Egetis Therapeutics AB (publ) (EGTX) Earnings Call Transcript & Summary

Good afternoon. It's my pleasure to welcome Professor Edward Visser from the Erasmus University Medical Center in Rotterdam. Professor Visser, he will give -- he will discuss some topics around MCT8 deficiency and the new treatment opportunities that we see. And we have scheduled this call to end at 15:30. So it's a 45-minute call. I think we will start with -- the call by giving Professor Visser the opportunity to give some background about his experience in the field, the patients he sees at his clinics and some other relevant topics. And I think we should open up for Q&A from the audience around halfway through this call. [Operator Instructions] My name is Lars Hevreng. I will moderate the call. And with that, over to you, Professor Visser. And perhaps you could start by giving some background to your experience in the field and what it is 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, and it's my pleasure. Yes, so 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. And 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 composes -- is composed of clinics, but also research unit, including a lab, which you do see behind me, which is actually a historical one because the Erasmus MC has a thyroid lab already, I think, since the '70s. So we are on historical ground. Perhaps good for the -- to be clear, Erasmus Medical Center receives royalties from Egetis Therapeutics on the commercialization of Triac or MCT8, but there are no personal benefits. Yes. So to give a little bit of background, but I don't want to repeat everything which I might have said on other occasions, so the thyroid group has always been interested in how thyroid hormone produced by the thyroid gland actually acts onto cells and tissues. And an important step is how thyroid hormones enter cells. And it was discovered actually in the lab behind me that it doesn't just diffuse into cells but there are transporter proteins required. And the most important transporter we currently know is MCT8, which was discovered in the Erasmus MC in 2003. And one year later, 2004, the first patients were identified again here in Rotterdam. And 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 therapy for these patients. So yes, that led, I think, to the development of Triac or currently called MCT8 for this disease. So just as a reminder. So 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. So females are carriers and males are affected typically. And basically, you can distinguish this syndrome in two components. So there is a strong neuro-developmental problem because the brain has insufficient concentrations of thyroid hormone because insufficient thyroid hormone enters the brain and thyroid hormone is important for brain development. And that brings about all these severe neuro-developmental features. And at the same time, other parts of the body are faced with elevated concentrations of the active hormone T3. So the heart, the muscle, liver, et cetera, are basically seeing too much thyroid hormone and that also brings about negative consequences like tachycardia, muscle wasting, low body weight. And together, this results in a high mortality rate of around 30% of patients dying during childhood. Yes, so this all started basically historically in our lab that also resulted in the fact that, yes, over time, patients got referred to our center, and 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. But 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. So when they counter a new patient, we are frequently e-mailed for advises on clinical management and MCT8 treatment. And what happens is that we receive information, blood samples are sent to Erasmus MC and based on that, we guide them on those. And 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, and once in a while, we report this in a scientific publication for the field. And I think this -- yes, well, personally, I'm convinced is a good way how to deal with a rare disease which is, in a way, centralized and knowledge is, yes, feedback to the -- all the individual physicians across the world. Yes, and 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. And I think over time, we have developed, yes, some experience in this area. I can go on for another 40 minutes, but there's no room for questions. So I think I'll 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. Can I just ask you about this field compared to, say, 5 years ago and your interactions with colleagues, et cetera? Do you -- would you say a lot of things has 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 identification of one patient and then the question is how to find other patients. And that has, I think, much to do with disease awareness, I think, which has grown over time, that's fine. And the other factor that contributes is I think that genetic panels are all over the place now. So even without thinking of this disease, it can pop up through a genetic panel. And I think that both has contributed to much more patients being identified, which is still ongoing. And I think also maybe in the early years, people were asking for a therapy. And I think now they are more approaching me, hey, how can we get -- can we be recruited for a trial or how can we get, yes, track of Triac.

And regarding Triac or MCT8, you have -- I mean, you have involved in these trials for many years. What could you say about your overall experiences in terms of randomizing patients, so to say, or recruiting patients rather to Triac and keeping them in the trials? And then what happens after the trial? What's the overall experiences and how do people or patients continue with their treatments after the completion of the trial? Could you tell us something about that?

Yes. Thanks. Yes, I would -- so initially our trial started back in 2014, which was an investigator-initiated study, and we were really fortunate that there were many physicians collaborating with us across the world. And that stage was not a problem. Actually, there was no therapy, yes, beyond supportive measures available. So there was a high willingness. I think that there was also -- yes, I think basically, all parents were quite enthusiastic and also willing to continue the treatment, at least also 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. But over time, we have seen patients who have been a few years off Triac again restarted on Triac and I think that situation has changed for the better in I think recent 5 years or so compared to the first 5 years when we started in 2014.

Okay, I see. So it has -- I mean, to get patients into trials, et cetera, that has been fairly straightforward.

Yes. So we have done -- so where the first trial was not problematic, I think the second trial had a more -- yes, was a bit more restrictive in terms of the age. So then -- yes, so that is more difficult for that reason. But I don't think that the willingness to participate was different. And then the third study, the ReTRIACt study, yes, 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 and they were willing to participate to the trial for, yes, let's say, for the greater good for registration purposes.

Okay. I see. 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 -- is that things that you in the field, your insight is 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?

Yes. So this -- so I think, obviously, it's always good for a disease, also for a rare disease when there are recommendations for treatment. And I think that greatly facilitates physicians who are less experienced with particular disorders to be guided. So 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. So -- but in general, I think it's -- yes, it's good that there are guidelines for disorders, yes.

Okay, I see. And if I would ask you to -- and also thinking about what we learned, there's some releases we saw from last year about the mortality effects from long-term treatment and not -- 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 driving -- the main driving -- that's a very difficult question, but the main driver, so to say, to have an impact on this -- 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?

Yes. So maybe if I can rephrase this a little bit. And so 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. And that -- and in parallel, we do see positive changes on body weight and heart rate, et cetera. So there I have little doubt actually or no doubt that that's beneficial. Then I think we have analyzed data from Triac Trial II on neuro-developmental 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 neuro development. Although we're, let's say, a university medical center, we still want to also run some post-op 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. So I'm a little bit more reluctant to say more than that has been in the abstract. And then 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. So 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. So we are -- I think we are close to saturation of all patients that are known in the world. And then we have asked a question, are those being treated with Triac, are they better off than those without Triac. And we did all kinds of proper statistics because, I mean, it's retrospective, you will never ever have a prospective trial, placebo-controlled on this. But we did all proper statistics trying to control for biases, matching, et cetera. And I think from different analysis, it seems that there is, with the data we had at that time, a 3x reduction in mortality rate, which might not be -- well, I think the effect itself is not a big surprise perhaps, which was also the reason why we asked that question because, yes, when you reduce the T3 levels and you reduce heart rate and you reduce blood pressure, yes, it's logical to think that you might improve patient strength, et cetera, and reducing chances of dying. So currently, we are adding more data, and we are planning to analyze doing the final analysis in the really foreseeable future. And then hopefully, at sometime we'll share the publication with the -- yes, with the scientific and clinical field. And then second thing and then I will stop is what we did, and we are also currently reanalyzing data from our first trial. So when we designed this trial and all the forms, we had a lot of also 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. And we asked things for sweating, et cetera. Now we are currently reanalyzing that, but that was also presented at a conference. And there also, the picture really emerges that on, let's say, parent reported outcome measures, Triac is also doing well. And I think that is reassuring to see because it really fits our observation, and not only ours but also of other physicians in the world, that, yes, that -- to summarize it, patients are just doing better and they're more aware of their environment, they are -- yes, they -- yes, so there are many more things to say about it. So how I currently would summarize 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 -- in young individuals with a high dose, it doesn't seem to improve neuro-development. So I'm not saying that Triac is the golden bullet for this disease. At the same time, Triac is doing good to the patients. And so there's always room to improve or search for perhaps novel treatments or perhaps even earlier during prenatal stages, for example. So that's basically how I feel the -- yes, where Triac should be placed. Sorry for my lengthy answer.

No, that's very helpful. And on that note, in terms of diagnosis 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?

Yes. Yes, so I think the diagnosis when -- is ultimately a genetic diagnosis. So when there is a known pathogenic variant, yes, then you have kind of proven the disease. Sometimes there are, let's say, novel variance. And 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. So I'm not so, yes, fearful for unclarity of the diagnosis. I think people could ask if -- so like any disease, there are all different kinds of -- there's a spectrum of severity. And 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, at that time, had a normal T3, was doing well for decades, I decide 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, Edward.

[Operator Instructions] Yes, I think we have a question from Suzanna. Please go ahead, Suzanna.

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. So 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 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, yes, there are less patients diagnosed in other countries. And it can't be true that this is due to geographical differences, but it's more likely with the health care 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 us know if it's not an answer to your question.

I mean, I think more simplistically, I'm trying to understand you are an endocrinologist, and 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?

Yes. So we get many questions from general pediatricians, pediatric neurologists, clinical geneticists and also endocrinologists. So I think these are the main four specialties we get referrals from. And it depends on how -- yes, how the specific setting of a certain hospital, sometimes physicians, for example, neurologists want to join forces with endocrinologist, sometimes they are happy to treat them themselves with proper guidance by us. So that's really dependent on the, yes, individual circumstances and infrastructure.

Was that answering your questions, Suzanna?

Yes, I'll take a step back and get back in the queue.

Oscar from BG, I see you have a question. Please go ahead.

Yes, Oscar here from Bryan Garnier. 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?

Yes. Thanks, yes. It depends, obviously, how you define that. But I would say that the far majority is what we call have a severe phenotypes, severe clinical phenotype. And with a milder phenotype, I mean, individuals that have the ability to stand and walk, sometimes with some support, are able to speak a few words or sentences and are clearly understanding you. So that is, I would say, maybe around 10% of the cases with the current knowledge we have.

It seems -- can I just follow up on in 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?

Yes, I'm afraid I can only speak for myself and my team.

That's good enough.

So -- yes, so there will be the International Thyroid Conference (sic) [ International Thyroid Congress ] in Rio de Janeiro in June. And we aim to present there updates on the -- some updates on the different research activities I just mentioned.

Okay. I got it. So that's in June in Brazil?

Yes.

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?

Yes. The short answer is from all over the globe.

Okay.

Yes. So yes. So basically, we have -- yes, yes, that's it. We communicate -- so we will be shortly publishing a, yes, I think, a big paper in the really foreseeable future in a medical journal also on MCT8 deficiency, and I think we have included data from patients from over 20 or 30 countries really across the -- yes, I think basically from all continents.

So you have the global perspective that's as of now.

Yes. At the same time, I don't want to overestimate myself because I don't know what I'm not seeing, but we have, yes, a bit of a feel what happens in different parts of the world.

Okay, I see. And how -- 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 -- 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 -- what I have learned from people is that, let us say once there is a therapy available, the diagnostic rate also increases. Yes, I think there might also be other means to do it, for example, harmonization of genetic panels across -- yes, across countries, for example, I think that would also be helpful.

Okay, I see.

And obviously, ultimately, but that could also be the far future, one can envisage that this could be included in your next screening programs, but this is certainly not something for the short term.

Okay. And coming back to the -- 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 and when you look at the baseline, so to say, parameters we see, the differences in the population seems to be great. I mean heart rates, for example, you have this span from, say, 160 down to 70, 80. Can you say anything general about why is the span so broad? And why does it look that way? Is it depending on how -- for how long this -- how long, what's the age, et cetera? And what's the reason really?

Yes. So specifically for heart rate, I don't know. I think there is, 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 their heart rate really goes up and down. So there's intrinsic variability. Yes, 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. And 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 several times elevated mortality rate. So that's not too dissimilar. At the same time, I can only speculate why the mortality rate, yes, is high and why it would come down. So one being indeed the cardiovascular system, which could be an explanation. At the same time, when they are doing better, they might be better in eating, in putting up some body weight, which might be a bit better to combat any intercurrent illness, but these are all speculations, honestly.

And you mentioned resistance to the thyroid hormone. How -- what -- how common is that would you say? What's your experience relative to MCT8 deficiency?

Yes. I think it occurs around one in 30,000 to one in 50,000 individuals.

Okay. So you see more of these patients in your...

Yes.

Okay. And could you say briefly something about the -- very briefly about treatments in that field, what do you do?

Yes. So there are -- many patients do not get any treatment because they are not overtly symptomatic. Then patients who suffer from palpitations are typically treated with a beta blocker to control the heart rate. And 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 treating 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. And 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, yes, logical to investigate that.

That's very interesting. So you see it's -- that's an area that could be explored with MCT8 as well.

Yes. Obviously, there should -- yes, I mean you can also think there about severity and height of the thyroid hormone concentration. So there are also many unknowns in that field, but it's -- yes. And 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 we don't have any more questions from the audience -- There, in fact, we have, Fredrik. You have one question. Please go ahead.

I just have one question about the label in Europe, which was for treatment of peripheral thyrotoxicosis from birth. Would be actually 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 or all patients?

Yes, 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, they're a very, very small minority. Like the example I gave earlier that does not have offered thyrotoxic features. But yes, in general, I think this would capture basically all patients, would be applicable to all patients.

All right. Thanks, 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 on -- about what we should expect to see in terms of the development of treatments in this field over the next few years. And of course, we will look forward to what you're going to present that is at the conference in Brazil in June. So maybe some final remarks from your side, and we -- and thanks again from Professor Visser for taking the time.

Yes. Yes, I don't -- not one single message. I think what we have seen over the years is that the drug is well tolerated. And 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. So I think that's something I'm looking forward to. I would also be curious to see whether Triac could be useful prenatally in -- when models 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 but that could well be -- it would be certainly interesting to investigate that. Yes. And 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. Yes, and basically, there could be one could think of other treatments, theoretically gene therapy or gene correction or all the modulators. Although I think they will all encounter the same issue that we are also facing with Triac in terms of improving the neuro-developmental part, what is the optimal time window there. So yes, I think -- yes, I'm really looking forward to see more patients being treated, so hopefully, we'll get a better picture over time. So yes, thanks for the questions and having me here. And I will leave it with this, I think.

Great. Thanks for taking the time to name all of you. Thank you.

Bye-bye.