, isn't it? Now, it will take time. It will take definitely time to have this read out of the proof of Concept study and we expect the study that is currently running to be completed by the end of this year. And then as I alluded to earlier in this podcast, is following a phase two study, there will be a phase three study. Phase three studies are large multinational studies, global studies, if you like. So we are talking about a timeline of years, unfortunately, for the patients now living with post COVID POTS every day. But we are working as hard as we can to complete the phase two proof of concept study as soon as possible, interpret those data and come up with the most effective design of the phase three study because it needs to be meaningful but also timely. Again, it will take time. We do not expect to see this approved in the next year. So that obviously is not something that the listeners should expect to see happen. But it's a meticulous, thorough approach where we also interact with the regulators who have to listen to what they feel is needed in order to ultimately and hopefully approve a product in the future. [00:43:20] Dr. Cathy Pederson: So folks, that means we're not going to have a medication out there in the next year or two years. But the good news is that we have hope again. Right? And that possibly help is on the way, which is exciting. I've lived with one foot in this world for a decade, and I don't remember hearing anything so exciting in that time. So we can dream a little longer. [00:43:45] Dr. Artur Fedorowski: I would like to add one thing that I used to tell my patients. When I see them suffering and being frustrated and giving up, I would like to tell 'em a few stories from the history of medicine, but such game changing events, they may happen anytime, and when they happen, when it occurs, it changes the landscape completely. One example that I like is diabetes. People were dying of diabetes. They had no chance to survive and suddenly one guy found out that the extraction with insulin could be given to these patients. It was a game changer. Since that day, they were able to survive and now they can live as long as we do. It means a lot that if we can find this holy grail, let's say for POTS, it's going to be game changing. It's going to change the situation. I believe I'm going to see during my lifetime very, very strongly. [00:44:48] Dr. Cathy Pederson: I love that. And I love the fact that people are looking, and I think as a POTS parent myself, I feel better knowing that people are looking for the holy grail instead of continuing with this whack-a-mole, where the head pops up and you go and you hit that symptom and then another one comes up and you try to hit that symptom back down again, which is really what we're doing right now, I feel like, in the community. So this is very exciting. [00:45:18] Dr. Joost Van Middendorp: Yes. And I like the analogy with diabetes. I alluded to myasthenia gravis before and what I personally like about the parallel between myasthenia gravis and POTS is the following. If you look at the clinical development program that took place before Argenx got the approved or from the FDA for acetylcholine receptor positive generalized myasthenia gravis and to be treated with that efgartigimod. That was a clinical development program that spent approximately six years after the healthy volunteer studies, phase one study. So that gives the listener a kind of perspective how long these trials and clinical development program take. This is not one or two years, but looking at myasthenia gravis, this is a autoimmune conditions with autoantibodies attacking skeletal muscles, so they disrupt the signaling that goes from the nerve to the muscle and resulting in weakness. If we think about POTS, it's primarily a vasomotor problem, meaning that there are difficulties in contracting the veins and the vessels. There are also some muscle tissue, not the skeletal muscles, but there are the smooth muscle cells. And they are also being innervated by the nervous system, not the same as the nerves that trigger the skeletal muscles, but those are autonomic nerves with other receptors. And we believe that the autoantibodies may hijack those receptors where there's transmission from the autonomic nerves to the smooth muscle cells that then result in a constriction or develop a vasodilatation of the blood vessels. So in both conditions, in myasthenia gravis and POTS, we have muscle cells involved with disruptive autoantibodies. So for myasthenia gravis, the culprit is very clear. These are the acetylcholine receptor autoantibodies. For POTS, it's a different story because we don't have such a specific autoantibodies identified yet. We have candidate autoantibodies wait for a number of receptors as Dr. Fedorowski alluded to. But it may also be that these autoantibodies are polyreactive, so reacting to more than one single receptor. So learning from other autoimmune disorders is something I really enjoy doing because we can take that knowledge from one autoimmune disorder to the other. So I really wanted to add that. And also it builds the narrative of the story the possible autoimmune involvement in POTS. [00:48:29] Dr. Cathy Pederson: That's really fascinating. I hadn't thought about that. I'm familiar with myasthenia gravis. Most of our listeners know I'm a college professor and I teach a wide range of things. So I knew that that affected the skeletal muscle. I hadn't really thought about that small fiber neuropathy that lots of POTS patients have, and that you're going after those in the blood vessels and hitting that smooth muscle instead. So that's a really interesting connection, I think, that you just made. [00:48:56] Dr. Joost Van Middendorp: Yes, indeed. So what we see in myasthenia gravis is particularly the more severe and long term myasthenia gravis there's also some sense of neuropathy involved because of the disrupted neuromuscular junction. It works both ways to the muscle, but also to the nerve that normally innovate the neuromuscular junction. So detailing the pathophysiology, what is involved and what is the effect that we see of the autoantibodies. And that knowledge could serve also other related autoimmune disorders which we believe may also be a process that could be going on in POTS. [00:49:42] Dr. Artur Fedorowski: I like this comparison or just a parallel that POTS is a cardiovascular myasthenia gravis. It might be. Well, so, but the same underlying processes there, but the targets are different. Just like we have thyroid gland issues. So this is also an autoimmune process and you have overactivity, hyperactivity and hypoactivity depending on which autoantibodies are involved. So we can see that they can produce a lot of different effects in your body, a lot of chaos in your body, depending on which different organs they target. And our best guess now is that the POTS is a autoimmune cardiovascular disease with disruption of normal controls circuits. And for some reason, it attacks more women than men just like myasthenia gravis and just like thyroid diseases. So there is some good analogy there. [00:50:41] Dr. Cathy Pederson: This is a fascinating conversation and frankly, I could go on forever, but I think both of you have very busy schedules. So let me just ask, if someone who's listening says, Hey, I got POTS after COVID, I do have that PCR test to prove I had COVID 19. Where can they go to learn more about this clinical trial and potentially try to sign up for this clinical trial? [00:51:11] Dr. Joost Van Middendorp: Yes. So there are various sources on the internet that lead to the clinical trial information for this particular trial. And patients at focusing groups like yourselves are aware of the study taking place. So yes we would then recommend any interested individual to follow those leads. [00:51:30] Dr. Cathy Pederson: So we'll put some links in the show notes, and then we'll also push it out through our social media. Okay folks. So if you have a pencil ready, you can take down the link for this trial. Just a reminder, we're talking about a clinical study of an investigational medication for adults with post COVID-19 POTS. So that's what's enrolling right now. And you can learn more at, are you ready for it? www.alphastudyforpots.com. And so that link again is www.alphastudyforpots.com. And again, we will include that in the show notes for you. Okay, listeners, we hope you enjoyed this discussion. Hopefully some of you'll be able to participate in this post COVID POTS clinical trial. We'll be back again next. Until then, thank you for listening. Remember, you are not alone, and please join us again soon.

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