Good afternoon. It's my pleasure to welcome Professor Edward Visser from the Erasmus Medical Center in Rotterdam. Professor Visser, he will discuss some topics around Emcitate deficiency and the new treatment opportunities that we see. We have scheduled this call to end at 15:30, so it's a 45-minute call. I think we will start the call by giving Professor Visser the opportunity to give some background about his experience in the field, you know, the patients he sees at his clinics and some other relevant topics. I think we should open up for Q&A from the audience around halfway through this call. Just as a reminder, if for questions later, please press pound key five. Pound key five. My name is Lars Hedving. I will moderate this call. With that, over to you, Professor Visser.
Perhaps you could start by giving some background, you know, to your experience in the field and what it deals with this very rare disease that we're going to discuss, and also some key learnings from the many patients you have treated across in the recent years. Over to you. And thanks for taking the time, Edward.
Thank you very much. It's my pleasure. Yeah, my name is Edward Visser. I'm an internist endocrinologist in the Erasmus Medical Center, which is, I think, perhaps the largest university medical center in the Netherlands, employing 17,000 employees. I think basically all specialties are present in our center. I'm currently heading the Division of Endocrinology as well as the Thyroid Center, which is composed of clinics, but also a research unit, including a lab, which you do see behind me, which is actually a historical one because the Erasmus Medical Center has had a thyroid lab already, I think, since the 1970s. We are on historical ground. Perhaps good to be clear, Erasmus Medical Center receives royalties from Egetis Therapeutics on the commercialization of Triac or MCT8, but there are no personal benefits.
Yeah, to give a little bit of background, I don't want to repeat everything which I might have said on other occasions. The thyroid group has always been interested in how thyroid hormone produced by the thyroid gland actually acts onto cells and tissues. An important step is how thyroid hormones enter cells. It was discovered actually in the lab behind me that it doesn't just diffuse into cells, but there are transporter proteins required. The most important transporter we currently know is MCT8, which was discovered in the Erasmus Medical Center in 2003. One year later, 2004, the first patients were identified again here in Rotterdam. I joined the team in 2006, so I was involved in the early kind of identification of patients and also had a chance to think along in potential strategies for clinical management and therapy for these patients.
Yeah, that led, I think, to the development of Triac, or currently called MCT8, for this disease. Just as a reminder, MCT8 is a thyroid hormone transporter, which is importantly expressed at the blood-brain barrier. If it is defective, patients have a severe phenotype, which occurs actually mainly in males because the gene is located at the X chromosome. Females are carriers and males are affected typically. Basically, you can distinguish this syndrome in two components. There is a strong neurodevelopmental problem because the brain has insufficient concentrations of thyroid hormone because insufficient thyroid hormone enters the brain. Thyroid hormone is important for brain development. That brings about all these severe neurodevelopmental features. At the same time, other parts of the body are faced with elevated concentrations of the active hormone T3.
The heart, the muscle, liver, et cetera, are basically seeing too much thyroid hormone. That also brings about negative consequences like tachycardia, muscle wasting, low body weight. Together, this results in a high mortality rate of around 30% of patients dying during childhood. This all started basically historically in our lab. That also resulted in the fact that, over time, patients got referred to our center. At the same time, it's a rare disease. We estimate this as occurring around one in 70,000 male individuals. I'd like to emphasize it's an estimation. It's at least that direction. I think we are currently seeing between 10 and 15 patients in the Erasmus Medical Center. However, we are involved in way more patients across the world because we guide physicians.
When they encounter a new patient, we are frequently emailed for advice on clinical management and MCT8 treatment. What happens is that we receive information. Blood samples are sent to Erasmus MC. Based on that, we guide them on those. By doing that, we have created an international, let's say, consortium and infrastructure where data is sent to Erasmus MC. We are collecting that. Once in a while, we report this in a scientific publication for the field. I think this, yeah, I think personally, I'm convinced this is a good way how to deal with a rare disease, which is in a way centralized. The knowledge is, yeah, feedback to all the individual physicians across the world. I think we are aware of maybe close to, I don't know, 100-150 individuals being treated with Triac.
There might be some more, but obviously, we don't have 100% of patients we are aware of. I think over time, we have developed, yeah, some experience in this area. I can go on for another 40 minutes, but there's no room for questions. I think I leave it with this. Unless Lars, you think it might be wise, I should also proactively say something else.
That's very interesting to hear, Edward. Can I just ask you about this field compared to, say, five years ago and your interactions with colleagues, et cetera? Would you say a lot of things have happened, so to say, between activity from colleagues, their ability to find patients, the kind of questions they ask, et cetera? Is this a more active field, so to say, in general today with your experience?
Yes, I would think so. Obviously, you start with the identification of one patient, and then the question is how to find other patients. That has, I think, much to do with disease awareness, I think, which has grown over time. Oh, that's funny. The other factor that contributes is, I think, that genetic panels are all over the place now. Even without thinking of this disease, it can pop up through a genetic panel. I think that both has contributed to, yeah, much more patients being identified, which is still ongoing. I think also maybe in the early years, people were asking for a therapy. I think now they're more approaching me, hey, how can we get can we be recruited for a trial, or how can we get, yeah, track of Triac?
Regarding Triac or MCT8, you have been involved in these trials for many years. What would you say about your overall experiences in terms of randomizing patients, so to say, or recruiting patients, rather, to trials and keeping them in the trials? What happens after the trial? What are the overall experiences? How do people or patients continue with their treatments after the completion of the trial? Could you say something about that?
Yeah, thanks. Yeah. Initially, our trial started back in 2014, which was an investigator-initiated study. We were really fortunate that there were many physicians collaborating with us across the world. Recruitment at that stage was not a problem. Actually, there was no therapy, yeah, beyond supportive measures available. There was a high willingness. I think that there was also, yeah, I think basically all parents were quite enthusiastic and also willing to continue the treatment, at least those who finished the trial. However, for various reasons, not everyone at that time, back in 2018, 2019, had a chance to continue with Triac in their country. Over time, we have seen patients who have been a few years off Triac, again, restarted on Triac.
I think that situation has changed for the better in, I think, the recent five years or so compared to the first five years when we started in 2014.
Okay, I see. It has, I mean, to get patients into trials, et cetera, that has been fairly straightforward.
Yeah. We have done so. The first trial was not problematic. I think the second trial had a more, yeah, was a bit more restrictive in terms of the age. That is more difficult for that reason. I do not think that the willingness to participate was different. The third study, the retrial study, at least what I can speak for our side, I was actually positively surprised that parents in the Netherlands were willing to participate because they had basically nothing to win with this because they already have the drug on a compassionate use basis. They were willing to participate in the trial for, yeah, let's say, for the greater good for registration purposes.
Okay, I see. No, that's interesting. Can I continue a bit with the recommendations we saw last year from the, I mean, the treatment recommendations we saw last year from the European Thyroid Association. I think it was published in August, September, somewhere around that. What would you say is the, I mean, how important, what should we say about that? Is that an important thing that you in the field, your insiders that you, is that new information for you, so to say, apart from the recommendations by itself? And how important is that in terms of when you communicate with colleagues, et cetera, treatment recommendations, what people should do with their patients, et cetera? What's the relevance really? Can you help us with that?
Yeah. I think obviously, it's always good for a disease, also for a rare disease, when there are recommendations for treatment. I think that greatly facilitates physicians who are less experienced with particular disorders to be guided. I think in that sense, it's really helpful. I think at the same time, at least in the current situation, I have the feeling that when physicians encounter a novel patient, they have a low threshold in reaching out to an individual doctor with more experience like me to ask advice as well. In general, I think it's, yeah, it's good that there are guidelines for disorders. Yeah.
Okay. I see. If I would ask you to, I'm also thinking about what we learned, some releases we saw from last year about the mortality effects from long-term treatment. Of course, not treatment experiences, not prospective trials, but of course, still, that's the data we have. In your view, what would you say would be the main driving? That's a very difficult question, but the main driver, so to say, to have an impact on this very high, on mortality and survival. What would you say is the key parameters to monitor and to have this, that you would have the confidence that this is some, these patients, this is something we should make an impact in terms of improved and prolonged survival?
Yeah. Maybe if I can rephrase this a little bit. I think the data we have, the data that are published, I think they show, I think clearly that the elevated T3 concentrations all come down towards the normal range. In parallel, we do see positive changes on body weight and heart rate, et cetera. There I have little doubt, actually, or no doubt that that's beneficial. I think we have analyzed data from Triac Trial II on neurodevelopmental outcomes. Or actually, we haven't analyzed them in detail, but I think the overall conclusion is that at a high dose in early life, it does not positively change the neurodevelopment. Although we, let's say, as University Medical Center, we still want to also run some postdoc analysis. I mean, is there a signal in a specific subgroup, et cetera?
Now, there are different ongoing activities, research activities, which have not been published, but only been presented at conferences. I'm a little bit more reluctant to say more than that has been in the abstract. I think there are two things that might be worth highlighting. First is indeed what you refer to is the positive effect on mortality rate. What we have done, we have reached out to actually all patients in the world that were known to us, but also actively looked up through the literature, actively contacted doctors. I think we are close to saturation of all patients that are known in the world. We have asked the question, are those being treated with Triac, are they better off than those without Triac? We did all kind of proper statistics because, I mean, it's retrospective.
You will never have a prospective trial placebo-controlled on this. We did all proper statistics trying to control for biases, matching, et cetera. I think from different analysis, it seemed that there is, with the data we had at that time, a three times reduction in mortality rate, which might not be, I think the effect itself is not a big surprise, perhaps, which was also the reason why we asked that question. Because, yeah, when you reduce T3 levels and you reduce heart rate and you reduce blood pressure, yeah, it's logical to think that you might improve patient strength, et cetera, and reducing chances of dying. Currently, we are adding more data, and we are planning to analyze, doing the final analysis in the really foreseeable future.
Hopefully at some time, we'll share the publication with the scientific and clinical field. The second thing, and then I will stop, is what we did. We are also currently reanalyzing data from our first trial. When we designed this trial and all the forms, we had a lot of questions, sometimes open questions on what did you think that was the most prominent change, being either positive or negative, or do you want to proceed with Triac after this first year of trial? We asked things for sweating, et cetera. We are currently reanalyzing that, but that was also presented at a conference. There also, the picture really emerges that on, let's say, parent-reported outcome measures, Triac is also doing well.
I think that is reassuring to see because that really fits our observation and not only ours, but also of other physicians in the world, that, yeah, to summarize it, patients are just doing better. They're more aware of their environment. They are, yeah, there are many more things to say about it. How I currently would summarize the effects of Triac is I'm convinced of the positive effects on what we call the metabolic part of the disease, potentially a substantial effect on mortality rate. At the same time, with young individuals with a high dose, it doesn't seem to improve neurodevelopment. I'm not saying that Triac is the golden bullet for this disease. At the same time, Triac is doing good to the patients.
There is always room to improve or search for perhaps novel treatments or perhaps even earlier during prenatal stages, for example. That is basically how I view the, yeah, where Triac should be placed. Sorry for my lengthy answer.
No, that's very helpful. On that note, in terms of diagnosis of the disease of the patients, would you say that there is any uncertainty, so to say, when that job is done, so to say, when people are considering if this is the disease or if it's something different, and then if the diagnosis has been established, do you see any reason why doctors would not consider to use this treatment?
Yeah. Yeah. I think the diagnosis is ultimately a genetic diagnosis. When there is a known pathogenic variant, yeah, then you have kind of proven the disease. Sometimes there are, let's say, novel variants. What we have recently done, we have built based on all the information we had, we have built a machine learning-informed classifier that highly accurately predicts the pathogenicity for new variants. I'm not so, yeah, fearful for unclearity of the diagnosis. I think people could ask if, like any disease, there are all different kinds of, there's a spectrum of severity. The majority of the patients have a truly severe disease, but there are also patients with milder forms of the disease with not so much elevated T3 concentrations, with a normal heart rate, with not too abnormal body weight.
I can imagine, for example, I've had an older patient with a relatively mild MCT8 deficiency who at that time had a normal T3, was doing well for decades. I decided to not start treating him with Triac because he had lived up to his, I don't know, 50s or 60s without.
I got it. That's very helpful, Albert. Just as a reminder to the audience on the telephone lines, if you would like to have a question, please dial pound key five on your telephone keypad. I should see people who ask on the question. Yes, I think we have a question from Suzanna. Please go ahead, Suzanna.
Hello, and thank you for arranging this call. I have one question. First of all, my name is Suzanna Queckbörner from Handelsbanken. I'd like to get a better understanding of how representative the diagnosis in the Netherlands is compared to other areas in Europe. Specifically in the case of Egetis and MCT8, we expect the launch to start in Germany. Do you know how diagnosis would occur there?
Thank you. I would think that the Netherlands and Germany are not too dissimilar from each other. At the same time, we do see different diagnostic rates across countries. I haven't done the maths, but we do see that from certain countries, yeah, there are less patients diagnosed than in other countries. It can't be true that this is due to geographical differences, but it's more likely with the healthcare system. For example, how early in the diagnostic process do you incorporate genetic panels? Or is the gene encoding for MCT8, is that incorporated in these genetic panels? Is that an answer? I mean, let me know if it's not an answer to your question.
I mean, I think more simplistically, I'm trying to understand. You're an endocrinologist. At what point in the diagnosis are the patients referred to you? Or how frequently are they referred to an endocrinologist in a maybe less specialized setting? Would they then just end up at the neurologist instead and never be referred further onwards?
Yeah. We get many questions from general pediatricians, pediatric neurologists, clinical geneticists, and also endocrinologists. I think these are the main four specialties we get referrals from. It depends on how the specific setting of a certain hospital is. Sometimes physicians, for example, neurologists, want to join forces with endocrinologists. Sometimes they're happy to treat them themselves with proper guidance by us. That's really dependent on the individual circumstances and infrastructure.
Was that answering your question, Suzanna?
Yes, I'll take a step back and get back in the queue. Thank you.
Oscar from ABG, I see you have a question. Please go ahead.
Yes, hello. Oscar here from ABG. Thank you for this event and taking my question. Just wondering if you could give us some more granularity on the proportion of patients that you identify as being mild versus severe with MCT8 deficiency.
Yeah. Thanks. Yeah. It depends obviously how you define that, but I would say that the far majority is what we call have a severe phenotype, severe clinical phenotype. With a milder phenotype, I mean individuals that have the ability to stand and walk sometimes with some support or are able to speak a few words or sentences and are clearly understanding you. That is, I would say, maybe around 10% of the cases with the current knowledge we have.
All right. Thank you. Very helpful.
It seems, can I just follow up on terms of conferences during the year or the coming years where you would expect, I mean, in terms of following new data which are being presented? Are there any particular highlights you would like to mention to us about future congresses that you think we should be having a look at?
Yeah, I'm afraid I can only speak for myself and my team.
That's good enough.
Yeah, there will be the International Thyroid Conference in Rio de Janeiro in June. We aim to present there some updates on the different research activities I just mentioned.
Okay. I got it. That is in June in Brazil. When you have these incoming questions, dialogues, et cetera, with colleagues in terms of how to treat patients, et cetera, there are questions. Do you also have a lot of contacts with your counterparts in the U.S.? Or is it primarily between European colleagues? How does that look?
Yeah, the short answer is from all over the globe.
Okay.
Yeah. So basically we have, yeah, that's it. We communicate. We will be shortly publishing a, yeah, I think a big paper in the really foreseeable future in a radical journal. Also on MCT8 deficiency. I think we have included data from patients from over 20 or 30 countries, really across the, yeah, I think basically from all continents.
You have the global perspective. That's as it is.
Yes. At the same time, I don't want to overestimate myself because I don't know what I'm not seeing. We have, yeah, a bit of a feel what happens in different parts of the world.
Okay. I see. What do you think will, or do you think, how do you think the, you can't call it diagnostic rates, but what do you, once we have an approved product on the market, do you think overall, I mean, generally speaking, disease awareness or knowledge or interest in finding patients, et cetera, with your back, do you think that's going to change in any way?
I'm unsure whether I'm in a position to answer that because I don't have a kind of helicopter view on other rare diseases where, I mean, when you have a, what I have learned from people is that they say once there is a therapy available, the diagnostic rate also increases. Yeah, I think there might also be other means to do it. For example, harmonization of genetic panels across, yeah, across countries, for example. I think that would also be helpful.
Okay. I see.
Obviously, ultimately, but that could also be the far future. One can envisage that this could be included in neonatal screening programs. This is certainly not something for the short term.
Okay. Coming back to your comments about and the data we've seen about long-term survival effects, when we look into the data, what would you say is the reason why in terms of heart rates and effects on that, as one example? When you look at the baseline, so to say, parameters we see, the differences in the population seem to be great. I mean, heart rates, for example, you have the span from, say, 160 down to 70, 80. Can you say anything general about why is the span so broad? Why does it look that way? Is it depending on how for how long, how long, what's the age, et cetera, and what's the reason really?
Yeah. Specifically for heart rate, I don't know. I think there's, in general, dependent on how you capture heart rate, there can be huge variability because they have many more problems than an elevated heart rate. They have dystonia, they can suffer, and if they are tired or excited, I think the heart rate really goes up and down. There is intrinsic variability. Yeah, I cannot exclude that maybe over time it gets more pronounced. In general, I think having a lifelong exposure to elevated thyroid hormones to different tissues is certainly not a good thing. If I can make a parallel with another rare genetic thyroid disorder called thyroid hormone resistance, where also patients are exposed to elevated concentrations of thyroid hormone in heart and muscle, et cetera, that's also associated with a several times elevated mortality rate. That's not, yeah, too dissimilar.
At the same time, I can only speculate why the mortality rate, yeah, is high and why it would come down. One being indeed the cardiovascular system, which could be an explanation. At the same time, when they are doing better, they might be, yeah, better in eating, in putting up some body weight, which might be a bit better to combat any intercurrent illness. These are all speculations, honestly.
You mentioned resistance to the thyroid hormone. How common is that? Would you say what's your experience relative to MCT8 deficiency?
Yeah. I think it occurs around one in 30,000 to one in 50,000 individuals.
Okay. You see more of these patients in your.
Yeah.
Okay. Could you say briefly something about the, very briefly about treatments in that field? What you do?
Yeah. Many patients do not get any treatment because they are not overtly symptomatic. Patients who suffer from palpitations are typically treated with a beta blocker to control the heart rate. Only if that's insufficient or there are other things like failure to thrive in childhood or some ADHD, that can trigger a signal to start treatment with Triac. On a personal note, I think that it would be very rational to try to reduce the thyroid hormone concentrations for which Triac could be a truly good means. Certainly with this recent publication that many of you might know in this enhanced mortality rate and cardiovascular mortality and morbidity in thyroid hormone resistance, it would certainly, yeah, logical to investigate that.
That's very interesting. You see that's an area that could be explored with MCT8 as well.
Yes. Obviously there should be, I mean, you can also think there about severity and height of the thyroid hormone concentration. There are also many unknowns in that field, but it's, yeah. I think there's also quite some experience with Triac in this disorder as well.
Okay. Great. I think we're soon time to wrap up this call. If you don't have any more questions from the audience there, in fact, we have Fredrik. You have one question. Please go ahead.
Yes. Hello and thank you. Yeah. One question about the label in Europe, which was for treatment of peripheral thyrotoxicosis from birth. Would be interesting to hear your thoughts about the label and if you see it as limiting in any way or if it's applicable for most of all patients.
Yeah, I don't think it's limiting because basically all patients also have this peripheral thyrotoxicosis. Perhaps strictly speaking, there might be one or two individuals. Now, that's a bit exaggerated, but a very, very small minority. Like the example I gave earlier that does not have overt thyrotoxic features. Yeah, in general, I think this would capture basically all patients. Would be applicable to all patients.
Got it. Thank you.
You're welcome.
All right. Thanks to all participants for the questions. And thanks to Professor Visser for taking the time today. I think before we leave, maybe you could perhaps leave us with some final remarks about what we should expect to see in terms of the development of treatments in this field over the next few years. Of course, we will look forward to what you're going to present at the conference in Brazil in June. Maybe some final remarks from your side. Thanks again from Professor Visser for taking the time.
Yeah. Yeah, I don't have not one single message. I think what we have seen over the years is that Triac is well tolerated. I think we will see in the upcoming time when you get really higher numbers of patients being treated, we will be able to do more robust analysis, perhaps identify subgroups, et cetera. I think that's something I'm looking forward to. I would also be curious to see whether Triac could be useful prenatally when mothers are carrying a known affected fetus. I wouldn't be surprised that that would be a game changer, but there are many things to think about that, obviously. That could well be, it would be certainly interesting to investigate that. Yeah.
On a similar note, to investigate or explore the possibility to include this disease in neonatal screening programs would, I think, be good to further explore. Yeah. Basically, one could think of other treatments, theoretically gene therapy or gene correction or other modulators. Although I think they will all encounter the same issue that we are also facing with Triac in terms of improving the neurodevelopmental part, what is the optimal time window there? Yeah, I think, yeah, I'm really looking forward to seeing more patients being treated. Hopefully we'll get a better picture over time. Yeah, thanks for the questions and having me here. I will leave it with this, I think.
Great. Thanks for taking the time today, all of you. Thank you.
Bye-bye.