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

A warm welcome to Egetis Investor Day here in December 2024. For those who haven't had the privilege to meet before, my name is Nicklas Westerholm, and I'm the CEO of the company. I'm very excited to see that we have a full room here in Stockholm, and I also know that many participants are actually joining online as well. Before I take a stab at reviewing the agenda and introducing the presentations going forward, I just wanted to take a step back and reflect on the announcement last week. And for me, personally, this is a great achievement for our company but also for the patients to receive a positive CHMP opinion on Thursday, the 12th of December last week. I would like to thank all patients, parents, caregivers and investigators who has taken part in the comprehensive development journey of MCT8 and making this happen over the last couple of years. I'm also very grateful to all our Egetis' employees and our collaborators, most importantly, the Erasmus Medical Center for their dedicated hard work and bringing this new therapy to patients suffering from MCT8 deficiency in Europe. There have been a lot of effort over a number of years, and we invested more than EUR 90 million since the back end of 2020, making this happen. And I wanted to calibrate this and put this in perspective because I think it's important to recognize this. One aspect of it is the EMA last year 2023, recommended 39 compounds, new chemical entities for a positive CHMP opinion. And going into 2024, it's most likely not going to be more. So again, 1 out of 40 roughly. Other perspective, I wanted to calibrate this with was around being a small Swedish biotech company -- sorry. And in the context of being a small Swedish biotech company with only 40 employees. One need to put in perspective that over the last 5 years, less than a handful of Swedish companies where the development regions from Sweden has received a positive CHMP opinion. So for me, personally, I'm really proud of this, and I want to extend my gratitude to everybody involved in this development program and the support from the investment community. So without further ado, let's move into the agenda. I will open up this session with some corporate reflections, looking back on what we have delivered over the last couple of months, but also touch upon the future strategy of Egetis Therapeutics. I will then hand over to Professor Edward Visser from the Erasmus Medical Center in the Netherlands, who will review and recap on MCT8 deficiency, the ultra-rare condition and the disease itself but also consolidate the view of the clinical data generated over the last couple of years, making this happen to receive a positive CHMP opinion. We're then going to segue over to my more esteem colleagues present here in the room, focusing initially on our global launch preparations with Europe in focus, but also some potential other opportunities. Subsequent to that, we will have a break and then turn over the U.S. Initial focus will be on the regulatory pathway in the U.S. clinical data generated for the upcoming new drug application in the United States and then segueing over into the opportunity we see from a commercial perspective in the U.S. as well. Last but not least, after a Q&A session, we're going to segue over to the other interesting opportunity we see for the company and for our collaborators. And that is around a different indication in a total different patient population named Resistance to Thyroid Hormone Beta. And there, we have Professor Aled Rees from Cardiff University that will join us for a presentation. We have left ample time for Q&A throughout the day and we're going to finish off the day with some concluding remarks from our Chairman of the Board. So without further ado, reflecting back on the last 6 months, I think it's -- I'm again here very proud to see that we have made some really important strides in delivering this very important therapy, first therapy to patients treat MCT8 deficiency. Starting off in June, we were designated a so-called PIM from the MHRA in the U.K., a Promising Innovative Medicine designated in the recognition of Emcitate as a promising drug candidate for the treatment of MCT8 deficiency. We have the Triac Trial II results that was announced in June. Triac Trial II, as a reminder, and I know Professor Visser will discuss this was designed to investigate a potential additional benefit on neurocognitive development in younger children below 30 months of age with MCT8 deficiency. Although disappointed that we didn't meet its primary endpoint, the trial confirmed the significant and durable reduction of endogenous T3 concentrations in all patients as well as confirming the well-tolerated safety profile in the subpopulation, i.e., young patients, which was a very important aspect that was part of the EMA submission. Moving forward, many of you recognize that there were some guidelines published during this summer -- back end of the summer, in July, and this was guidelines from the European Thyroid Association, which recommends use of tiratricol or MCT8 as a long-term therapy for all patients with MCT8 deficiency as well as for certain patients with RTH-beta. And for us, this is, of course, also a very important, it's somewhat unusual being an ultra-rare disease with no approved product that diagnosis and treatment for such a disease are actually featured in guidelines. So obviously, this is a very important aspect for us in further embarking on disease awareness journey across the European Union. Furthermore, there were some very, very interesting data published through an abstract, ahead of the European Thyroid Association Annual Meeting by the Professor Visser and his group at the Erasmus Medical Center which illustrated through reword cohort study, where 228 patients were investigated with focus on mortality and very interesting to see here that in patients with MCT8 deficiency, one saw with the treatment of tiratricol roughly a 3x lower risk of mortality, which really confirms our thesis by normalizing T3 levels have an impact on the clinical symptoms of thyrotoxicosis such as heart rate, blood pressure, et cetera. Also theoretically you can translate into survival benefits. Segueing into further investments we have done, and this is something many of you fully appreciate that today, Egetis Therapeutics holds orphan drug designation for MCT8 defficiency, both in the U.S. and in EU, which currently provides market exclusivity of 7 and 10 years, respectively, from the dates of regulatory approval. During the last couple of years, where we have invested and put efforts into upgrading our manufacturing process, refining our manufacturing process and ensuring that we are up to the quality standards required for a potential approval as well as making the process more efficient, has actually enabled us also to apply for a patent and this is a patent around the process and preparation of tiratricol. And if granted, it will be our first patent. It will be a significant patent. And generally, the exclusivity term of new patents in the U.S. is 20 years from the date of the application was made to the Patent and Trademark Office in the U.S. From a financial standpoint, we also carried out a directed share issue of roughly USD 30 million. This was important to ensure that we are well set for the future and being able to invest responsibly in the areas we need to invest in. We're very pleased with the directed share issue, one, it was oversubscribed, including both new owners, but also existing owners. The subscription price was at market, which was for me, something I'm very proud of, recognizing the challenging dynamics in the capital markets over the year. And it was led by Frazier Life Sciences with an investment of roughly 1/3 or USD 10 million out of the USD 30 million raised in total. So the high point of the year still coming back to that at the end of my initial presentation is the CHMP opinion and what that means for the company also looking forward and strategy. And our view is that this is by far the single most important milestone in our history as a company and a major step forward in building a sustainable rare disease company. From a strategic perspective, nothing has changed. The strategy was put in place 2 years back aligned with the Board. It's clear, it's simple, it's focusing on over a period of time, building a sustainable rare disease company. Initial priorities in that is, of course, MCT8, ensuring that MCT8 is developed through to approval both in U.S. and Europe, but also other jurisdictions, being able to maximize that opportunity and commercialize MCT8 in U.S. and Europe and through partnerships in the rest of the world. We're also focusing on realizing the full potential of our product MCT8 through life cycle management and consideration of that. And as I mentioned before, one potential opportunity will be in resistance to thyroid hormone beta which we'll hear more about later on through the day. Fast and broad access, making sure that we provide access to patients around the world is also a very important feature of our long-term strategy. And there, as many of you know, and also an aspect we are very proud of is that today, even before approval, we have a managed access program where we provide MCT8 to patients around the world in 28 countries to more than 230 patients in total. The other important aspect to call out further down the line in our journey to building a sustainable rare disease companies, of course, identification of further assets that address significant unmet medical need for patients with rare diseases. So that's something that we, in the coming period, will focus a bit more time. So that concludes our very simple and crisp strategy. What does that mean? And how does that then translate over into the coming year or 2. We see that we have some very exciting milestones that we need to deliver and we'll deliver over the 2 coming years, of course, is the formal European approval by the European Commission early next year and the subsequent launch in Europe and roll out, focusing on access, reimbursement and being able to find patients. We have declined results for the ReTRIACt study, obviously, very important for the submission, the new drug application to the U.S. FDA. Subsequent to that is, of course, the U.S. approval and launch. And with that potentially comes a U.S. pediatric disease voucher, which is from a financial perspective, also very important. We have Japan and the development together with our current partner in Japan, Fujimoto Pharmaceuticals. We are now -- where we are now engaging PMDA and considering the most optimal regulatory pathway in bringing MCT8 patients even in Japan. And an interesting aspect there is that MHLW. So the Minister of Health in Japan issued new guidelines for rare diseases on the 23rd of October this year, where it's now an opportunity to move towards a submission without generating -- without generating any clinical data in Japan. And that's a major step forward in the regulatory landscape in Japan. Last but not least, when it comes to MCT8 deficiency, we are also considering Middle East and Northern Africa and partnerships there contingent on the European approval and the opportunity, both for access and also potential commercial opportunity, which will feature further down in the presentation today. And when it comes to RTH-beta, that's something we are contemplating regarding an initiation of an investigator initiated study together with our collaborators. So with that, that takes us to the end of my opening remarks. Hopefully, you've got provided with a good overview of what we have delivered. The key milestones for this year and also how the future look like and the upcoming milestones we set out to deliver. And with that, I will hand over to our esteemed collaborator, Professor Edward Visser, who has joined us via Zoom.

Yes. Thank you very much, Nicklas. Unfortunately, via Zoom because the virus kept me here in the Netherlands, but I hope everything will be as clear as possible through these means. Yes. So today, I would like to give a bit of background updates on MCT8 deficiency and the use of Triac in this rare disorder. This is my disclosure slide. So what I would like to do is to kick off with a very short background in thyroid hormone signaling, then provide some background on MCT8 deficiency, the main results of the Phase II Triac Trial I. Then I will discuss some real-world data we have obtained, and then I will finish by giving some new data on quality of life, survival and Triac Trial II. Right. So I really apologize for the simplicity of these slides, which are really kind of year 1 medical school. But the thyroid gland is located in the neck, and if you would zoom in on the thyroid, it's like many tissues -- actually all tissues composed of cells. So this is a thyroid cell and the cell produces hormones, hence, they are called thyroid hormones and they travel towards all tissues and cells of the body to exert their effects. Now when we look at such a cell of the body, for example, a brain cell, it looked like this with a plasma membrane and a nucleus. And for the hormone to exert its effects. It needs to enter the cell, fully plasma membrane. And this is a process which is facilitated by transporter proteins, these are actually gates that facilitate the entry of the hormone across the plasma membrane. Inside the cell -- actually inside the nucleus T3, the active form of thyroid hormone combine to its receptor to switch on and off transcriptional programs. So today, I will focus on actually one of the key transporters in the human body, which is MCT8 and later on, my colleague Aled Rees, will discuss on the thyroid hormone receptor, particular, the beta form. So there are different disorders when one of these key steps are defective. And as I mentioned, I will focus on MCT8 deficiency. So when MCT8 is deficient that gives rise to a severe developmental and metabolic disorder, which occurs in about 1 in 70,000 male individuals. So MCT8 is located at the X-chromosome, so mainly male individuals are affected. So I took 2 pictures of patients that I see on the outpatient clinic which are very illustrative. For example, the absence of head control, hypertonia on the left side, dystonia and being wheelchair bound is also frequently seen, patients have a low body weight and feeding problems. Actually, there are many more disease features, which you do not see on the picture, but are certainly present, which you are able to capture through an international consortium and a registry. The disease can be, in a way, easily diagnose when the different thyroid hormone are measured so there is a particular thyroid signature in the blood. So the TSH concentrations are normal, but the T4 is low and the T3 is elevated. And this is rather specific for this disorder, certainly, when such clinical features are present. So what about the mechanisms of disease? So basically cells and tissues that are fully reliant on MCT8 for their supply of thyroid hormones will be hypothyroid if no T3 can enter the cell. And because MCT8 is importantly present at a blood brain barrier and also in neural cells, the brains of these individuals are hypothyroid, which brings about the severe neurodevelopmental problems as thyroid hormone is crucial for a normal brain development. At the same time, all tissues, other cells which do not depend on MCT8, but on other transporters will be exposed to the high levels of the active form T3 and these cells are actually thyrotoxic, such as the heart and the liver and the kidney and muscle. And together, this results in a high mortality rate in these patients, about 30% of patients died during childhood. So when thinking of a disease around 10 years ago, we had a rather simple idea because one would like to increase the thyroid hormone action in the hypothyroid tissues and one would like to reduce the thyroid hormone action in the thyrotoxic tissues. So how can one achieve this? So we thought to make use of the principle of so-called T3 analogs, and we decided to go for tiratricol or Triac which is a molecule which is very similar to T3, which you can see on the right-hand side, except that the side chain is just a little bit different. And the advantage is that Triac does not need MCT8 to enter cells but can enter the cells through another transporter. But once inside the cell can act like T3 on its nuclear receptor. So having some other pre clinical studies done, which I will not bother you with, we asked ourselves the question, is Triac-effective in patients with MCT8 deficiency. And we decided to first look at the thyrotoxic part of this disease. And hence, we started Triac Trial I. So Triac Trial I was an international Phase II trial, investigator initiated that run in 9 different countries. We were able to enroll 46 patients of whom 40 completed that trial. And basically, we treated them for 1 year with Triac and had an extensive baseline and study visit. So the primary outcome was to see whether T3 could be reduced by the application of Triac. And the answer was, I think, convincingly, yes. So actually, all patients T3 was reduced and basically came down into the normal reference range, our target range of -- in all patients. So a couple of secondary outcomes, so we look at body weight. So this is on the Y axis you do see body weight corrected for age, which should be between plus and minus 2, indicated by the grayish area. And you can see that the majority of patients are well off this normal reference range, and that 1 year of Triac treatment leads to an increase in body weight corrected for age in the majority of patients. Likewise, we saw a reduction in heart rate, particularly in those who had tachycardia at the beginning. And also, we know that so-called premature atrial complexes which were present to a high rate in patients, which is actually very unusual in healthy individuals, and they subsided in the majority of patients. We also tested different biomarkers for thyroid hormone action in different tissues. For example, SHBG, sex hormone binding globulin, which is produced by the liver was reduced, and we also had similar findings for cholesterol and creatine kinase for the muscle. So basically, say or basically anything that the other tissues, liver and muscle are getting towards the thyroid range. So in the meanwhile, when Triac Trial I was about to finish. We were able to guide different physicians across the world who are either unable to participate in the trial or just too late. And we collected most of the same outcomes as in Triac Trial I or not most, but a couple of them, which were exactly the same. And I would like to show you them now. So this is data from 33 sites in 18 different countries in the world. Again, shown a reduction in T3 concentrations in fact, actually in all patients. And these results were also sustainable because we had data up to many years of treatment. So this is a busy slide, and I will guide you through. Again, this is body weight corrected for age on the y-axis. The grayish area is the normal reference range for children. The orange line indicates the natural history in the untreated patient with MCT8 deficiency. So you do see that deteriorate in body weight in early life and during puberty and the blue lines indicate what happens in individuals treated with Triac and as you can see, hopefully, you can see is that the majority of patients either stabilize or improve. So basically confirming what happens -- what happened in Triac Trial I. So, yes. So basically, for us, this was really reassuring to see that not only in a well-controlled setting of a trial, but also in real -- real life across different areas of the world, we do see the same effect happening at different outcomes. And so this was also true for heart rate and different biochemical markers. Okay. So now I'll go to the final part of my presentation. I have to admit that -- those might be more boring slides because they contain data, which has not yet been published, it has only been presented at scientific conferences. And we are very, yes, what's the word -- cautious to not provide data in the public domain when it has not been published as yet because it could preclude us from publishing. So this is data we collected on quality of life. So what we did, we went through our data of Triac Trial I, some post hoc analysis of caregiver reported patient-centered outcome measures. So during that trial, we had semi-structured interviews at baseline during the follow-up visits and also the end of study visit in total, in 40 individuals on the complex needs and daily care challenges. And we asked them at the end of the study what were the most prominent changes, either being positive or negative during Triac treatment. And the parents reported that improved interaction was seen in a substantial percentage of patients also improved alertness actually both things we can -- I can confirm because we also had the same observation in our clinic when treating these individuals. They mentioned improved motor skills and also improved sleep. In one patient, increased constipation and increased unsettledness was reported. And also less perspiration was reported in patients treated with Triac compared to their baseline. And when we ask the question, do you prefer to continue Triac or not, 40 out of 40 prefer to continue the Triac treatment. So we are currently further exploring these data and they're planning to draft a manuscript on this, hopefully, to be published next year. Then another question we had, and Nicklas already alluded to this, is so basically, based on the effects we saw on Triac and Triac Trial I in the real-world data namely the reduction in T3 and the reduction in heart rate and blood pressure and the improvement of body weight. Has Triac the potential to improve the mortality rate, which is rather substantial in this disorder. To do so, we went through our -- or actually explored our consortium we have. So basically 173 sites in 48 countries and we screened close to 500 patients. We excluded a couple of quite a substantial number of patients because they were born before the disease was actually discovered or we had really limited data or whether the loss of function category of the mutation was unknown. And ultimately, we ended up with 111 patients with and 170 individuals being treated without or not treated with Triac and the baseline characteristics were actually similar, except that expectedly there were less untreated patients in Western countries. So we had a median follow-up time of close to 5 years. And we observed 5 deaths in the treated group and 27 in untreated group. And we have done different statistical approaches. And basically, they all come down to a similar estimate, namely about 3x reduced risk of all-cause mortality. So we are currently aiming to confirm the robustness of the data by increasing the number of patients to perform additional statistical analysis. But we are really hopeful to -- yes, that these data are actually quite correct. And finally, so based on the data we have and the question we initially asked, so is Triac effective in patients with MCT8 deficiency? I would say, in terms of the metabolic or the thyrotoxic type there's undoubtedly yes, based on the Triac Trial I and the real-world data. But what about the neurological part of the disease? And hence, we designed Triac Trial II. So the background to this trial was partly some preclinical data. So these are [indiscernible] cells, brain cells in wild-type mice, and this is the same type of cells in the model for MCT8 deficiency. So, yes clearly, there's abnormal development of the [indiscernible] cells. When these animals are administered Triac right after birth you do see that it's completely prevented or reversed. And they are indistinguishable from their wild-type litter mates. And also in Triac Trial I, we had exploratory analysis of the GMFM, the gross motor function measure in which 100% represents the score of a healthy 4-year-old kid regarding motor capabilities. And we test this as an outcome in our Triac Trial I. And we know that at the group as a whole, there was no difference. But actually, those that seem to have an improvement were all younger than 4-years of age. So together, we thought there was a sufficient reason to move on with a second trial. And this was Triac Trial II, an international multicenter open-label trial, where we included ill patients with MCT8 deficiency, young patients, meaning below 2.5 years of age. Patients were excluded if they had received Triac Trial -- Triac treatment before or any other thyroid related treatments. The Triac outcomes were these so-called GMFM score and yes, the same motor or similar motor score from Baby Score, a well-known neurological score, and we compare that with the -- with historical controls. So patients that have not been exposed to Triac. And secondly, outcomes we predefined clinically relevant outcomes. For example, Item 10 and 24 in the GMFM representing head control or sitting independently. With other outcomes like the full BSID, the clinical examination, the clinical neurological examination and actually different parameters of thyrotoxicosis. And in contrast to Triac Trial I, we went much higher Triac dosing, so up to 200 microgram per kilogram per day. So we were able to screen 23 patients of whom 22 were enrolled and 21 finalized the closer 2-year treatment with Triac. And the results were, in a way, disappointing. So we did not see a statical clinical relevant change in the primary outcomes. We did see that there was a strong reduction in T3 concentrations, which was not a surprise and also in line with the Triac Trial I and the real world data, Triac was very well tolerated. So to conclude from Triac Trial II, there is no effect on brain development with Triac in early life, which is obviously, unfortunate for the patients. At the same time, I think it's also important to get a clear answer, and I think this is a clear answer. We confirm the reduction in T3 concentrations. Not a surprise, but always good to see. And we are currently investigating in more detail whether we might perhaps see a signal in subgroups, for example, the youngest patient or a specific type of mutations or associations with body weight, et cetera. So is Triac effective in MCT8 deficiency? Yes, for the metabolic phenotype and no, so far in young patients regarding the neurology phenotype. So I'm close to ending my presentation. So MCT8 deficiency is a rare, severe disorder comprised of Hypothyroid -- thyrotoxic features with a high mortality rate. And Triac is able to alleviate the signs and symptoms of the metabolic or thyrotoxic phenotype, it doesn't improve the neuro development in patients younger than 2.5 years of age. And it's also good to see that in the community, apparently, the people are convinced that Triac has positive effects. Hence, it was recommended in the European Thyroid Association guidelines on such rare thyroid disorders, including MCT8 deficiency. I'm really indebted to many of my coworkers, particularly Stefan Groeneweg and Ferdy van Geest [indiscernible] for our -- the full team in Rotterdam and I'm really thankful for all the collaborators across the globe who are really great in collaborating and trying to get the data in and feeding it back to the community. And obviously, also for all parents and patients that have contributed to the studies, we have performed. So thank you very much. And obviously, I'm happy to take any questions.

Thank you very much, Edward. I hope you can hear us fine and thank you for taking time out despite that you're somewhat ill and hope you recover soon. This takes us to the Q&A and I think we have a microphone here in the room somewhere, and I'll ask one of my more esteemed colleagues to pass it around. So any questions so far? You're always the fastest one, Mattias.

Mattias Häggblom, Handelsbanken. I have 2 questions, please. Sort of related to each other. So the Triac II Trial was published after the guidelines were published. And the guidelines alluded to long-term therapy and at the time of the guidelines, how they were phrased -- the guidance referenced, we don't know the outcome of the ongoing Triac II Trial. So I guess the question is, how do you think, if at all, the guidelines will be changed. And sort of related to that, with the CHMP recommendations for approval that says treat from birth. How will physicians apply this therapy now when it gets available in Europe?

And Edward, do you mind giving the view from a physician standpoint, et cetera. And I can maybe segue into that later on the commercial company perspective.

Yes. Thank you, yes. Yes, so the Triac Trial II has not been published as yet, but the kind of headlines have been presented. I don't feel that this will impact the recommendation in the guidelines because we try to distinguish the 2 parts of the phenotype. So the metabolic thyrotoxic part and the hypothyroid or neurological part. And I think that Triac has positive effects on this metabolic part regardless of the effects of the neurological part. So I think that Triac can do well in all patients, irrespective of their age, and this -- I don't know whether maybe it went too quick, but for example, body weight typically starts to deteriorate already during the first year of life and one would hope that Triac is able to prevent that because a having normal body weight is actually good for basically everything, to combat infection, for interaction, et cetera, yes.

Thank you, Edward and I might chip in. I think, Mattias, you referred to also the positive CHMP opinion and the language around indication, which states MCT8 is indicated for the treatment of peripheral thyrotoxicosis and MCT8 deficient patients from birth, right? And I tend to very much agree with Edward here that we have 2 different and distinct clinical phenotypes. All patients with MCT8 deficiency actually suffers from peripheral thyrotoxicosis, part of the whole marker of the disease. So we, of course, see from a corporate perspective as well that all patients should be eligible, all patients should be treated to prevent further down the road effects on the cardiovascular system amongst each other. And as you rightly said, Edward, as well that chronic thyrotoxicosis is of course, believed to contribute to the increased mortality for these patients. So I think that's our perspective as well, Mattias. Any further questions? Mark?

Thank you. And it's obviously excellent but Triac alleviates or MCT8 alleviates the thyrotoxicosis. But I have a question regarding the neurological thing. And the first question is, I don't know if epilepsy is due to abnormal brain development or if it is because of low T3. So my question is, does MCT8 alleviates some of the seizures. That's my first question. And the second one is, it's possible that since you gave a mouse's MCT8 from birth, but the children were 2 to 4 years of age, the motor development does occur in the first months of life. Is it possible that if you tried Triac on a mouse and actually gave it to that mouse during the time that corresponds to 2 to 4 years of age and then compare the pictures that you could see a change, and then you can...

Sorry, go ahead, if you have a third question.

I think there was only two Edward. So please go ahead.

Yes, sorry. Yes so regarding the first question on the epilepsy I don't know what I would presume this is part of the abnormal brain development. We haven't analyzed or checked that in particular where Triac improved the epilepsy, what I can say from our clinical observations, is that it doesn't do so. And that would tie in with the absence of strong effects in Triac Trial II. Regarding your second question, so we -- in Triac Trial II, we treated patients up to 2.5 years of age between, yes, I think the youngest patient was I think, 6 months to 2.5 years of age. But you're very right that the developmental time is different. Brain development in mice takes place to a larger extent postnatally than humans. And there's also been other data that If you give mice Triac not right after birth, but a few weeks after, there's still a positive effect, but not so outspoken as from day 1. So one of the speculation from my side, but I'm not giving up here is -- if we would be able to get screening at a neonatal stage for MCT8 deficiency. I wouldn't be surprised that there would be at least some alleviation of the phenotype. And in that respect, we do have some positive signals or the possibility to get MCT8 deficiency diagnosed at birth. For example, in the Netherlands, we have a T4 based screening mechanism and the majority of MCT8 deficiency patients had a low T4, and there's also a collaborative Japanese-American study, which also showed that with different thyroid function test at birth, it is -- it should be possible to distinguish these patients from healthy -- otherwise healthy patients. So the fact that in Triac Trial II we did not see, I would really say we did not see it in patients treated below 2.5 years of age, but I would be still open to test or to try to see what happens if you were able to diagnose them at birth or perhaps already prenatally in models that are known to be curious. This is a bit more farfetched, but this is certainly something which is in the back of my head.

Thanks, Edward. I think we have time for one more question, if any. Yes, sir, here in the front of the room.

I've seen figures that the medium life length is 35 years for the 4 patients. And with this MCT8 treatment and the fact that you say that you have 3x less or 3x higher death rate without the medicine. Can you say anything about the expected life length with the treatment? Or is that too early to say?

My answer can be short. Yes, I think it's too early to say now. For that, we have to really that we're trying to do to get more patients in to get a more robust answer to, hopefully, a more robust answer to this. So I cannot say any more at this stage, unfortunately. But actually, that's what I would expect, honestly.

Thank you so much, Professor Visser. Pleasure having you joining and hope you get better soon. I think we need to move on in the agenda.

And the next agenda topic is global commercialization with focus on European Union and Germany as a case example. I'll hand over to you, Henrik, and you can introduce yourself.

Thank you, Nicklas. Very happy to be with you here today, especially given the recent positive opinion from the CHMP. And my name is Henrik Krook. I've been with the company since the establishment 4 years ago. And today, I will give you a little bit of an update of where we are with the global launch preparations for Emcitate. And today it's almost 25 years ago since I had the opportunity to be involved in my first launch of a pharmaceutical drug. That was at Roche at that time, after that, when working for Novartis and Alexion, I had the opportunity to be involved in additional 10 product launches. But it's actually with MCT8 deficiency, that's the most severe and devastating disease that I have worked with so far. And therefore, it also feels extra motivating to be able to launch a product for the benefit of these patients. I would like to start by showing a film so that also you get an opportunity to learn a little bit more about how it is to live with MCT8 deficiency. [Presentation]

So I think this film is a good reminder of how important it is to develop effective treatments and make them accessible to these patients. And when talking with parents to children affected by MCT8 deficiency, I also understood that actually every step forward in treatment not only offers relief but also for them a hope for a brighter future. And with the launch of Emcitate, our vision is really to make sure that everyone who can benefit from treatment gets access to reimbursed Emcitate as soon as possible after regulatory approvals. And to make that possible, then, of course, first, the patients need to be diagnosed. And here, as in many other ultra rare conditions, MCT8 deficiency, is unfortunately, sometimes misunderstood in the health care. So that means that these patients can have been misdiagnosed with other conditions, such as, for example, cerebral palsy or more general terms as neurological developmental delays. And that, of course, hinders them to get access to the best possible care. And therefore, we have embarked and focused a lot on disease awareness activities, including educational activities to really make sure that we help and contribute to making sure that these patients are accurately diagnosed. Another important area is, of course, to make sure that Emcitate becomes reimbursed and can be prescribed by physicians. And for doing that, we are working on delivering a solid value proposition to both payers and to physicians. We at Egetis, we will execute the launches ourselves in Europe and U.S. For other regions, we will work through partners to ensure broad access. And there, as you might be aware, we have already signed a license agreement for the development and commercialization in Japan with Fujimoto. We have quite some interest also from other companies for other geographies in the world. And we're right now in dialogues with several different companies related to the MENAT region, which is abbreviation for Middle East, North Africa and Turkey. For the launch in U.S. and Europe, there's actually quite a unique setting for Emcitate in MCT8 deficiency. First of all, MCT8 is addressing an unmedical need and MCT8 is expected to be the first regulatory approved drug for this condition. We have had the benefit of working with medical experts and key opinion leaders for the clinical development program. And there's already, as you have heard, European treatment guidelines supporting the use of Emcitate. It's also a global community, both for medical experts and caregivers. So that means that thanks to this unique setting, we will be able to, through our global team, generate a lot of great impact but then closer to launch in different countries, we will be able to complement our existing core team with small, efficient teams, for example, in some of the European regions and of course, also in U.S. I would just again like to take a moment to reflect on this European Thyroid Association guidelines because it's actually quite extraordinary for a pharmaceutical drug to get into these kind of guidelines before there is a marketing authorization. So that is quite unique. And I think one of the reasons behind this is that we have been able to supply patients through our managed access program with Emcitate. And this program, we now have approximately 230 patients in it. They are spread over more than 25 different countries. And this is actually also quite unique for an ultra indication to have such a big managed access program. And we're really both proud and happy to be able to supply Emcitate to these patients already ahead of marketing authorization. For our launch preparations, we have started to stepwise establish a commercial and medical affairs team. We have done that by recruiting people, having a long experience of successfully launching pharmaceutical drugs all over the world. And as you see by the logos here, we also have representation and experiences from many different international companies where some of them are leaders in the ultra rare space. With this team, we are focusing a lot on driving disease awareness to support diagnosis of affected patients. And we're doing that partly through face-to-face interactions, for example, at advisory boards with both physicians and caregivers. We use them to understand more about the needs within the health care and the care of these patients. And then we use these insights to fine-tune and develop as good programs as possible to be able to diagnose the affected patients. Then we complement the face-to-face interaction with digital channels to make sure that we also get the broader reach. And there, we have our website, the mct8deficiency.com as our center hub. And here, we have educational materials, for example, films like the one we just saw on Nate and his mother, so that people can be able to learn more about MCT8 deficiency. There is also an expanding disease awareness momentum in this area. This year, we have actually exhibited with disease awareness exhibitions at 33 different scientific congresses around the world. We also see that the scientific community is contributing with more and more data in this disease. As an example, at the recent European Thyroid Association's annual meeting, there were 7 abstracts related to MCT8 deficiency. And that is quite extraordinary for a rare disease. And one of them was the abstract, the promising survival data that Edward Visser talked about earlier. Then we also have the patient advocacy groups. They are also very focused on driving more disease awareness about MCT8 deficiency. So taken together, I think the efforts made by us at Egetis by the scientific community and by the patient advocacy groups really contribute to increasing the diagnosis rates in MCT8 deficiency. And this is, of course, fantastic because it will then help to optimize the care of these patients. To make sure that we get reimbursement, it's very important to make the payers understand and support the benefit of Emcitate and we will do that by delivering a solid value proposition to them that will consist of both our clinical data package but it will also be supported by recent data from a Caregiver study that we have sponsored around over the last years. So with that, we feel that we will be able to provide them with what they need to be able to assess this properly. So both showing the high burden of MCT8 deficiency, also stressing the significant unmet medical need in addition to the benefits by Emcitate. And these benefits, I think, has already, to some extent, been validated now by both physicians in the ETA guidelines and also by regulators, given the recent positive opinion by CHMP. After the marketing authorization, we will execute a pricing and reimbursement strategy in 2 different ways. So we will start with the largest 4 countries in EU, so Germany, France, Spain and Italy. In Germany, this process takes 1 year but it is possible to have reimbursed sales or in parallel with this process. In France, Spain and Italy, the process normally takes 1 to 2 years for a drug in the ultra rare setting, but also there, there are possibilities for funded sales in parallel with the process. And to optimize this, we are working with local firms for pricing and access in these countries with people who have a positive track record of getting ultrarare -- or drugs for ultra-rare conditions reimbursed. So in summary, we are working towards broad patient access and value creation. With Emcitate, we have started the execution on our ambition to build a sustainable rare disease company. And we are right now preparing for launch in Europe and U.S. by a lean and agile Egetis team and other regions, we will work through partners for broad access. We're very focused on disease awareness initiatives, and we are encouraged that these initiatives really help to improve the diagnosis rates. We will deliver a solid value proposition to payers to secure reimbursement and broad access. And by doing so, we're hopeful that we will help patients and families, not only to relieve, but also to a brighter future. And with that, I would like to hand over to my colleagues, Raymond and Henna to talk a little bit more about the details for the preparations for the launch in Germany.

Thank you, Henrik. It's a pleasure to be here. My name is Raymond Francot. I've got a legal and business background over 30 years -- thank you, Karl. Over 30 years experience in the life science industry, of which the vast majority in German and German-speaking countries. For instance, I've been working for Gilead Sciences, where I established the HIV and hepatitis franchise for Germany. Austria and Switzerland, so I've been part of the beginning of that success story of Gilead Sciences. After that, I moved to Vertex, where I got my experience in rare diseases, launching products in cystic fibrosis. And so I've been part of the beginning of that success story at Vertex Pharmaceuticals as well. Before I continue, I would like to introduce my colleague Henna.

Yes. My name is Henna Oittinen-Corbinelli, I'm a medical doctor by training. I am a board-certified specialist in Pharmaceutical Medicine. I am in the industry since 2008, and I've been in different positions in medical affairs. And at the moment, I am taking care of medical affairs in international and focusing on Germany.

So, very good. Thank you, Henna. So yes, a few words on the preparation for launch in Germany. And on this slide you see 3 critical success factors for launch. Many of these aspects have been already addressed this afternoon. Starts with the pricing and reimbursement. Obviously, very important, the critical elements there are developing a very solid value dossier and making sure that we get a good benefit assessment and then also, obviously, pricing negotiations. And the aim of us is obviously to ensure a market price, which reflects the value of the product, but also ensures a broad access for patients. The second success factor is finding patients. That's always a thing in -- an important thing in rare diseases, ultra-orphan diseases because by nature, low number of patients so that the awareness of the disease is almost nonexisting. So that's where we're spending a lot of time and you've heard already that a couple of times this afternoon. So it's disease awareness not only disease awareness, but also the diagnosis, right? The pathway is very much undefined in many cases. So we need to work on that as well. And that is also through target customer interaction. And what we want to do, what we aim for there supporting HCPs to identify eligible MCT8 patients. The third is stakeholder engagement and our stakeholders, we define, obviously, key opinion leaders and HCPs but also payers and health insurers where we have quite some interaction with and that will continue as we move into the launch phase, but then also as third but -- last but not least, patient advocates. And what we aim there is to leverage this -- the strongest stakeholder support. And as you can see, these circles, they overlap a bit, they're very much intertwined. Okay. So I'll start off with pricing and reimbursement. This year is the process, as you can see in Germany, what we call the AMNOG process. On the right-hand side, you see that there are 4 parties involved in this process. Obviously, it's a company because we are submitting the dossier, we are going to negotiate the price. The second is the GBA, that's the authority that is going to issue a benefit assessment and benefit statement at the end of the process or halfway the process. Then IQWiG is involved and IQWiG is Institute for Quality and Efficiency in Health Care in Germany. They're going to validate our data, especially the patient population and the cost estimations. And then we've got GKV, which is the overarching statutory health insurers with whom we're going to negotiate our price. So at this moment, we're very much at the beginning. We're prelaunch. We are developing our benefits, dossier. And this is already going on since I think we started with that in quarter 1 this year. So we really took a year to develop that a strong -- very strong dossier, we can submit that at the moment that we get EMA approval. So EMA approval we need to complete a few administrative elements and then we can submit the dossier to the GBA. GBA will take 3 months for a initial benefit assessment. And after the 3 months, so we get this preliminary benefit assessment, then we got to come to a very important point where we can, again, provide input into the process. That's the moment where we will have a oral hearing, a public hearing. That's the moment where we can submit written positioning statements and at that moment -- then at that moment, GBA will go back again and issue after 3 months, a final benefit assessment. With that final benefit assessment, we'll go into the negotiations with the GKV, and that, again, is going to take 6 months. Two points here to address. As orphan drug, we go by law, we will get a benefit assessment. How that is going to be augmented by GBA, that is something that's going to be dependent on the quality of the dossier and these positioning statements. The second point that I would like to make, this is a very almost like German engineered process, it's exactly 1 year. It starts at day 1 of submission, and it ends at day 365 of submission. A few opportunities that we see in this process, first of all, I mentioned already, orphan diseases. We are an ultra-orphan disease so a benefit is going to be granted. It's a high unmet medical need, which we can allude on. And then there is already quite some experience through the Managed Access Program in the German market, not only in the German markets, but also in other markets, which we can leverage in this process. We're gathering together with key opinion leaders, the stakeholder support, I already mentioned, that's going to be very important, and we see that as emerging through all the work that we're doing in this area. What is also an opportunity for us is there's no alternative treatment available and GBA always pays good attention to that. And then we use our data like the ETA guidance that we have already talked about today. So the implications for us are, first of all, implement and execute on a very solid dossier strategy, develop the best dossier and make sure that we focus on the right things like it's -- like I mentioned, the first treatment available and develop our value story around that. Then it's all about stakeholder support, make sure that we are aligned with stakeholders who can also input into the process. And then the last phase of this process is going to develop and execute on a negotiation strategy to get a price as I mentioned, that is going to reflect the value of the product and ensuring access -- broad access for patients. With that, I hand over to Henna.

Thank you. So I want to talk to you about medical affairs strategy, especially in increasing the disease awareness. Obviously, this is a very important phase to increase disease awareness to prepare for a successful launch. We've noticed in our discussions with HCPs that it's important to not just increase awareness of MCT8 deficiency as such, but also the awareness that there are 2 distinct concomitant clinical presentations that there are 2 phenotypes of this disease. And we've been on 9 Congress this year in the German-speaking area. We are planning for 10 congresses next year. We've had countless interactions either online or in person with HCPs, with key experts about the disease and what the scientific questions are and also through the Managed Access Program, the HCPs have been able to gain first-hand experience in treating these patients. And the last pillar is obviously stakeholder engagement. If you look here the map of Germany, you see about 10 clusters of centers where we have identified the most expertise and knowledge in this disease. So those would also be consistent of centers of rare diseases that are dedicated for rare diseases in children and associated social pediatric centers, which are the centers where these patients usually first get referred to when there's a suspicion of MCT8 deficiency. And we are engaging with the experts in these clusters, obviously, to increase disease awareness also from their side them training their teams and colleagues but also to advance collaborative efforts on monitoring and treatment guidelines to support clinical studies and basic research but also then to advocate for importance of local publications, for example, for case reports and things like that. But it's not just important to engage with the experts but also for every HCP, who is involved in the patient journey because if more people are aware of this disease, then also the diagnostic pathways are accelerated. We've been able to gain strong German experts support for increasing disease awareness and for discussing the challenges in this disease. We have a great cross-functional core expert group of endocrinologists and pediatric endocrinologists, of neuro pediatricians, of researchers, of laboratory specialists, and we've had 3 advisory boards so far since 2023, where we've talked about diagnostic pathways about laboratory monitoring potential newborn screening, thyrotoxicosis and cross-functional guidance on clinical monitoring. And these experts, they do agree that interdisciplinary work and collaboration, but especially in the sense of clinical monitoring is needed to improve the standard of care in this disease. And the shared objective in this group and in the discussions with the different specialists is to increase the expertise in MCT8 efficiency by interdisciplinary exchange and collaboration of the main specialties, which are the endocrinologic specialists and the neurologic specialists. And just to close off here from medical affairs, awareness and collaboration are key for adequate diagnosis and treatment and also being aware of this disease. Thank you.

Good afternoon, everybody. My name is Peter Verwaijen. I'm from the Netherlands. I've been in the industry for 20 years. It's almost impossible to believe, but it's true. I'm working as General Manager for the Benelux as well as the Global Head of Brand Strategy and the part I'll be talking about is about commercial business expansion, hence the title of my presentation, providing access in MENAT. Henrik already kindly explained what MENAT stands for, so it's the Middle East, North Africa and Turkey. And as you might have seen on Henrik's map, it's a significant territory in terms of patient population. But on top of that, it also has very well-established health care systems. And the important and interesting part of it in most of those countries, rely on the EPA approval for early access. And as Henrik -- as Nicklas said, during the discussion of the company's strategy, fast and broad access is one of our priorities, and this is perfectly aligned with that priority. So if you go and look at all those countries, it is immediately clear that it requires local knowledge, and feet on the ground. And as already mentioned before, that is very difficult to cover by a team of 40 people. So for that reason, we are looking at local parties that can help us and support us in providing broad access and making sure that patients in the MENAT region are being served in the most optimal way. Also already mentioned, U.S. and Europe remain to be core focus and strategic priorities for the company. So we are looking for strategic partnerships outside of those geographies and also specifically for the MENAT region. We have currently shortlisted a couple of companies. And the main criteria we've used 1 and 2 go 1 in hand, is they need to have a proven track record and reputation as well a lot of experience in loss in rare diseases -- products and rare diseases. Then because we can't cover this region or by ourselves, and we already have people in regulatory affairs that have a lot of work on their plate. We are looking for companies that can assist that and basically offer the whole broad range of functions like regulatory, market access and medical affairs, commercial, but also supply chain in pharmacovigilance. And finally, which is very important, of course, to us, is that they are committed to deliver the value of MCT8 to patients in the region. Let me conclude by ending and saying that we are very committed to have our first partnership agreements signed in 2025. So please stay tuned for more. And with that, I would like to invite my colleagues over to the stage for a Q&A.

Thank you very much, Peter. Thank you very much, Henna. Thank you very much, Henrik and Raymond. Really appreciate your input today. And we now have time for some questions and answers in the room. And I think Alexander, you were the first one in the back.

It's Alexander from ABG. I have 2 questions. So first question is on the Managed Access Program, which you have. I know you have talked about it in the past, but could you be a little bit more specific maybe today on the geographic composition there? So how many do you have in the U.S. versus Europe versus rest of the world? And then I have a second question afterwards.

Yes. I guess somebody would ask that question today. So let me start off with that one. And as you mentioned, Alexander, we actually are very proud of providing access to patients for more than 230 patients today, actually around 28 countries. We haven't disclosed the exact number in the different regions, but I can say that the majority of the patients are based in Europe.

Okay. And my second question relates to your local partners that you have on ground in the different countries in Europe and Germany, for example. Could you maybe comment a little bit, like what is your feedback you have received from them regarding like pricing, which kind of prices they think could achieve as they really have this long-standing experience with like this pediatric rare drugs in the local territories. So maybe that can give you some feedback there?

Sure. Maybe I can take a first stab at that, and then I'll hand over to Raymond and Henna potentially for a potential German experience. But I think very important to recognize, and this goes throughout the day and has gone the same position has been in the past as well that we don't disclose our price assumptions for MCT8, simple reason behind that. One, for the European Union, we are also pending the European Commission's granting of the marketing authorization, hopefully, that takes place in February. And subsequent, as Raymond alluded to, we'll enter into pricing and reimbursement discussions, which are contingent on many, many factors, and it's somewhat -- I shouldn't say complicated process, but it's a very focused process with many elements to it. So we don't disclose our price assumptions for Europe, U.S. or anybody anywhere else in the world. I don't know if you have some high-level feedback in discussions around the value proposition without quoting any numbers, Raymond.

No. No. I think you said it all. The only thing that I can add is that I've been through AMNOG a couple of times, and I've always and perceived it as a very fair and straightforward process. So confident that we get through that process and come out with the price. As I mentioned, that reflects the value of the product and ensure access for patients.

A very quick one to add in the end. I mean previously, we had this list of peer drugs. Is this list like -- is there like anything new to added to this list or could we like still considered this up to date?

Yes. I think the list of analogs we have used before in discussions has been mainly featuring the U.S. and the composition and how it works with regards to pricing and reimbursement there. And I think actually, our team will come back to that after the break when it comes to the U.S. perspective. When it comes to Europe, we haven't disclosed any analogs in the past. Then I think it's Anders or Mattias. I don't know who was first.

Mattias Häggblom from Handelsbanken. So I have 2 questions. Firstly, on the Early Access Programs. So could you help me think about why the pace of increase of patients have appeared to be at least slowing somewhat, although I am well aware of it, it's been lumpy in between quarters. But is there any is there any suggestion that we're sort of getting to a saturation in terms of -- or people dropping off? And also, how should we think about you continuing to report that number as some of them will eventually convert into commercial patients? And then second question is around helping us think about the pace of the launch. I guess on one hand, you could argue for a fairly rapid uptake. You have strong guidelines, no competition and large unmet medical need until you have support. But on the other hand, you are first in class, and we're talking about an ultra rare disease. So help me think about the 2 alternative factors for framing the launch trajectory, I guess.

Sure. I can start, and I'll hand over to you, Henrik, to build. And I think you rightly pointed out, Mattias that when it comes to the number of patients in absolute terms in the Managed Access Programs has been lumpy. But if you look at over the last 2 years, I think would have an average increase of 10 to 15 patients per quarter. I think the important thing there is to recognize that, that are patients in the Managed Access Program, i.e., patients we provide drug too. My more esteemed colleagues from the U.S. will elaborate a bit further in the afternoon session or after the break around the number of patients we have found in the U.S. actually. And there, the base started off at around 20 patients that we knew about 2022. And today, we have awareness of more than 100 patients in the U.S. alone. But that doesn't mean they necessary are part of the Managed Access Program because in the U.S., as we all know, the ReTRIACt study is the key focus for the company to conclude that. And hence, we are very restrictive on adding patients for the U.S., as an example, through the Managed Access Program. I hope that answers your question. Mattias you had 2 questions. I haven't forgotten the second one. So the second question was around launch trajectory and what to expect. And I think Henrik covered parts of it in his update. And I think we all recognize that repricing and reimbursements generally are slow in Europe. That's how it is our home country here in Sweden, it can take up to 2 to 3 years before and even an orphan drug is actually fully reimbursed. And what Henrik alluded to in his presentation is one would assume 1 to 2 years in average across the countries in Europe depending on the priorities, of course, we will start off with, and I think that is the important thing. We will start off with what we call Wave 1, which is Germany, France, Spain and Italy. And as Raymond also mentioned, in Germany, we can generate sales in parallel with AMNOG process and our equal potential possibilities in France, Germany and Italy as well. Henrik, do you want to add something?

I think you covered everything well, Nicklas.

Thank you.

Andres [indiscernible] an individual investor. I wonder about that you can sell parallel, what does that mean in Germany? Can you start immediately and then sell parallel at what time? And what is it? Is it preliminary prices? Or do you get paid afterwards? I guess, around 100 of these 230 patients or from these countries or where so they can start when? Maybe a reimbursed.

And maybe, Raymond, do you want to use Germany as an example on how sales work in parallel with the AMNOG process.

Exactly. So in Germany from the moment that you enter the AMNOG process by submitting your dossier you can charge for patients, for medicines. So from that moment, we start generating revenues. That is a price that we go in with into the AMNOG process and after 6 months, as I mentioned, then we need to start negotiating that price. So we'll have that price for 6 months. Then after 6 months -- after 12 months, we've got a negotiated price and that will be then the new market price after 12 months.

That's a lot of questions. Eric, in the back.

Could you put some light on the kind of significant collaboration with Fujimoto in Japan? How is the collaboration progressing?

So the collaboration is progressing really well. I think we had an ambition to engage with the FDA during the second half of this year, being very transparent here. What actually made us change that strategy is the new guidelines that was introduced by MHLW, which really plays in our favor. So there were new guidelines introduced by MHLW, which is the Ministry of Health in Japan on the 23rd of October this year, that stipulates if you fulfill certain criteria, rare disease, devastating condition and generated substantial pivotal data in other regions, one can move forward through the PMDA to discuss -- and not having the requirement to execute on a clinical study in Japan. So that's where we have changed actually our regulatory approach, and we are now planning to engage with the PMDA soon after the New Year. And I think also I have time for 1 or 2 more questions. We have Fredrik and Johan in the back.

Well, yes. Just a follow-up on in Europe on the 4 big countries that you are going to target initially. Of course, it's very important with the diagnostics and the promoting -- identifying patients, how is that going? Could you give some examples.

Thank you. Maybe I actually I hand over to you, Henna, because you're out there speaking to physicians and stakeholders and collaborators and...

So yes, we have a lot of discussions with the different neuro pediatricians or endocrinologists and they do seem to remember sometimes that they have diagnosed the patient 10 years ago. And then they get reminded of the symptomatic of these diseases. And I guess it's just really the interactions that we have one-to-one with the doctors that we are talking to, and it really needs that as well. I don't know if you have anything further to add to that.

No, I think that's said at all.

It's no magic wand. It's about interacting.

Interacting, yes.

The second question was regarding the U.S. market and the launch, but perhaps we should save that to later, or...

Could you save that to -- after the break, Johan, if you don't mind. And then Fredrik, the last question from you? No pressure, [indiscernible].

Yes. So you mentioned the Wave 1 and Wave 2. Can you just be more specific on Wave 2, how broad is that? Is that all European countries or a few more and then a few more so?

Yes. There -- I mean, we would like to ensure broad access. So there, it's more how we do it in the different countries. If we go through the national reimbursement approach or some alternative pathways that do exist in these countries. But we are really aiming for broad access in term to [indiscernible].

And I think that's something really important to reassure that despite we are illustrating it here, as Wave 1, Wave 2, access is one of the highest priorities for the company in general, not just in Europe, but in general, so we, of course, will look at alternative options, making sure that this is available for patients in Europe contingent on the European commercial approval, of course. Thomas, last question from you.

What about the chances to be included in newborn screening. You mentioned it that you talked to the German doctors about this. What about authorities how prepared are they for this?

We've had some discussions with the German Society for newborn screening and looking at the different opportunities that you would have, but as we all know, the screening is T4 based. So you cannot really detect these patients with that screening. So there should be some pilot studies done first with alternative biomarkers to detect this. For example, reverse T3 or other things, but that is not yet active. So these discussions are ongoing.

I can maybe build on that because I think what we see is becoming more and more prevalent because the costs are reduced. This genetic screening and genomic screening as we have in the U.K., where we are actually part of a pilot program where SLC16A2 mutation is actually included. So I think there are opportunities really going forward, especially now when we have an approved therapy because usually from authorities, they're tend to be some reluctance when you don't have an approved therapy to including in any type of screening program. So I think there is an opportunity now with the science moving forward, cheaper tests, so to say, to be included in the different countries in Europe, of course. So with that, thank you very much for your questions and your attentions -- your attention. Now we have scheduled a 15-minute break. And we'll be back shortly. Thank you. [Break]

Okay. Welcome back. It's now time to turn our attention to the United States. So the upcoming sessions will feature an update on the clinical data, of course, summarizing that, we have generated and have attended for the upcoming submission to the FDA, the new drug application as well as the status of the ReTRIACt study. We'll then segue over to the U.S. commercial opportunity with 2 additional my esteemed colleagues will join the stage and focusing on, again, patient access and reimbursement and the commercial opportunity. And then we'll have ample time for Q&A. So without further ado, let's move into it. And I think it's important to reflect back and I was really pleased to see Professor Visser at the beginning, reflecting on the clinical data that has been generated over the number of years, both Egetis and EMC has been active in the space. And I think the conclusion from my humble opinion is when you let this and take a step back, it's a very robust data set being in an ultra-rare disease. So taking a step back here and reflecting the marketing authorization in Europe to the EMA actually consisted on clinical data from 3 studies. The first one, you heard the Professor Visser talk about. It was the Triac Trial I, 46 subjects enrolled to that study, investigating the effects of treatment on thyroid hormone concentrations and the relevant clinical end points. That was then confirmed by the Erasmus Medical Center cohort study, 67 patients that was followed up to 6 years. And together with that, a third study was included in the EMA, which was an extensive natural history study an untreated MCT8 deficiency population, which actually enabled an indirect comparison to assess the clinical benefits of our treatment. Since the submission of the marketing authorization application in Europe, we have also concluded Triac Trial II. Yet again, you heard Professor Visser referring to that. It generated a lot of valuable data that will be used in the upcoming and new drug application in the U.S. and especially establishing the well-tolerated safety profile in younger children. On top of that, you also had Professor Visser referring to the survival study. The data is not published yet, but the survival study but also add a very important part to the totality of MCT8 and the potential effects of treatment. That to aside and in consultation with the FDA, we are also running a separate study in the U.S. called the ReTRIACt study. And let us remind you what that actually compromise (sic) [ comprised ] of. So the design of the ReTRIACt study is displayed schematically as you can see here in the picture of the -- to the right. MCT8 patients included in the trial could be either on therapy or being treatment-naive. During a running period patients are titrated to achieve stable T3 levels before being randomized to either continue MCT8 treatment or to withdraw MCT8 treatment and instead receiving placebo. The length of the study varies by patient and is naturally expected to be somewhat lower in the treatment-naive patients, driven by a longer run-in period. The special features in this study compared to a typical clinical study is that patients are not randomized to receive therapy. They are randomized to withdraw therapy they're already on. And when MCT8 is withdrawn, it's reasonable to anticipate a reversal of the treatment effects on T3, which could lead to clinical manifestations of thyrotoxicosis. Therefore, the randomized treatment period includes a rescue criteria of above T3 upper limit of normal. The primary endpoint of the study is the proportion of patients who meet the rescue criteria once a patient meets the rescue criteria or after completing the 30-day randomized treatment period, whichever comes first, the patients entered to a 6-week follow-up period. So the primary endpoint is really is the proportion of patients who meet the rescue criteria above upper limit normal during the 30-day randomized treatment period. Then when it comes to the status of the ReTRIACt study. Here, we need to be adamant that the performance of executing this study hasn't been up to our expectations. We are working very hard and diligently to address that. And by doing so, we have, for example, introduced 3 new clinical sites mid-2024 to speed up recruitment and those sites are located in the U.S., Texas, Georgia and North Carolina. So at the moment, we have 6 open sites in the study, 2 in Europe and 4 in the U.S. And the current study status, it's an update compared to what we last communicated as part of our quarter 3 report is that 18 patients have been enrolled in the study so far, of which 8 patients have completed the randomized treatment phase, 1 patient are now in the randomized treatment phase, and 4 are in the running period. And please note that as for any clinical studies, there will be a few dropouts and hence not all patients included will be randomized. Additionally, as we see the light at the end of the tunnel. We have an additional 4 patients being planned for screening in January and another 6 to 8 patients under evaluation for study inclusion. And rest assured, we have full focus on the execution of the ReTRIACt study, and this is one of the highest priorities for the company. When it comes to time lines, we will update the market as soon as the recruitment of the ReTRIACt study is closed. At that point in time, we will also be able to provide information on when to expect top line results as well as when we plan to submit the new drug application to the FDA. So that was a very brief update on the situation in the U.S. from a clinical development and regulatory standpoint, and I now have the pleasure to hand over to Anny and Ann-Marie to elaborate further on the U.S. opportunity.

Thank you. Good afternoon, everyone. My name is Anny Bedard. I'm the -- there we go. I'm Anny Bedard. I'm the President of Egetis North America. I joined the company 2 years ago. And my background is 30 years in the biopharmeutical space. And I spent the last 20 years focusing solely in the rare disease area. I had the opportunity to build from scratch rare disease businesses in different countries around the world and also lead the growth of several of these companies as well. Just for example, in the last few years, some of those companies included Shire Therapeutics and also Sarepta Therapeutics. So I'm happy to be here this afternoon to be with you.

Thank you, Anny. So greetings, everyone. My name is Ann-Marie Redmond. I'm heading up our market access and pricing for North America. I also have been in the industry for about 30 years. I know we look to young , but yes, it's true, 25 of which has been in market access. I've been launching more than 10 products predominantly in rare disease for both small molecules as well as biologics, at big pharma like Novartis, when they first started their oncology division as well as most recently at Otsuka Pharmaceuticals in the nephrology space. I've been able to establish market access and pricing teams, both in the U.S. as well as globally. So really looking forward to bringing MCT8 to the United States.

Excellent. Thank you. So today, we're pleased to provide you with a brief update on the progress that we've accomplished in the U.S. as we prepare the anticipated launch of Emcitate in the United States. And we've been mostly focusing on driving the 4 key strategic priorities that you see here and that we've also previously shared with you in the past. And our aim and the -- what we will be talking to you more broadly about today, is the efforts that we've done in terms of improving our understanding of the journey of the MCT8 deficiency patient, the profile of these patients to really help us optimize the patient fine efforts. Ann-Marie is also going to talk to you about the efforts that we've done in terms of progressing and solidifying our access and pricing strategy in order to make sure that we strike the right balance between the treatment cost and the reimbursement criteria and make sure that we are in a position to provide broad access to as many patients as possible. So as you are now experts on, you all know that patient finding is really critical when we're launching an orphan drug. We've said it multiple times today. And that is also one of the obvious priorities in the U.S. And we feel very confident that we have the right expertise and the right knowledge in order to develop the right strategies and tactics to maximize patient finding in the United States. We've been partnering with different advocacy organization, engaging directly with the patient and the caregiver communities via strategic partnership with advocacy groups and also engaging and leveraging high-impact media channels in order to raise awareness broadly. We've also continued partnering with commercial genetic diagnostic laboratories in the U.S. in order to help patient disease identification. And already, these types of collaborations and partnerships have allowed us to gain a much better understanding of the potential number of patients in the United States and also to better understand what these patients look like, what is the phenotypic profile and as well already generate important publications that will serve to increase the broader awareness within the health care professional and patient community. In terms of engagement with health care professional, we continue to focus on targeted education efforts with some of the activities that are described here. And those activities are also supported by the great efforts that we've been doing in terms of raising awareness with the clinical -- with the recruitment of our clinical trial ReTRIACt and also with the efforts on our Expanded Access Program. So the patients that we have found to date, the diagnosed patients, are the ones that really have been fortunate to see a physician who was able to make the diagnosis. Unfortunately, in the rare disease space and for these patients as well, the journey is often much longer, and unfortunately, some of these patients never get to a final diagnosis. So to help us better find those patients and reduce the length of their journey, we've leveraged real-world data and advanced analytics in order to better understand what does the -- what do the undiagnosed patients look like. So what we've done is we've used de-identified, anonymized data from insurance billing reports combined with electronic health records and combined as well with genetic test data. And by doing advanced analytics on this data, we were able to get a really good picture, significantly better than what we have until now, about what does the profile of these patients look like to -- and we refer now to this as our footprint or blueprint to help us, as we move forward, better identify patients earlier in the diagnostic and develop tools that will also help educate the community to reduce the journey and get these patients earlier to care. So these efforts have really led to some significant progress in terms of our efforts of finding diagnosed MCT8 deficiency patients. And as Nick referred to earlier, in 2024, we've already identified more than twice the number of patients that we had identified last year. And so we're really pleased with this progress, and it really highlights that the initiatives that we've put in place are really doing what they're supposed to do and bearing fruit. In terms of the Expanded Access Program, we now have 18 sites across the country, 10 of which are actively enrolling patients and 8 that are in the advanced process of being activated. So this is also contributing significantly to raising awareness of MCT8 deficiency. And one of the things that we're really proud of is that most of the patients who have been identified and that the physicians want to include in the Expanded Access Program have access to an EAP site within 4 hours of driving distance to their home. That was an objective that we set for ourselves in order to facilitate access for these patients. So as we move forward in our patient identifying efforts, we are going to leverage the efforts and the momentum that we've created with what we've already put in place. And we're also going to combine this with the data-driven insights that we've generated, and we believe that this will help us accelerate the identification of patients as we move forward closer to the launch. So I will now pass to -- the microphone to Ann-Marie, who's going to share with you a little bit about how we are progressing as well in terms of our pricing and access strategy.

Yes. Thank you, Anny. So pulling through that momentum, our ambition is to secure broad access for Emcitate. We have 2 payer segments that we're focusing on, and that's predominantly due to where the patients obtain their health care insurance coverage. The first being Medicaid, this is a federally funded program for people that have low income or limited resources. While it is federally funded, which means at a national level, each state has the ability to implement that program based on their unique processes. So it might look a little bit different in each state, and it's something that we need to be mindful of. Second is the commercial payer. And this is for people that are of working age, typically 65 years or less, and get their insurance through their employer as well as they can also cover their family members. So a caregiver would cover for their child in that instance under commercial if they're working. These 2 segments come up to the top or rise to the top, predominantly as a function of the disease MCT8 deficiency, because it's severely debilitating, these patients cannot work, their caregivers likely have alternate work arrangements or also are taking care of them full time like we heard in the video as well as, unfortunately, these patients die at an early age. So they are the lower population or lower age population. So that's why Medicaid and commercial are our focus. What this means to us is we have to understand each state, their new drug policies. So what is it that they do? How do they behave as new therapies come out? What is the timing of the coverage as well as what is the criteria that they put in place? And what have their past behaviors look like? And so we are already doing that work. In addition to that, on the commercial side, while there's not 50 states, there are 3 key players. I'm sure you've heard of it, called the Big 3, in the United States for commercial: UnitedHealthcare, ESI called Express Scripts and CVS. Those are the big guys that cover the majority of the commercial lives. And what we're looking to do is also understand their new drug policies in terms of timing as well as the criteria. Based on the work we've already done and already embarked on, we anticipate that between 3 and 6 months, coverage will begin to open up for Emcitate after launch. So to support our efforts, we know we need to strike a balance between annual treatment cost as well as that broad access or the criteria that's going to get put in place. We've done a lot of work in that regard this year to be able to really understand that right balance, validate our original thinking as well as kind of refine some of our assumptions. Based on that, we've done digital deep dive on data and analytics to understand behaviors. We have done formal research with payers post Triac Trial II to get their perspectives as well as had further discussions with payers. And what we were able to do in that regard was bring forward some additional analogs -- I think it was mentioned earlier about analogs, bring forward some additional analogs that either the payers have brought up to us or that is more -- it's newer therapies that have come to market, so more recent behaviors by which we can learn from. And no analog is ever perfect, but different elements that are more reflective of Emcitate and what we can expect. What we do know in some of this work as well is that there is an inflection point that the payers have shared in terms of where they feel more restrictive criteria is warranted to be put in place, and that's not what we want. That's not our intention. We already said we want to secure broad access. So what we're doing is understanding what this right balance is. And based on the work we've done thus far, we've really validated our thinking, and being able to feel that for severely debilitating ultra-rare, it is achievable to achieve this right balance, commensurate with those types of diseases in ultra-rare. So how are we going to go about it? We're going to focus on those activities that are most impactful, first, engaging early with our payers. We need to educate, educate and reeducate. This is an ultra-rare disease. It's not top of mind for them. They have a lot of other things like diabetes they're focusing on. So being able to give them the information so that they can make informed decisions on how to behave and how to manage this therapy is something we're working on. But we're not doing it alone. We are working with our key opinion leader network because while the payers want to hear from us, of course, they also want to hear from the health care providers that are taking care of these patients as well as the patients themselves. So we're leveraging that network to be able to elevate that education. Complementary to that is we are standing up a patient provider model, one that is fit for purpose for this disease state in these patients. So looking at distribution, looking at patient support, looking at affordability, taking insights from our stakeholders and building a fit-for-purpose model. It has to be unique to this disease state so that they have a good experience getting on therapy and then staying on therapy. And then finally, looking at continuing to develop and expand on our data and evidence base around normalizing T3. We know it's important. We see the benefits of it, but expanding that body of evidence to ensure that we're getting that information out there, not only from clinical trials but from real-world data. So with that, just in summary, we know who we're going to. We know what we want to achieve, and we want to -- we know how we're going to approach it. So with that, I'll give it back to you, Anny, to talk about the capabilities.

Excellent. So -- great. So moving forward in '25 as well, we will be building our team, starting to build more capabilities and infrastructure in order to ensure success. And we -- these include supply chain, market access, medical affairs, marketing and commercial operation in general. So finally, we feel -- these are really -- in '25, those are the priorities that we will be focusing on and -- in order to get us more ready for the anticipated launch of Emcitate in the U.S. And we will continue to build diligently with a phased approach. We have a good strategy. We have -- we are using investment very strategically, and we have a great team. So we're very confident with the future, and we look forward to coming back and reporting on additional success next year or maybe earlier. So thank you for your attention, and we'll be happy to answer any questions. Do you want to move it?

Thank you, Ann-Marie. Thank you, Anny. And I totally agree, you look a lot younger, both of you. That said, let's open up for Q&A. Mattias, you're always the first. Go ahead, please.

Mattias Häggblom, Handelsbanken. Two questions, please. So 18 sites in the U.S. are part of the early access program, but there appears to -- according to the map you shared, to be more than double the number of hospitals with known MCT8 deficiency. So what is the driving force for a hospital to activate and be part of the early access program? And what means -- what is the main reason some sites are not part of it? And then secondly, in terms of the enrollment pace, which has been a disappointment for the U.S. regulatory trial, what's been the biggest disappointment or the biggest surprise in terms of the patient enrollment pace for your team compared to original expectations?

And maybe I can start, Anny, with the ReTRIACt study, and then we can segue over to the managed access or Expanded Access Program in the U.S. and your views on the number of sites, et cetera. And I think -- no, and we shouldn't shy away from it. The question was around ReTRIACt study. We shouldn't shy away from that we're disappointed on the progress of that study. I think it's coming back to some of the features we have heard today that this is an ultra-rare disease. We're learning a lot as we go along. One of the things where we went wrong, being very transparent, is our assumption of the patients being already on treatment actually accepting -- so success rate, accepting to be part of the study. Our original assumptions on patients on treatment being accepting to be on the study was pretty high. And what we have seen now is that, that hasn't materialized, unfortunately, driven by a number of reasons. I think they -- all the parent see it's for the greater good of the community. We have an acceptance rate of roughly 50% of these patients already on treatment, but that's lower than we expected. And that's driven by, as you heard and seen throughout the day, the management of caretaking of these poor children in a very devastating condition, adding another burden to them going to a clinical study or some clinical site, taking blood samples, et cetera, et cetera, even though it's not that often, which we also have mitigated through home nursing, et cetera. Still adds a burden to the caregiver. So I think that's one reason. The second reason is geography actually. And this is more related to the U.S. rather than Europe. And here, we have learned throughout that the distance to the clinical sites we have up and -- or had up and running is a key feature of a parent accepting to be a part of the clinical study or not. And that comes back to what I said. It is a burden to take care of these children. It is a challenge. As you can imagine, Mattias, traveling more than a couple of hours either in a car or get on an airplane, where the poor patients can't sit up independently, this is a challenge. We mitigated that through opening 3 new sites, as you've seen, in Texas, Georgia and North Carolina, just to get a better geographic spread. And what you have seen, despite poor performance in the past, that the recruitment rate now is picking up, and we see the light at the end of the tunnel. Anny, do you want to share your reflections on the hospitals being part of the Expanded Access Program?

I think it's linked to what you said because traveling -- the challenges for families to travel is something that we've discovered that we did not really understand at the very beginning. So that is a challenge, and that's why we set ourselves the objective that for all of the patients who want to -- who are eligible to being enrolled in the expanded access that we are going to do everything that we can to have treatment sites within 4 hours of driving distance, which is pretty much the maximum that the families are sharing that more than that is really, really challenging. So that's been a factor also from the clinical recruitment. And that is also one of the reasons why we do not have -- all the red dots are not equal to a star is because we're trying to serve the patient within a 4-hour geography of these trial sites. And also depending on the size of the hospitals, having an expanded access site requires there's an IRB that needs to be done. There's administration. So not all of the physicians or hospitals want to go through this. So we always need a champion in some of those hospitals to be able to lead these initiatives. But we're getting great traction, and also, the patients that are included in the Expanded Access Program are the ones who are not eligible to the clinical trial because that's what we've been really prioritizing.

And I can maybe add a tiny thing to that because I think that is so important. And when we speak about managed access program, it's not one program. It's an umbrella for providing a preapproved drug to a specific patient in a specific country. In Europe, that is much easier. The legislation in Sweden, for example, allows a physician to make a request to national authorities and get the permission, and then they can just receive the drug from Egetis, whereas, as Anny explained, in the U.S., it's slightly more complicated when you have an early access program, where you need to have a hospital, a clinical protocol in place, which requires a IRB approval, a contract in place with that site, et cetera. So there are different dynamics in different parts of the regions around the world.

It can take up to 6 and even a little bit more months to -- from the very beginning of a physician having saying that I want to be part to the full completion. So -- and we've gone better and better and better at helping narrowing this down. But we're -- it just takes time administratively at the EAP sites.

Thank you, Mattias. Next question, Johan, in the back.

Yes. First question then, rather interesting with your proactive approach to collaborating with labs and data-driven sort of searching for the patients that are not diagnosed. Could you expand a bit on that? Or is that going through and see what characteristics are on the insurance and how -- yes.

Yes. So we initiated this project in the second half of 2024. And what we've done is in the United States, we have access to a lot of de-identified, anonymized database from insurance billing, electronic health records. And since most of the genetic testing labs are commercial, we also have the opportunity to, again, get access to anonymized data to these labs. Of course, we need to purchase this data, so -- but this gives us a really helpful bank of information to be able to then do multiple analysis to better understand what patients look like. And since there's no ICD-10 code to easily find the diagnose -- a confirmed diagnosis in this database, then we need to put together initially all of the potential symptoms that we know of and then find some of those patients or take some that we know are confirmed diagnosed and follow their journey, what are all of the different diagnosis that they've had, all the number of different physicians that they had to go see before they were diagnosed. So really, the whole journey of what happens with these patients until they get a diagnose and then even what happens after. So this is really informative for us to kind of get some form of a blueprint of what happens prediagnosis so we can leverage this data, put it back in bigger database and help identify suspected patients that we can then share, in a compliant way, with the physicians so that to help them look for these patients in their practice.

Setting up protocols, sort of 6 months. It's very interesting. And what about when the product is approved in the U.S. and reimbursement guidelines are in place? Could you sort of reverse that process as well, perhaps bringing the product to the patient with collaborations with more local professional and specialists or...

And I think that's a really good question. I think Ann-Marie touched upon it and how the mechanism and process works in U.S. and the split between the different payer types. But I don't know, Ann-Marie, if you want to elaborate a bit further on it.

Yes, I think the work's being done with the real-world data is important in this blueprint because the payers will ask, like, who am I looking for? Where are these patients? And so being able to provide that blueprint as well as have them look in their data is something that is possible and has been done so that they better understand what are these patients costing the system, we need to get them treatment, et cetera. So there are partnering opportunities that have been done in the past. I think it remains to be seen. We have to do it in a compliant way, of course, but it is something that we are looking at and investigating as we move forward.

On the Medicaid side, sort of north of 80% of the expected market. Could you remind us of the process of getting into that? Sort of is that a committee once for all? Or is it more regional formula listings or committees that you need to work with and get approval from?

So as a manufacturer, we sign up to say that we will be part of this program. So once you sign up, you're allowed to be available to that federally funded program. However, even though it's nationally funded, each state has their own processes that they put in place from a new drug policy perspective. So they do receive money from the national government, but they can also look to either expand that as far as their services or do things on their own time line. There are certain dates that are put in place, an optional date, a mandatory date for coverage, et cetera. But we have to understand each state's processes. All 50 of them have their own unique way in which they work, but that's why we're doing the work now to really understand what their past behaviors have been, get them educated on Emcitate so that they understand the need to move quickly once this is approved.

And that brings the final point. We have seen before that you -- of course, you will need capable sales resources, sales teams, but sometimes the need for support and the ability to work with, collaborate and then -- what's the word? Well, sell in and educate and get a kickoff from these committees, that is quite -- can be quite a lot. What...

I think you can talk first about the support of how we communicate and educate the payers with the market access team, and then I can talk about the sales.

Yes. Given this is ultra rare, we did talk about there's a concentration on the commercial side. You've got 3 big payers. So we get to them, we've got good coverage, right, in moving this forward. The states, there are something called pooling group. So there's entities that kind of speak on behalf of a handful of states, shall we say? And we're able to engage with them as well. So we are looking to put people on the ground early next year -- early to mid next year to do just what your suggesting as far as making sure we're continuing to educate and doing this before approval rather than waiting until approval and then having to educate them, and that delays the process. So that is something that's already in the works. And I think we also have to be mindful that this is ultra rare. So we don't necessarily need a large team. We just need the right team that's focused and understands who to get to.

Exactly.

Thank you very much. And I'm so excited about the number of questions, right? But we, unfortunately, have to stop there. We're already 3.5 minutes late into the next session. Thank you very much, Ann-Marie. Thank you very much, Anny. And I'm very delighted to invite Professor Aled Rees up to the stage. And now we're truly changing gear, Aled, right?

Absolutely.

Now we're going to talk a bit about the unmet medical need in resistance to thyroid hormone beta. Thank you.

Thanks very much, Nick, and thank you very much for the invitation. It's a real pleasure to come over to such a beautiful city at this time of year. So I'm Aled Rees. I'm an endocrinologist working in Cardiff in the U.K. And I'm going to take you through some thoughts around RTH-beta and when I see being the unmet clinical and medical need at present. So throughout this presentation, the full name of this condition is known as resistance to thyroid hormone beta, but we abbreviate that sometimes to RTH-beta. And I'm grateful to my colleague and collaborator, Dr. Carla Moran in Dublin for helping me provide with some of this overview, which I think has been presented in part previously. And what do we do in terms of endocrinology. So we look to understand how hormones work in both health and disease. And what we're going to be talking through in the next 20 minutes or so is, first of all, an overview of thyroid hormone, thyroid hormone action. We've heard a little bit already this afternoon from Edward about this. But we're going to talk also about specifically what RTH-beta is; how we diagnose resistance to thyroid hormone beta; what the effects are clinically; what the current treatment options are and how those are limited and, therefore, how we have unmet needs; some recent epidemiological data, which has really transformed our understanding of the natural history of this condition and reminded us really of the important of developing new treatments for this disorder and some future research programs. So an overview of thyroid hormone, and apologies for those of you who understand this very clearly, but I thought I'd go back to first principles. So there are 2 main organs here that we are focused on. One is the pituitary gland, and the other is the thyroid gland. We've heard already about the thyroid gland in the neck as being a major source of the circulating thyroid hormones that we call T4 and T3. Thyroid hormone production is regulated by the pituitary gland, which we can think of as being the master organ, so the master system in charge of all the hormones in the border -- body. And you can almost think of it as a conductor of an endocrine orchestra. So it produces a hormone called thyroid stimulating hormone, which will stimulate the thyroid to make thyroid hormones T4 and T3. And they keep themselves in balance through what we call a feedback loop. So when there's enough circulating T4 and T3 around, there will be a signal from the hormones themselves that will go back to the pituitary gland and will tell the pituitary to stop making TSH and keeping things nicely in balance. So most of us -- hopefully, all of us in this room will have thyroid function tests that are very stable throughout the day and throughout our lives. Sometimes this goes wrong. So here's an example of a patient with a common condition that we will call Graves' disease, which is the commonest cause of an overactive thyroid, and we can see the typical biochemical pattern shown in the table at the bottom here, where the levels of the circulating thyroid hormones, T4 and T3, are high, as shown in red, and that will feed back to the pituitary gland to switch off its own production of TSH. So that is a very clear readout to us as endocrinologist and as clinicians, where we see a characteristic biochemical pattern where we've got high circulating thyroid hormone levels and an appropriately low TSH level, and that will point very clearly to a diagnosis or a small range of differential diagnosis. How do thyroid hormones work? Well, thyroid hormones are critically important to all aspects of physiology really. And I've shown some of the key organ systems here that are regulated by the thyroid hormone. So in the top left, as you look at the screen, is the pituitary gland and the thyroid hormone -- thyroid gland itself, rather, underneath, producing its thyroid hormones T3 and T4. Some of the downstream targets include the liver, which is important in how insulin works and cholesterol metabolism. Thyroid hormones also have an important action on the heart, regulating electrical signals within the heart, but also how the heart pumps. Within the brain, it's very important, as we've heard earlier, with respect to neurodevelopment, so brain development and myelination or formation of the coating around the neurons as the brain develops. It has an important role in bone strength and growth and in the muscle as an important action also in controlling metabolism. But how do they really actually work? Well, we've heard already from Edward a little bit around this, and he gave us a helpful reminder really that to address this, we really need to go inside the cell, and it's the nucleus within the cell where the action happens. And we're talking about thyroid hormone receptors here. So to introduce you to that concept. So thyroid hormone receptors will bind to downstream genes really within the nucleus of a cell regulated by thyroid hormone binding and it responds to thyroid hormones getting into the cell. We've heard about these 2 hormones, T4 and T3, which we can measure clinically. It's T3, which is the biologically active form, which binds to thyroid hormone receptors within the cell and exerts its downstream consequences. But it's not as simple as having 1 receptor. There are at least 2 receptor isoforms, beta and alpha. So we're talking about RTH-beta here, and this is a genetic condition where there's a mutation or DNA change, if you like, in the thyroid hormone receptor beta. And the downstream consequences for patients depend in part on the distribution of the beta and the alpha receptor. So shown in blue are the beta receptors here. We've heard the pituitary gland. The importance of that is beta dominant and the liver is also beta dominant. In contrast, the heart, the brain, bone and muscle tissues are alpha dominant. And we'll come back later to how that characteristic distribution of receptors impacts on our understanding of the clinical presentation of patients. So moving on then to talk a little bit about RTH-beta, what do we mean by this condition? So I'll come back to this chart again just to remind you what's going on here. So shown in red now are the resistant pathways. So resistant to the thyroid hormone action is at the level of the pituitary gland, first of all. So in contrast to that early diagram, what I showed you that, that feedback loop was working normally here because the pituitary expresses a mutant thyroid hormone receptor beta the signal is not recognized correctly, and that will result in a downstream consequence of an increased stimulation to the thyroid gland resulting in high levels of T3 and T4. The liver is also beta dominant. So that will result in a relatively resistant action within the liver itself. In contrast, the other tissues are alpha dominant. So they're not going to be affected with respect to a mutant receptor as such, but they are seeing higher levels of T3 and T4 in the circulation. So they will be stimulated to an excess extent, which varies between patients, but the heart, the brain, the bone and the muscle conceptually, if you like, will be thyrotoxic and the liver and pituitary are relatively hypothyroid. So we get this characteristic mixture of the tissue level of varying degrees of hypo and hyperthyroidism. How do we diagnose it? I come back to this example. So in a patient with RTH-beta similar profile with respect to the T4 and the T3, so these are high. But in contrast to patients with common thyrotoxicosis such as Graves' disease that I showed you earlier. The TSH is within a normal range or even slightly elevated because it's not sensing this high level of circulating hormones appropriately because of the mutant TR beta. So this biochemical signature is quite characteristic for this condition. And again, so we can see this characteristic pattern of high blood tests, so high free T4 and free T3 levels and often a normal range TSH. And sometimes that in fact, results in excess stimulation to the growth of the thyroid gland giving what we clinically term, an enlarged thyroid gland or a goiter. How do we diagnose it? Well, there is a DNA test, there's a reference laboratory in the U.K. based in Cambridge laboratory, which is where we tend to do the genetic diagnosis. And we have a rich data set going back for a number of years with a list of all patients really within the U.K. with a genetically confirmed diagnosis of RTH-beta. So it's a simple blood test, a DNA measurement. Inheritance pattern tends to be an autosomal dominant pattern. So if you're a father or mother with RTH-beta, the children will have a 1 in 2 chance of having the condition. There have been 2 relatively large-scale prevalence studies, which have suggested a prevalence of between 1 in 20,000 to 1 in 40,000 of the population because it's inhibited in an autosomal dominant pattern males are affected equally as females. It can be diagnosed at any age, and it can cause many symptoms. But in fact, some people have very few symptoms for reasons that we don't completely understand. It may relate partly to the degree of biochemical disturbance and the underlying genetic mutation and where those receptors are distributed. And symptoms indeed can vary over time. What are the effects of RTH-beta? So I've mentioned some of the key tissues or organs that we're really interested in this condition. So if we are thinking about clinical trial programs, for example, in this condition, we need to think not just in terms of symptoms, not just in terms of biochemistry, but also beginning to understand what are the actual actions of thyroid hormone at the tissue level? And can we begin to modify those in a way that will benefit patients downstream. So I've mentioned that the liver, for example, is resistant because beta receptors tend to dominate there. That will have potential adverse consequences with respect to a lipid profile that includes the high cholesterol, insulin resistance. We don't have good long-term data as to whether that leads to increased risk of type 2 diabetes or fatty liver disease, but we believe that it may too. In the heart, and in the brain, in the bone and the muscle, they're exposed to access circulating levels of thyroid hormone because the alpha receptors are dominant there, they will respond to those and be relatively thyrotoxic. So that will result, for example, in failure-to-thrive in childhood and raised metabolic rate, reduced bone strength, short stature. Patients also sometimes have problems with hearing and ENT infections. There is a high prevalence of ADHD phenotype in children, which can persist into adult life anxiety, hyperkinetic behavior, some patients have reduced IQ. And in the heart, which is a focus for some of the later slides in this presentation palpitations are reported not uncommonly with patients, and we've got some natural history data in relation to cardiac outcomes in particular, which has changed our focus now treatment priorities in this condition. And with that in mind, this was a study that we published last year based in something called the SAIL Databank, which is a very rich data source based in Wales in the U.K. that's got population-wide coverage for all health outcomes. And we wanted to ask the question, what is the natural history of long-term outcome for patients affected with this condition. So we captured 55 patients in Wales, which is about 80% of our total, we estimate, with a genetically confirmed diagnosis of RTH-beta and matched those to over 2,500 patients from the general population who are unaffected. And we found overall that this is all cause mortality. So patients with RTH-beta shown in the blue interrupted line here compared to control, background population patients in the red, were 2.8x as likely to die from or causes compared to patients. So patients are more likely than the control is 2.8 fold. And I'll draw your attention to the bottom left as well. So the median age, the time, the age at which they had their first event, whether that was death or major cardiac outcomes was 56 years in patients with RTH-beta compared to 67 years in the general population. So that's an 11-year difference in outcomes, which we consider to be very clinically significant. And that's really changed our understanding, I think, of what we need to be doing about this patient group. As I'll allude to in just a second, there has been a degree of therapeutic, I don't know, nihilism, about this condition that we just tend to ignore it or maybe just monitor patients and see them once a year. But I think this natural history study has really changed our thinking in that regard. I mentioned that I would focus on the heart. Here is some of the data that we also looked at with respect to heart outcomes. So atrial fibrillation is this condition that I'm sure many of you will be familiar with, which is common as people get older, it's about 2% of older people will be affected with AF. It predisposes people to stroke and to heart failure, and this is a condition where the electrical signal is awry and you have an irregular heartbeat really that centers around the atria. Look at the risk here, it's over 10-fold increase in patients with RTH beta shown in blue again compared to control groups. So quite significant effect on the electrical signal aspect to the heart. And when we think about heart failure, we also looked at this and again found a very significantly increased risk for patients with RTH-beta, this time sixfold in excess of the control population. So heart failure and atrial fibrillation were major signals that we could see in our study that is likely to be contributing to the overall increased mortality and adverse health outcomes in this patient population. We heard about the ETA guidelines for rare thyroid hormonal disorders or disorders of thyroid hormone action earlier, including MCT8 deficiency. This guideline is also on RTH-beta that has emerged as part of that publication early this year. And to remind us of the importance of what we should be doing in terms of monitoring of patients with RTH-beta. That includes some clinical assessments. So looking at school performance, for example, in childhood, ENT appointments necessitating the hearing assessment, looking at behavior, looking at growth, clinical symptoms, some blood tests that include thyroid function, the lipids that I've mentioned, diabetes tests. Looking at the bone health. Sometimes an ultrasound scan to look for an enlargement of the thyroid or a goiter. The heart health has increased emphasis in those guidelines now based on our data, which have incidentally been replicated in a larger population in Italy but very, very similar findings to our own, emphasizing the importance of monitoring both from a rhythm and function perspective for cardiac function at least on a 1 to 2 yearly basis. And then selectively, ADHD testing, hearing tests and so on and cascade screening for first-degree relatives. Treatment options and unmet needs. So I've mentioned this resistant pathway. We have current treatments for conventional thyrotoxicosis or an overactive thyroid for example, with that patient that I showed at the start with Graves' disease. We can use 3 broad approaches really. We can use antithyroid drugs. We can think about surgery to remove the thyroid gland. We can knock out the thyroid gland with radioiodine therapy and each of these treatments are used fairly widely on a worldwide basis for those common or [indiscernible] thyrotoxic conditions, but they don't work in RTH-beta. And we were able to demonstrate that in the interest of time. I haven't got time to show you the data. But we found that patients who had historically been treated with those -- with RTH-beta, with those conditions with those treatments rather, their outcomes were not affected with respect to long-term health. So we've got unmet medical needs at present for the current treatment options because they don't address the fundamental underlying problem here, which is the resistant pathway itself and the imbalance that we're seeing in thyroid hormone exposure in all tissues. So how do we approach treatment in a current patient with RTH-beta? Well, we address the downstream consequences. If a patient has raised cholesterol, we think about cholesterol-lowering medication such as a statin. We use beta blockers in patients who've got tachycardia or perhaps atrial fibrillation just to try and slow the heart rate down, but beta blockers don't really prevent progression to a diagnosis of atrial fibrillation or prevent progression to heart failure. So it's symptomatic grounds more than anything else. We don't have good treatments for -- or any treatments really for the central nervous system consequences. We can try to optimize bone health with calcium and vitamin D and sometimes some other medication for bones -- sorry, I'll go back on. And we don't have very effective treatments for the problems with failure to thrive or the raised metabolic rate. So a clear unmet medical need with the current treatments that we have, which is where tiratricol is a drug of interest to us in the community because we've heard already that it has a potential benefit with respect to MCT8 deficiency in a rich clinical trial program data set there that gives us reassurance with respect to potential efficacy in that disorder and a safety signal. Tiratricol in vitro, so in cellular models and in animal model systems and indeed from case reports, but not previously studied in the clinical trial has been shown to bind to and activates mutant TR-beta receptors, which reduces what we call the dominant negative actions that can normalize TSH and normalize thyroid hormones, T4 and T3 in a vast majority of patients where this has been studied previously. We've got some experience through collaboration with colleagues at Cambridge through a managed access program of 8 adults with RTH-beta treated with tiratricol monotherapy that we've looked at recently with a mean age of 36 years and a duration of treatment that varied from 13 to 143 months. The mean treatment duration is around about 14 months. And here before therapy outcomes on the left-hand side is the T4 concentration. The T3 concentration is on the right and the nadir, so the lowest level reached. And I should emphasize this is not a clinical trial. It's a managed access program. So relatively unclean data, if you like, and the priority here was to demonstrate improvement in symptoms which I'll come to in just a second. So we weren't deliberately escalating the dose necessarily to normalize these drugs -- these T3 and T4 concentrations. But despite that, we can see that it was very effective in lowering T4 and T3 in all patients with 7 of the 8 studied getting normal T3 and other 1 almost achieving that. So very effective in normalizing the thyroid function, which is what we want to achieve from a pituitary thyroid perspective. What about the symptoms. The Cambridge team studied the hyperthyroid symptom score. And again, you can see individual patient data here with the dotted lines being what we would call a normal score. And the vast majority of patients again demonstrated a significant improvement in the hyperthyroid symptom score, averaging overall a significant reduction down by 8 points. We've also collected data on other aspects. So resting energy expenditure, we demonstrated at the muscle, if you remember earlier, was an alpha dominant tissue. So increased resting energy expenditure is a characteristic of this patient group. And the diamonds here compared to the circle is the baseline results and then the lowest level of T4 or T3 achieved is the circle, the time point for that, and we can see that the resting energy expenditure, again, approaches 0, which is where the age-adjusted sort of Z score should be. So patients again demonstrated benefit with respect to improvements in resting energy expenditure. So we count this as very good preliminary evidence that what we are seeing from a signal from in vitro and animal model studies is really playing out in clinical practice, and I think justifies the need for us to continue to investigate as a potential useful treatment from a research perspective. So what those future reset priorities look like? What should we be considering here. So we're in the middle of a collaborative study looking to develop an idea around clinical trial around this. And as part of that preparation, we undertook a patient webinar last year, we've recently or in the middle of the moment actually have a patient acceptability survey. The results of that will be out in January, but have a design in mind and want to ensure that, that is acceptable to the patients. The patient webinar feedback was uniformly positive. We have a health registry. We've heard about the SAIL Databank in Wales. Myself and a colleague from Cardiff have now got grant funding from the Clinical Endocrinology General Foundation in the U.K. to support, a much larger scale health registry study to not only replicate hopefully what we've demonstrated with respect to the cardiac and mortality outcomes in this group of patients, but to begin to explore the real-world health outcomes from all the other phenotypes that we would expect to emerge in this condition, for example, risk of diabetes or fractures or raised cholesterol and so on. Treatment, I think I hope I've demonstrated that understanding heart health and the actions of thyroid hormone at the tissue level are going to be critically important in understanding the effect of treatments in this disorder because we've got treatments that are ineffective, the ones that we've currently got available. So understanding whether a new treatment has a benefit with respect to heart action is going to be critically important, I think, in demonstrating efficacy. Very happy to have some questions. [Foreign Language] to use my own language of Welsh and thank you very much for listening.

Thank you very much, Aled. Pleasure having you here in an excellent overview and presentation of RTH-beta. We'll open the floor for questions. We have Alexander in the back.

It's Alexander from ABG. I have a question regarding the epidemiology of this disease, this indication. I mean -- and also since this disease is very heterogeneous. You presented some numbers 1 to 20,000, 1 to 40,000. I guess just like we did the diagnosis rate like how many patients actually get diagnosed properly with this disease also since the disease is very heterogeneous. So some patients or like such a proportion of patients. They were never or do not receive the correct diagnosis because conditioning is quite unknown or like underdiagnosed. Could you like maybe give some estimates here, like what are the diagnosis rates.

Yes, it's difficult to know diagnostics rates, but people have tried to look at population level. Again, we heard earlier about screening programs and stuff. So we didn't know exactly sort of at the population level. People are beginning to study that in a bit more detail. It is heterogeneous, and it's one of the curiosities to the condition that people either present in extremes with quite significant complications and others don't. But I think what our data challenges is this established dogma within the medical community, at least that if patients are relatively asymptomatic that we can just continue to monitor them because to my mind, to see those hazard ratios as we've demonstrated that risk of that magnitude. It's not going to be explained by 1 or 2 patients with quite significant biochemical effects you're going to need. Our best guess is this has increased the lifelong exposure to circulating thyroid hormone levels at the level of the heart. So we'll wait and see from any trial that develops in this area to understand whether it's all patients that we should be considering about treating or whether there are particular groups. We don't know the answer to that at the moment. But I think the heterogeneity that's out there in literature, I think is potentially partly a bias because we haven't got effective treatments, and we haven't gone looking in enough depth for any adverse downstream consequences. And I think the natural history studies are beginning to challenge that assumption.

And maybe like a follow-up question. Like in your -- in a country, let's say, in the U.K., like -- do you have like a number of confirmed -- like how many confirmed RTH-beta cases do you have in the U.K. roughly.

Over 300 to 400 genetically confirmed.

Thank you, Alexander. Any further questions, we have Fredrik there in the back.

Maybe this is a bit too early, but in a clinical program, what type of end points would you look at for this heterogeneous disease?

So I think because of where this is at, because it's just case reports, we're starting afresh, if you like. So I think the view would be that probably we would go initially with the primary outcome that's biochemical focus because we've got very good preliminary data that's likely to be beneficial, and we demonstrated that circulating thyroid hormones are an important target to normalize there. But I think we would include key secondary outcomes that would inform potential larger studies if there was one needed for Phase III, for example, recognizing that we -- that Egetis have got an orphan drug designation obviously for this. But those key secondary outcomes would likely be cardiac-focused. And we've got collaborators and colleagues who have helped inform us on that, but it would be both from what we call the inotropic and the chronotropic effect. So something that's a robust intermediate measure that predicts downstream outcomes. So that would include, for example, premature atrial contractions that we've heard earlier, there's a signal for that already in the MCT8 deficiency study, sinus tachycardia, heart rhythm monitors that can be attached noninvasively for up to 14 days. cardiac MRI, I think, is going to be very important because it's more reproducible than echo. It shows, and we can get some very good intermediate cardiac phenotype from such as left atrial size or left ventricular and diastolic/systolic volume. So I think it's going to be very much key secondary cardiac end points.

And maybe if we get this more broadly, but what are your expectations in terms of registrational program? Could it be similar to MCT8 deficiency? Or could it be a more extensive program or have you done any research.

I think that's a really good question. I think it's unfortunate. I have to say, it's premature to comment on. I think what we know, as Aled alluded to, we're contemplating an academic collaboration here with some investigators for an initiated -- investigator-initiated study. I think we'll start with that. And then in parallel, if that materializes, we work on a full-blown regulatory development, clinical and regulatory development program. So I think it's a bit premature to guide on that. Thank you very much. Thank you for the good questions, and thank you so much, Aled.

Thank you.

And that brings us to the end. I would like to thank you all for your attention. And then, of course, the highlight of today is the closing remarks of our esteemed Chairman of the Board.

Thank you. There's only 1 slide, so you don't have to worry. Well, no, there was 2 actually. No. So I just want to thank everyone for coming here today. And I think, and I hope you all concluded what's on the slide behind me here or on the wall over there. that we believe with Egetis that we have rather derisked biotech by now with the European CHMP positive opinion, which normally would lead to an approval in, I guess, it's the end of February or something like that in Europe. We have strong clinical data. We strongly believe the drug works. And we're working hard on getting this data also for a U.S. NDA, hopefully, soon. The CHMP opinion is, of course, so far, the biggest external step in our journey, but as you've seen here today, there's so much going on in the background that we don't do in press releases. And I also hope you can understand and have seen the quality of the people we have in the company and the quality of the work is being done in the background, which is so important once we get to the market. So also the life cycle management opportunity we saw here in the end, although as we understand it's early, but it's also patient with significant needs, and that's why we are here. So thank you all for coming here today, and we look forward to seeing you all again and keeping you informed on the progress with the company. Thanks.