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

Thank you. Good afternoon and good morning to everybody. I'm very pleased to see so many participants here in the room and a warm welcome to everybody joining online as well. For those who haven't had the privilege to meet before, my name is Nicklas Westerholm, and I am the CEO of the company, which will run through the Investor Day here at Redeye on the 19th of December. What we will cover today is an overview of our strategy and ambition that we have agreed with the Board. We're going to then segue into focus on MCT8 for the development of treatment for MCT8 deficiency, our lead asset, and the regulatory pathway as well as an update on the ReTRIACt study. We then have the privilege to have an external speaker in the key opinion leader, Professor Andy Bauer from the Children's Hospital of Philadelphia, who would join us to elaborate further on MCT8 deficiency as a disease and the unmet medical need. I'm also very pleased to have members of the management team here today joining us to elaborate further on some of the key activities we are actually doing in the prelaunch space. So we have Henrik Krook speaking about the global commercialization plans. We have Nigel Nicholls that will speak about the MCT8 deficiency from a patient perspective and the caregiver needs. And then we have Peter Verwaijen speaking about how do we drive disease awareness and improved understanding of the disease. And last but not least, Anny Bedard with activities on the U.S. launch preparations. We'll then have a break for a Q&A session. And then move on to another exciting opportunity as part of our strategy, building a sustainable rare disease company, such as the potential indication expansion into a different patient population, different disease setting called resistance to thyroid hormone beta. And then, we're also very pleased to invite an external speaker in Dr. Carla Moran from the University College of Dublin. And then we will conclude with some remarks at the end of the day. So starting off with the Egetis strategy. And I think it's important to take a step back here and tell that Egetis has only been in its existence for 3 years. The company came about from the merger of 2, where the privately held company Rare Thyroid Therapeutics and PledPharma public listed joined forces in the back end of 2020. With a clear focus on orphan drug development, late stage with the ability to commercialize in Europe and U.S. The strategy and ambition developed together with the Board is to build a sustainable orphan drug company by bringing unique therapies to patients with rare diseases that improve and extend lives. And there, we have taken strides and started to deliver on our long-term strategy and some of the goals as you can see here on the left-hand side of the slide. Key for us is, of course, to successfully develop MCT8 for European and U.S. approvals. Commercialize MCT8 and then through an in-house organization, which you will hear more about the buildup of the same. And then partnership in the rest of the world to ensure that we maximize the opportunity. And as you might have seen, we issued a press release a couple of weeks back with our first partnership in Japan, which I will elaborate further on. Furthermore, other aspects of it is, of course, to ensure fast and broad aspect as access to our drugs making sure that it benefits the patients worldwide, further identify opportunities to broaden our pipeline, both with indication expansion through Aladote, or through external assets being identified in the future. And by doing so, we truly believe that will increase the value for shareholders over a period of time. A quick lens at our pipeline then. The lead candidate MCT8 for the treatment of MCT8 deficiency is what we're going to focus on initially. We're then going to also touch briefly upon the resistance to thyroid hormone beta. But in order to deliver the strategy and to deliver both short-term and long-term objectives, it's very important to have a strong team around you to achieve these objectives. And here, I'm really pleased to say that over the period of time, the last 12 to 24 months, we have built an experienced team with proven track record in late-stage development, registration and commercialization of orphan drugs. We have also strengthened the team further over the last 2 months with the new Head of Regulatory Affairs, Desiree Luthman, being based in the U.S. with experience from companies like Verona Pharma and Celgene, amongst others, proven track record to take products to the market. And additional to the team is also a new General Counsel that joined us a couple of weeks back [indiscernible], who actually will be based in Belgium. [indiscernible] just recently joined us from AM Pharma, but previous experience from UCB and Abbott amongst others. And with me today here in the room and joining remotely is our Head of IR, Karl Hard; our Head of Commercial, Henrik Krook; our Chief Medical Officer, Kristina Sjöblom Nygren; as well as Anny Bedard joining us on the phone. On top of that then, it's a few words around the board. And here again, we must be saying that we have a very supportive and engaged Board, again, with the right experience catering to where we are in the journey of a biotech company. Among studies, our Chairman, Thomas Lonngren, who joined the Board a couple of years back has, of course, a previous tenure as the Head of the European Medicines Agency for 10 years, which, of course, caters very well to where we are in the journey for the company. We have Gunilla Osswald, CEO of BioArctic; and Elisabeth Svanberg, both of them seasoned drug developers that brings a lot of experience in that space. We have Mats Blom from a capital markets perspective, previous CFO of Zealand Pharma. Behshad Sheldon in the U.S. with experience on commercializing products in the U.S. market and can navigate that. And last but not least, Peder Walberg, 20 years of experience in the orphan space in many different roles amongst others, co-founder of Wilson Therapeutics together with [ Health Cap ]. And Peder has also been very instrumental in the journey of development of MCT8 for registration and approval. So let's turn our attention to the recently delivered in our opinion, transformative milestones. I will elaborate a bit on, during the next couple of minutes, on the submission to the European Medicines Agency on the 9th of October, which, as you can imagine, we are very excited about bringing the potentially fast therapy to market in this devastating condition. We have secured a long-term combined financing of SEK 462 million and also adding a top-tier U.S. investors as part of that. We have concluded a license agreement with the Japanese company, Fujimoto, for the development and commercialization of MCT8 in Japan. So let's start off with the EMA submission on the 9th of October. Again, an achievement we're very pleased with. The dossier was submitted on the 9th of October, and we got a confirmation of validation from the EMA on the October 27, which actually means that the dossier is viewed to be complete. And the clock is starting for the review time line. That means that one should expect the 120-day questions, so the first formal interaction with the European Medicines Agency in middle of February. The media review time lines just to calibrate a potential approval, of course, driven by all the interactions and clock stops for marketing approval applications in Europe is between 13 and 14 months today. And obviously, just to reiterate that the orphan drug designation that we have been granted in the past, will provide 10 years of exclusivity at the time of the European approval. Another item we're very pleased with is, of course, the long-term financing of SEK 462 million. which is unique in its sense. And I think it's important to reiterate this that it's a combined financing comprising of SEK 172 million in a private placement at a premium in the market, together with SEK 290 million in debt financing. And here, from our perspective, we are very pleased with attracting Frazier Life Sciences from the U.S. as our largest shareholder where they actually took SEK 155 million out of this private placement of a total of EUR 172 million and are as of now our largest shareholder in the company, very important from a strategic perspective and the long-term prospects of the business. On top of that, of course, they are adding a lot of sector expertise across the world. That aside, we also concluded a SEK 290 million debt financing obtained from BlackRock divided in 2 tranches, a tranche A of EUR 10 million and a Tranche B of EUR 50 million. And there, as you might have seen, we drew down the first tranche, Tranche A of the debt financing on the November 30. When it comes to Japan, and here, you will hear more about other opportunities in the rest of the world for distribution agreements and potential license agreements to make sure that we make MCT8 available as broad as possible. Here, we signed a license agreement on the 10th of November with the Japanese company, Fujimoto Pharmaceuticals. Fujimoto has a significant experience from registration and launching medicines both in the blood neurological and orphan disease space. And when it comes to the structure of the deal, one recognized a somewhat modest upfront development and regulatory milestone payment of a totaling of SEK 45 million. Having said that though, 2 important aspects to recognize is Fujimoto will, of course, finance the necessary development in Japan and be responsible for the regulatory interactions, and more important, Egetis will retain 1/3 of the value for future revenues, [indiscernible]. And I think that's a key message to take away. And here, the current plans are through the joint steering committee we have between the two companies focusing on finalizing a development plan for Japan and the subsequent engagement with the regulatory authorities, PMDA, in making sure that we have a sanctioned and agreed pathway forward to approval. So with that, we'll now take a look at the ongoing development program for MCT8 in the treatment of MCT8 deficiency. So the marketing authorization application submitted to the EMA consisted of clinical trial data from 3 studies. In the first one, Triac Trial I conducted in 46 patients, the effects of 12-month MCT8 treatment on T3 levels, and clinical endpoints related to peripheral thyrotoxicosis were established. The EMC cohort study confirming these treatment effects in a real-world setting in 67 patients with treatment up to 6 years. The third study included in the MAA was an extensive natural history study of an untreated MCT8 deficiency population, which enabled an indirect conversation to assess the clinical relevance of treatment effects seen with MCT8. For the U.S., in consultation with the FDA regarding an NDA submission, the FDA requested a small placebo-controlled withdrawal study to verify the effects seen on T3 in the single-arm studies, Triac Trial I and this EMC cohort study. This is what we refer to as the ReTRIACt trial. In addition to that, we have also successfully completed the recruitment of Triac Trial II, which is to establish effects on early intervention on neurocognitive development. So let's turn our attention to the design of the ReTRIACt study, which is displayed schematically in the picture 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 withdraw MCT8 treatment and instead receive placebo. The length of the running period varies, of course, by patient and is naturally expected to be longer in the treatment-naive patients. The special features in this study compared to typical clinical study is that patients are not randomized to receive treatment. They are randomized to withdraw treatment they are already on. When MCT8 is withdrawn, it's reasonable to assume and anticipate a reversal of the effects on T3 which could lead to clinical manifestations of thyrotoxicosis. This is challenging considering the vulnerability and the limited neurocognitive capability of the study patients and their limited ability to communicate this comfort, especially since many of them would be children. Therefore, the randomized treatment period includes a rescue criterion of T3 above the upper limit normal. The primary endpoint of the study is the proportion of patients who meet the rescue criteria once a patient completing the 30-day randomization treatment period whichever comes first, the other rescue criteria. And then the patient enters a 6 weeks follow-up period, where all patients are receiving MCT8 as a treatment. The design has been agreed with the FDA and the ReTRIACt trial will serve as the pivotal study in the forthcoming new drug application in the U.S. Based on the already established effects in Triac Trial I and the EMC cohort study, combined with what is known from patients who's been on drug holiday and the short half-life of the product our position is that the study has a high likelihood of being successful. This is a slide where I want to recap and illustrate the road map to site initiations for the study. Given the importance of the ReTRIACt trial, significant attention has been paid to facilitate a smooth and efficient execution of the trial. However, we are also very adamant that it's not been without challenges. After completing the first round of reviews by regulatory authorities and ethics committees, we received regulatory feedback that required us to update parts of the clinical study documentation, which led to the need for a second review to get renewed ethics committee approvals. This led to a delay in the start-up phase of the study, but eventually, the first participating site in the trial was initiated at the end of June 2023 and the first patient was enrolled in July 2023. During this process, we have also experienced somewhat longer-than-anticipated budget reviews and contracting with the sites and longer review time lines for IRB, which in hindsight may not come as a surprise given the vulnerability of the patient population we're studying. And the fact that the study is designed to withdraw treatment, what by many may be regarded as a functioning treatment of the disease. While this has been cumbersome and frustrating period for the team, I would very much like to tap the opportunity to thank the investigators, the patients, the parents, and the guardians for their commitment to participate in this trial, which is crucial for bringing the first possible treatment for MCT8 deficiency to patients in the U.S. Let's turn our attention then to the current status of the ReTRIACt trial. As of today, we have 7 patients being recruited out of a target of 16 evaluable patients. This has occurred at the 2 sites actively recruiting since July and August, respectively. One additional site very important, started recruitment mid-December and the fourth site is expected to start recruitment in January. This should lead to a faster recruitment time line going forward. During the delay of the site initiations, we have, in parallel, of course, worked with the participating sites to identify further patients. Currently, there are 27 eligible patients identified across the 4 participating sites for the remainder of the recruitment, consisting of 8 patients on treatment and 19 patients being treatment-naive. As previously communicated, there are several factors affecting the completion of the ReTRIACt study, such as initiation, recruitment capacity at the site, patients' ability and their families to travel, and the higher proportion of treatment drive patients in the study, which require longer run-in period. We have actively taken measures, of course, to mitigate these factors and we will be updating the market as soon as recruitment has been completed and at that point, inform about the timing, availability of top line results and the expected timing of the NDA filing. Taking a step back, to summarize the overall regulatory position of the project. We have several significant value-adding regulatory features. MCT8 has orphan drug designation in both Europe and U.S., which comes with market exclusivity, 10 years in Europe and 7 years in the U.S., respectively, at the time of approval. We have a fast track designation in the U.S., which lead to the eligibility for a Priority Review Voucher and the rolling submission. On top of that, we have a rare disease designation being granted in the U.S., which makes us eligible to apply for a Priority Review Voucher at the time of approval. And just a few words on the Priority Review Voucher and what that means. A Priority Review Voucher provides accelerated FDA review of a new drug application for another drug candidate in an indication chartering the time to market where the voucher could be valuable. This voucher may be sold or transferred to another sponsor and considering the situation for a small biotech company like us, it's a high likelihood that Egetis would sell this for the future long-term financing of the company. So a very, very important part of the longer prospects from a financial perspective for the company. So closing up, what else do we have out there? So the ambition to build that I have elaborated on a rare disease company on top of MCT8 for the treatment of MCT8 deficiency. We also see a number of other exciting opportunities ahead of us. We have a potential opportunity in indication expansion into a separate indication called resistance to thyroid hormone beta, you would hear, Dr. Carla Moran elaborate a bit further on the disease and the unmet medical need later today. The second opportunity is, of course, is the development of the Phase III study, Albatross for Aladote for the prevention of acute liver injury caused by paracetamol poisoning. And last but not least, the company is also continuously evaluating possible new assets with their orphan potential that will fit into the strategy of developing late-stage assets in the rare disease setting for market approval and commercialization. So on that note, I'm running a bit ahead of time, but I see Professor Bauer is online already. So without further ado, if that's okay, Andy, I will hand over to you to elaborate further on MCT8 deficiency and unmet medical need. Thank you.

So I'm Andrew Bauer. I'm a pediatric endocrinologist with the fortune, good fortune of being someone who's been afforded an opportunity to focus on thyroid disease. So today, I'm going to just briefly go over MCT8 deficiency, what the pathophysiology is, what the challenges are to diagnosis, and where we are clinically as far as opportunities to meet needs for families and caregivers with patients with MCT8 that for years, up until 2019, there really was no opportunity to offer any therapy. So we're going to start with what is MCT8 deficiency. So in 1944, this disorder was initially described by 2 physicians and their administrative assistant and a family of 24 males that span 6 generations. So as early as 1944 has identified that this is an excellent disorder that was associated with intellectual disability in males. In 1990, the effective gene was located to the X chromosome, and in 2003, the gene was identified to actually encode a transporter of T3, which I'll show you in a couple of slides, that allows thyroid hormone to get into the cells, which is then [indiscernible] actions in the nucleus. The following year, there was the association made between the gene, the transporter, and the clinical symptomatology. So thyroid hormone is critical for many regulatory processes and really important for neurocognitive development during the first trimester of pregnancy. The entire endocrine system is organized into feedback loops and the central commonality between endocrine disorders is the hypothalamus that releases or produces a releasing hormone, which communicates the pituitary, which then releases a stimulatory hormone which then acts on the end organ, which in this case is the thyroid. So the figure on the left shows the hypothalamus making thyroid releasing hormone, to pituitary then subsequently making thyroid stimulatory hormone and the thyroid products being T for thyroid and 4 for the number of iodines, so T4, which is the pro hormone and T3, which is the active hormone. On the right-hand portion of this slide, you can see that T4 of the pro hormone is actively converted in humans to the active form through a process called Deiodination, where an iodine is removed to convert T4 the pro hormone into the active T3 active hormone. The organs that are listed there have various needs and at various times of development as far as how thyroid hormone impacts normal physiology, normal growth in development in pediatric patients. In adult patients, thyroid hormone continues to be important, but not really for neurocognitive development or growth, physical growth, but for cardiovascular health, well-being, lipid metabolism. And so over our lifetime thyroid hormone is a critical endocrine hormone for normal physiology. So as I mentioned, thyroid hormone acts at the nucleus of the cell, and it binds to the thyroid receptors in the nucleus, which on the figure is highlighted in a red box. But for thyroid hormone to be able to get to the nucleus, it has to be transported, and there's 5 protein families involved with transport of thyroid hormone into cells, MCT8 is one of them. So MCT8 is critical for T3 to get across the blood brain barrier and also critical for hormone to get into the cells in our brain. There are certain parts of our body that are dependent on MCT8, and as I mentioned, the CNS, that is an MCT8 dependent organ. But there are other processes in our body, other organs in our body where thyroid hormone can get into the cell independent of MCT8, whether it's relying on one of the other 4 proteins, third-hormone transporters, but it's not relied on MCT8. And this is really the basis of what we see clinically for patients who have inactivating mutations in the MCT8 transporter. So as I'll show you in the next couple of slides, there's alterations in thyroid hormone and T3, which is the [indiscernible] hormone that's elevated, has varying effects because initially, they can't get into the brain during the critical terms of neuro development. But because the levels are elevated after a period of time, the high T3 levels then can cause peripheral hyperthyroidism because the rest of the body is not dependent on MCT8 for T3 to get into the cells. And so we get the terrible mix, clinical mix of central hypothyroidism, hypothyroidism to the brain because of the lack of the hormone during development. And we got peripheral hyperthyroidism where you have thyrotoxicosis, which is associated with elevated heart rate, increased metabolism with decreased ability to gain weight, decreased muscle mass and ultimately has negative effects, which I'll show you in some slides as far as life expectancy. So when a baby's born that has MCT8 deficiency, they otherwise appear to be a normal baby. So there's pregnancy oftentimes, there's nothing during the pregnancy that marks it as being abnormal or concerning. The [indiscernible] scores, when the baby is born, they seem to come out during delivery and don't have any acute issues in the delivery room. And our newborn screening processes right now, whether it's T4 dependent or if it's TSH dependent, are really not designed to pick up MCT8 deficiency during that newborn screening process. Babies that are born with MCT8 deficiency typically have a normal TSH and they can have a normal, although sometimes low, T4. It's over the next several months after delivery that the baby then develops clinical symptoms. And during that time frame, that's when the T3 starts to increase. So the parent report that initially the baby seem to be fine, some parents report even having some developmental milestones achieved, but then over 2 months, 3 months, up to 6 months and 9 months, the baby seems to not be able to continue to achieve developmental milestones and even start to develop some loss of milestones. Overall, after that newborn period, because there was no treatment previously, the life expectancy, as I mentioned earlier, was attenuated. And so in this study, looking at 151 patients with MCT8 deficiency over the time frame that you see there, the median overall survival was 35 years. 21% of patients died during the review process for this study and the median age of death was 10.5 years. From the pie chart that you see on the right and the highlighted docks in red, most patients that they die from MCT8-related pathophysiology is because they're malnourished, they don't have normal cardiac function, they're tachycardiac for many periods of time, they don't have the ability to fight infections, they don't have the ability to protect their airway and they ultimately typically die of hormone sepsis, aspiration pneumonian sepsis. And so that's what's the most common cause of early death associated with MCT8 deficiency. The very difficult part clinically and working with families with MCT8 deficiency is even during that time frame, it's not an easy life for the patient, and it's not easy life for the family or caregiver. The patients because they're not achieving milestones, really never developed activities of independency of independent living, they have terrible sleep patterns. They have inability to transfer to ambulate, and decreased ability to communicate, and certainly no real ability to communicate verbally and so it's a very, very difficult existence for patients with MCT8 deficiency in their caregivers. Because of the kind of the pattern for how MCT8 develops, and not just clinically but because of the labs as well, and the newborn screen now being designed to identify patients with MCT8 deficiency, there's an under diagnosis, a likely under diagnosis for this disorder. That's compounded by the fact that most patients, when they come in, are presenting to the healthcare system, most commonly to neurologists sometimes to gastroenterology and nutrition. But to a group of providers, that's less adapt and experienced in assessing thyroid hormone levels even for endocrinology because most patients that are ultimately diagnosed with hypothyroidism during this time frame, we're thinking about congenital hypothyroidism or any hypothyroidism, the most common labs are TSH and a T4. By exception, individual providers including endocrinologists do not order a T3. And as I said, T3 is the marker to help identify patients that may have MCT8 deficiency and elevated T3 level, not present in inborn period but develops over the first 3 to 6 months. And so we're not picking up on newborn screenings, the neurologists, the gastroenterologist nutrition, and even the endocrinologists are not oftentimes ordering a lab. So education of this disease is really one of our main missions. And so knowledge and awareness of MCT8 has been relatively poor, but I think there's also some reason to be excited that we're starting to be able to pick this up more often as there's more studies coming out really after the 2019 study [indiscernible] endocrinology that identified a potential therapy for patients with MCT8. And so it's under diagnosed, but there are an increasing number of patients being diagnosed and being diagnosed earlier. So this is from that 2019 study into showing you patients more before 2017 and you look at the distribution at the time of diagnosis. And then on the right-hand side of the slide, you can see that since 2017, around the time when they're starting to increase activity and what is MCT8, what can we do about it? Is there a potential therapy. There's more and more awareness for this disorder. There's also improved genetic testing for all disorders. And so for patients that have intellectual disability, oftentimes with a single gene analysis that was part of our initial clinical evaluation. But now because of multi-gene panels and whole exome sequencing, there's an increased number of patients also being identified because of improved genetic testing. The other thing, which is not surprising, it happens in all rare disorders is the initial group of patients that are identified are typically presenting with the extremes of the disease. And as we start to have an increased number of patients being tested. We start to realize, one, that there is a much broader spectrum than we otherwise thought. There are some patients even with MCT8 that are more mild. We have at least 1 or 2 patients that walks into clinic although the majority really have neurologic devastation and inability to maintain or perform daily activities. But there really is a breadth to this disorder and there really is not just clinically a variation of -- a broad variation of spectrum of clinical presentations, but there's also more genetic mutations that are being identified that have now an increasing list of pathogenic variants. And so the most common ones with severe disease, we've known about for a longer period of time but with more testing we're identifying clinical spectrum of disease as well as genetic variance associated with the broader spectrum of disease. And so in summary, MCT8 deficiency is secondary to this mutations and the transport that's critical for T3 to cross the blood brain barrier and enter into the CNS. It is identified, it's a gene on the X chromosome. So it's an X-linked genetic disorder. Although there are some female patients that have the clinical spectrum of disease. Babies are born at normally, normal pregnancies, normal delivery and our new born screens don't pick them up. It's usually in the first 6 months of life that they're picked up. And because of all these things, late diagnosis and ability to treat there really are multiple areas where there's opportunities to improve what we're doing. So there's a great unmet needs that we need to address. So what's currently available for treatment. Historically, there's been this block-and-replace approach to treating patients with MCT8 were [indiscernible], which is a [indiscernible] and it blocks production and release of T4 and T3, and then you can replace T4. So you can change the peripheral T3 levels by blocking endogenous production and then you can replace it by whatever the amount of T4 that you want to prescribe. The 2 problems with this current -- or this approach is, one, PTU since 2010 has an FDA black box warning because of associated necrotizing hepatitis that required a liver transplant. And so we don't use PTU clinically very often because of that. And it really doesn't [indiscernible] developing a molecule [indiscernible] that it allows any hope for T3 or to get into the brain or the thyroid hormone to get in the brain, where there may be some impact, not just on the peripheral effects but on the central effects from the disorder -- associated with the disorder. So tiratricol satisfies that. It does not use -- you don't need to use PTU for this drug. And it is a molecule that's been found to be able to cross into cells without -- an independent fashion from MCT8. So tiratricol is a [ bioactimetabulator ] thyroid hormone. We had very small concentrations of it in our body. It has a preserved [indiscernible] pattern, and it just alters which you can see by a difference in a [indiscernible] group. And so we can bypass the defective MCT8 and make it into the cells. There's a natural history study, there is a published data, the Triac Trial I, which was 2019, and then Erasmus Medical Center cohort study, which we'll just go over very briefly. And then as Nicklas highlighted, there's a Triac Trial II study, which we were involved in my center and many other centers. It's an international multicenter study which is now closed to recruitment with data analysis, continuing to be accrued, data continue to be accrued and analysis patenting and the recently launched ReTRIACt trial. So the 2019 study, the Triac Phase I trial really showed that this drug can be associated with a decrease in T3 levels. So baselines in red, and you can see the drop in T3 levels across the number of patients that it has access. And not only is there a drop in T3 levels, but there's a drop in alteration in other thyroid hormone levels. And you can see the mean changes there, which we won't go into the details, but the drug seems to impact the endogenous TSH, T3, T4 levels in a positive way of decreases peripheral circulating T3 levels. Clinically, it's also associated with a decrease in the signs and symptoms associated with peripheral hyperthyroidism. So there's a decreased immune heart rate, there's changes in -- favorable changes in blood pressure, and even in some thorough hormone-dependent proteins like sex hormone-binding protein, total cholesterol, creatine kinase. So there really is a significant clinical peripheral effect from the use of this drug that was shown in the Phase I trial. The Phase I trial also showed, of course, safety and tolerability. So there's no patients that required a dose reduction or discontinuation because of a drug-related toxicity and you can see in the box that many of the side effects or adverse events that were recorded, were hard to figure out if it was just the disease itself or just being a child because these are common signs and symptoms in childhood or really if they were related to the drug or a combination between the drug and the clinical viral illness or something else affecting the child. The Erasmus Medical Center cohort study then took that group of patients and recruited some others that were on tiratricol, the 67 total adult and pediatric patients just to see what would happen over the long term. They were treated for 6 years. And what that study showed is that there is a fast and sustained normalization of total serum T3 level. So again, read as baseline in blue is a decrease in T3 levels. And if you go from left to right, it's increasing amounts of time on tiratricol and maintenance of T3 levels without any associated increased risk for side effects or adverse reactions. And so that study showed that the concept that this is a well-tolerated long-term drug with the ability to maintain a peripheral impact from lowering T3 levels. But that leaves us with the final closing slides and what are the continuing needs and unmet needs. And some of these are just data analysis that need to occur to see where we are in this time frame. So from a provider perspective, prior to 2019, there really was no treatment that was available. So this is a devastated thyroid disease with the worst possible combination central hypothyroidism with peripheral hyperthyroidism and really nothing we could do. In fact, we're now started getting involved in the evaluation in care of patients with MCT8. We discovered some patients at our own center that had seen endocrinology and then disengaged from endocrinology because there's no treatment available. And then were continued to be followed by neurology, GI Nutrition, mostly for symptomatic care, and some patients saw cardiology for the tachycardia. But really it was only symptomatic care and endocrinology was not involved despite it being a thyroid disorder. So if we were to develop an ideal target of therapy, we would want to improve the neurocognitive deficits and we won't want to decrease the peripheral hyperthyroidism. The challenge for the neurocognitive deficits is that babies that are born, specialty index patient for the family -- and the first patient for the family won't be identified at the time of consumption during pregnancy and they won't be identified until later in that first year of life or later, there's a delay in diagnosis for many patients still in 2023. And so that window of opportunity during organogenesis during the first trimester is typically missed. And there's a low likelihood from whatever negative consequence that occurs during that time frame that we're going to be able to recover. We know this data from congenital hypothyroidism, which has similar impacts with a different pathophysiology. And so that would be ideal. If we got to identify babies early and treat early. But even if we can't do that, there still is a possibility because there's neuroplasticity up to about 3 years of age for babies that whatever deficits occurred, we can't fix, but maybe we could prevent the ongoing negative impact on the brain during that first 3 years of the like after the babies born and developing during that critical time frame. 75 years after [indiscernible] syndrome MCT8 deficiency, it's been 60 years after the first use of tiratricol clinical study and this drug had been used for thyroid associated mixed edema prior to the development synthetic levothyroxine, there is now a drug that can decrease the peripheral hyperthyroidism, and this is just some various figures from 2019 study. We looked at the T3 levels. There is the figure for decreased heart rate, decreased body -- and improved body weight. Again, red is baseline, arrows show a change in values in the direction that's favorable and negative, not out patients being value-weighted as you can see from that figure. That early study though identified a group of patients that may have improvements as far as our neuromuscular or neurocognitive function, and that seemed to be the youngest group of patients. So you can see here the age at the bottom on the X axis. So under 30 months of age, under 36 months of age during that critical time frame, there is a suggestion running on patients to determine maybe this can have a positive impact on neurocognitive neuro development outcome as well. From the parent's perspective, it's a little bit different. So when you talk to parents, as I said, this is a very difficult disorder to help manage, but when you talk to parents, they're, of course, just like us and anyone trying to improve care for any disease, but particularly for MCT8 at all of us want to find solutions for neurocognitive, but if you look at this study that was just published in 2023, which is a parent perspective, from a national registry, international registry, the things that bothered parents on a daily basis are feeding difficulties. It sometimes takes parents hours to feed the child if they don't have a G-tube and that's still a work in progress. We need to convince people that G-tube's may be a more effective way earlier on for improved nutrition and better outcome. They have very disturbed sleep patterns, where they are waking constantly at night, which is terrible quality of life for the patient and for the caregiver, the parent as well, limited mobility and as they get bigger, to more difficulties transferring from bed to wheelchair and wheelchair to anywhere else that into a car into a plane, anywhere that they're going, the mobility issues continue to be an issue. Some dystonic movements, some jerky movements that sometimes are difficult to figure out if their seizures or not and then they get undergo seizure evaluations. And so it's really the day-to-day challenge is that are the most disturbing for the patients in the short term outside of the bigger picture for development. And the good news is, I think, when you talk to patients and families, not to patients, to families and caregivers, is that they are seeing some changes because many of the signs and symptoms, we think are related to the high T3, and there is a positive impact on that as we went over and the parents are reporting that there's improved sleep patterns, weight gain seems to be improving besides decreasing heart rate. And so I think of the 2 unmet needs we are heading towards and we have data to show at least improvements in the day-to-day living with a patient with MCT8 deficiency. And more to follow as far as what the impact is from the Phase II trial. And so to close those things out, I think the summary is the checklist for clinical improvements using this drug we decreased circulating T3 levels that is associated with a decrease of peripheral hyperthyroidism signs and symptoms. There appears to be very low side effects. We need to more patients on it, obviously, to determine if that continues to hold true as the population of patients on this medication seem increases. And when I ask patients and family says, I ask them every time they come in, are you happy being on this treatment even it requires more blood draws, more visits to the hospital, parents brace a positive impact and a desire to stay on medication. And so that's an observation. There's no data. I don't have the graph to show you or power analysis. The parents seem to be satisfied with this drug, understanding, again, it's a vulnerable population, but they seem to think that there are improvements, not just what we should see biochemically, but also clinically. We don't have a lot of evidence to show that we can cure this disease, and that's one of the most important things we tell patients when they come in and we consent them if they're interested in this drug and actually most of the patients are approaching us if the drug is available, and the improvements or potential improvements on neuromotor, neurocognitive development for the Phase II trial patients treated under 30 months of age is pending. So I can't give you any information on that, but I am as excited as anyone else to see what those numbers ultimately show as we have more patients treated. So with that, I'll end, and I think we move on to the next part of the agenda, or I think next part of the agenda is we're happy to take questions if there are any. So thank you.

First of all, thank you very much, Dr. Bauer for your excellent presentation, and also taking time out from your incredibly busy calendar because I know you have clinic duty today. So thank you very much for taking time out to spend an hour or so with us. So with that, I'll actually start the first Q&A session, and we'll take questions from here in the room first. And Andy, the person asking question has a microphone. So I hope you'll hear it as well.

I'm here for ABG Sundal Collier. And I have a question about the ReTRIACt trial actually to Nicklas. So my question is about the speed of recruitment. You previously guided that for H1, '24. And now today, we have learned that you have 2 trial sites running since summer. Two trial sites are added now in December, January. Like how do you see the speed of recruitment developing into Q1 specifically? And where are these 27 eligible patients? Are they in the sites that are already fully active? Or do you -- are mostly in the sites that are actually just starting up?

Thank you, and a very good question, Alexander. I think the important aspect taking a step back is that we have learned a lot during the last 12 months. And as I mentioned during my introduction with focus on the ReTRIACt studies that there are several factors actually impacting the completion of the ReTRIACt study, such as site initiation, the recruitment capacity at site. Dr. Bauer also mentioned, the patient's family's ability to travel to the site and also the running period. So [indiscernible] down to normalized T3 levels will obviously take longer for treatment patients when they are enrolled compared to patients already on treatment. So there are a number of factors and uncertainties that actually will impact the completion. Obviously, now with 7 patients on board so far being enrolled in the study from 2 sites we see that having 4 sites on board from the third site from now middle of December and the fourth site from actually beginning of January will, of course, accelerate the recruitment rate. But due to the uncertainties I was just referring to, we would feel a lot more confident in actually giving guidance when top line will be available and subsequently when NDA can be expected when the recruitment is completed because there are so many swing factors. I think an important aspect also to recognize is that, of course, the site initiation piece is important because, again, we should take a step back and recognize that this is a study that requires 16 evaluable patients. It's not a lot right. So with having one site being delayed, for example, for a quarter in being able to recruit patients that will have also quite a substantial impact. So I think that's the background of why we decided to guide on when recruitment is completed, which we expect to, of course, grow faster going forward with 4 sites being available for recruitment, then we can also update at the point of completion of the recruitment when the top line will be available that will inform that, but also subsequently when the NDA is expected to be filed.

And a follow-up question here on the ReTRIACt. So you said that you had 27 eligible patients. And what will decide like which patients in this eligible patient pool actually will be recruited so to have this remaining 9 patients that you're missing to reach your 16 patients.

That's a really good question. Obviously, nothing that we, as a company decide, it's very much due to the physician, to the center. I think in principle, it's very important to recognize, and I think I mentioned that before that, for example, in Europe and in the U.S., there are guidelines that recommend that treatment-naive patients should have priority to enter a clinical trial versus patients already on treatment through single patient IND or named patient use as in Europe. But maybe I'll ask you, Andy, how do you view that treatment-naive patients versus patients already in treatment and how to enroll.

We've taken into consideration the treatment-naive patients first, but it's always the combination of where does the patient live and what's their ability to participate. So even if we start with that as our initial entry point, we end up having to negotiate trying to balance which patients are being the person who has the greatest ability to make appointments and to travel. The other challenge we face is, Nicklas knows is, these are -- even the design of the study is very nice for the families. They don't have to travel for every appointment. There's a lot of regulatory requirements and just the clinical research coordinator time is another factor that comes into how fast patients can be recruited.

Thank you, Andy. Thank you. We have another question here in the room?

Yes. A couple of questions to Dr. Bauer, if I may. I mean it's quite evident that this is a disease with a high medical need. As you said, there's not really any good treatment options. So on the back of that, would there be any patients that you would not recommend using tiratricol for.

Although I think I have more experience than I had 5 years ago, patients with MCT8, again; one, because I've been fortunate to be involved on the trials; but two, because there's increased awareness we started off with under 5 patients. And now we've been contacted by over 50 families. We're starting to see the spectrum. And most recently, I had a patient who walked into clinic, we could react to questions, who was playing maybe hadn't achieved complete normal developmental milestones based on age. But he's a patient that we wondered, would there be any benefit. And his peripheral hyperthyroidism because his lab still showed an elevated T3 were also mild, and so he was gaining weight, he had mild tachycardia. And so I think we don't know, but we've had a discussion. I talked to Dr. [indiscernible], talk to the family, like all of this is on the table. We don't know if there's going to be the same benefit. We don't know if there's going to be a benefit. And the one thing we don't want to do is obviously have a negative consequence for treatment. But that's the rare patient in my experience and the majority of our patients I would consider for treatment based on having more extremes of the disorder. So far I've had one, of the 50 patients that I'm aware of. So I think it's possible, in medicine anything is possible. But I think so far, it seems to be less common than more currently.

Okay. A quick follow-up. I guess, as you also said, patients seem to benefit more if treatment is initiated at an early age, would that have any influence over your treatment strategy?

We think, we hope. That's part of the data analysis that we need from the Phase II trial. And we don't see a negative consequence of treating early. But yes, I think that's part of it. We have a couple of patients that are treated in the 18s in early 20s. And the patients that seem to be, the patients that are younger, we seem so far, again, unofficially not research quality data, just observational data, we see greater improvement as far as improved -- adverse and side effects associated with the peripheral [indiscernible] and the families well-being and quality of life is just easier to care for their patients and some increases in neuromotor maybe neuro development on this, it's just to compete too early to know what that data shows. But earlier definitely seems to be better with no complete proof yet, but no clear evidence of negative consequence.

Okay. And then last one, if I may. I guess on the back of what you said that we're getting to know that there is a spectrum of severities in this disease. Do you see any risk that this could have influenced the outcomes in the clinical trials? Is there any risk that they may have recruited a population that was potentially easier to treat than the average patient in this disease.

I don't think because I haven't seen very many easy-to-treat MCT8 patients. Most of them are very clinically affected. So I think of the patients I've seen, and I can't speak for the other centers, it's as I said, the rare patients that we struggled to decide if it's worth trying the drug versus a patient that if the family is interested to understand the risks and benefits, which I think the potential benefits are higher than the risks which are quite low. We just don't know for certain what those benefits are that those patients. I don't think they're selection bias. I think we're treating the most severe because that's the more common presentation.

Considering we have time for one last question in the room.

What is it that MCT8 creates in the brain? Is it remyelination or are there other factors? There seems to be an improvement on motor function rather than cognitive function? What's your take on that?

I don't think we've seen evidence for changes or improvements in myelination. And I don't know. And I think one of the things we wonder is the synaptic connectivity. When is that established? Is there any impact on that? And I think those are going to be more in vitro studies, animal studies to help us figure that out. And there is ongoing research into that area. So I think on the clinical side, we see the improvements, and we do wonder how much is medicine, how much is progress in development and how much effort is being put into increase in physical therapy, acute patient therapy. So there's a lot of unanswered questions in the CNS that I think for now, it's still pending. It's still a question mark with mouse models and in vitro studies to help hopefully figure that out over time. But I don't think it's as simple as changes in myelination as a [indiscernible], I'll put that caveat in.

Thank you very much, Andy. Great pleasure to have you joining us today, and we'll speak soon. Thank you very much.

Take care. Happy holidays everyone.

Happy holidays, Andy. So on that note, we will switch gear a bit and focus more on the global commercialization plans within the company, but also a very nice segue into disease awareness, as Dr. Bauer referred to, how do we building the knowledge and also further understand the patient journey and the situation they're facing. So I hand over to Henrik.

Happy to be here today. So I'm Henrik, and I'm responsible for commercial operations at Egetis. I've been with the company since the start 3 years ago. Before that, I've been roughly 20 years in the pharma and biotech sector, most of the time at international companies such as Roche, Novartis, Alexion and they have been involved in preparing and executing several launches in pharmaceuticals and also including several outdoor events. And today, I'm here to give you an update on where we are with the global commercialization preparations related to Emcitate. So I will start by saying a few words about the unique setting for Emcitate in MCT8 deficiency that actually makes it possible to execute this launch with a relatively small team. So first of all, I think it was very clear for everyone based on Andy Bauer's presentation about high unmet medical need in this disease. And even though it's ultra rare, there are actually a couple of thousand patients in U.S. and Europe, respectively. And of course, it would be fantastic to provide a treatment to these patients. There are no treatment available as of today and Egetis is actually also the only company having an active clinical development program in MCT8 deficiency. We are working with medical experts in our clinical development program. And the care of these patients is concentrated to selected specialist centers in each country. So the care is overall as also in other ultra diseases centralized. There is a global community, both the medical experts and patient advocacy groups. So as you see, this is actually quite different compared to the more average pharmaceutical drug, where a company when launching needs to invest heavily because of that there are other competitors available and that care is more scattered. But in this unique setting, we will be able to have quite a lot impact by our global team. So we will not have to establish large commercial organizations in every single country. Instead, we will work through the global team and then complement with smaller efficient teams in some of the larger European countries and, of course, also in U.S. So actually, at the time of launch, we will be 40 to 50 employees across U.S. and Europe. And by maintaining the U.S. and European market ourselves, we will also be able to retain most of the value related to Emcitate. And for the rest of the world, we will make sure that we will provide broad access to treatment through working with partner companies. And Nicklas earlier mentioned the deal that we did with Fujimoto license deal for development and commercialization in Japan. That is an excellent kind of deal for Japan because there it's relatively thorough regulatory processes. In some other markets, there are different opportunities where we, for example, can make more of distribution partnerships and an example is the Middle East region where it's actually is possible to sell Emcitate and other drugs based on FDA and EMA approvals. So there, we can do this kind of distribution agreements and then also maintain a larger proportion of the sales in those markets. And by this partnership strategy for the rest of the world, we will also be able to focus even more with our resources on the important launches in U.S. and Europe to really make sure that we do those in the best possible way. And we have started the stepwise establishment of our commercial organization. And I'm actually really pleased with the team that we have recruited to Egetis. It's a team of people with a long experience of executing launches in the orphan space. And the people are also highly capable. So they have this great mix of a good strategic thinking, but also very much enjoying to execute on the plans and get the work done, which is great. So I think we generate a lot of good output from this team. In parallel with our launch preparations, I'm also very happy that we already today ahead of regulatory approval can provide Emcitate through our managed access program actually now to over 190 patients in the world. And this continuous expansion on this program really confirms that there is a high unmet medical need in MCT8 deficiency. And at the time of regulatory approval and reimbursement, then these patients will be transferred to commercial drug. So for example, in U.S., we will be able to then have sales already the first month after regulatory approval. Our vision in our launch preparations are really to ensure that everyone who can benefit from treatment gets access to reimbursed Emcitate as soon as possible after regulatory approval. And to make that possible, we are very focused on ensuring fast and accurate diagnosis of the affected patients and also to ensure payer support for reimbursed price at an optimal level. And to make that happen, we are focused on some key initiatives, for example, understanding and addressing the needs in MCT8 deficiency. And Nigel will soon talk a little bit more about the work that we are doing, that they are also together with patient advocacy groups. Then we are working on disease awareness and diagnosis initiatives, and Peter will soon address that from a global perspective and then Anny will talk more about the activities that we are doing in U.S. in this area. And to ensure the payer support for reimbursement at an optimal price, of course, we will demonstrate and communicate the Emcitate value. And I will say a few more words about that in the next slide. So here is -- or a few words about the landscape that Emcitate will be in. So as you know, payers in general do accept higher prices for orphan drugs compared to more traditional drugs and especially if they address an ultra-rare disease, which is very severe. And Emcitate fulfills these criteria and will be very unique because there are no other treatment alternatives in MCT8 deficiency. So we will develop a compelling clinical and economic value proposition to secure reimbursement and access. And in this work, we are describing the unmet medical need and also how we are addressing that with the MCT8 clinical development program. On top of that, we are generating data so that payers more easily will understand the burden of the disease from a patient, caregiver and healthcare perspective. So in the Vignette study, physicians are quantifying the impact of the disease on the patient's quality of life. The caregiver study is focused on cost and quality of life for caregivers, which in most situations are the parents. And then in the third study, we are describing the healthcare resource use for the management of these patients. And when being successful in this payer-related work, it's actually possible to generate quite swift sales uptake in the ultra-orphan setting. And to the left here, you see some ultra-orphan analogs and their sales the first year after regulatory approval. And some of the factors that are contributing to a swift sales uptake for ultra orphans is, first of all, I mean, the unmet medical need, the nonexistence of treatments and at the time of regulatory approval, then, of course, the use of a registered drug picks up. And it's also actually the situation from -- in many orphan setting that at the time of -- when there is a drug approved, then also physicians see a higher incentive to actually diagnose more patients because then they have a tool in the toolbox for these patients. So we normally also see then that the diagnosis rates increase. And then to compensate for the more limited number of patients, payers do reimburse at higher price levels for ultra orphans. And at the time of regulatory approval and reimbursement, patients are shifted from managed access programs to commercial drug. So I think we are in a very good position with Emcitate, and we will, for sure, continue with preparations to make sure that this will become an excellent launch. And we really aim to make sure that as many patients as possible will get access to reimburse to Emcitate as soon as possible after regulatory approval. And with that, I would like to hand over to Nigel, who will talk a little bit more will talk a little bit more about what we are doing together with patient advocacy groups.

Thank you very much, indeed, Henrik, and great to be able to share this space with you. I think many of us sometimes ask the question why are we here? And one of the focuses that I've had, of course, is having a journey through many rare disease companies, mainly because of my own experience. And so I want to introduce pictures, they say tell 1,000 words. But my son was born 27 years ago with a very rare condition. And as a result of that, I dedicated myself to working with rare disease companies because of that experience with him. And of course, that journey has been a long when I started with Orphan Europe but then went to one of my most significant 10 years as a GM of BioMarin, working with CLN2 Batten's disease, one of the analogs that many of you know about. So that experience is one that I want to and have transferred back into Egetis. And it's that focus really on and a commitment to these patients that many leave on the side is one of the reasons why I'm here at Egetis. The other reason actually is a significant one, and I love the picture of my son with the heart because it actually speaks to the fact that many of these children, in this case, these young men, actually don't need our pity, what they need is our support and are walking alongside them. And so I just love that picture. And of course, I have the profound privilege actually in my role now of the global Director of Advocacy to go out and meet these patients. And so I was really delighted when I got an invitation to go and meet Joshua and his mom, Katie, and really to speak to them and actually see how much life he is living. Great, of course, to hear that he's benefiting from the drug, great to hear that he's putting on weight, great to hear that he's enjoying music and really trying to live the best life he can. And so that's incredibly fulfilling, incredibly privileged position to be able to meet with Joshua. So rather than me talking, I thought it would be great for you to hear just a little bit about Joshua's pathway to diagnosis and his journey. So at this stage, we'll just listen to a video for 3 minutes as you hear his story. [Presentation]

That -- all of us recognizes a profoundly moving, but also insightful film and movie about the condition. And one of the, I think, insights from that is the fact that the diagnosis takes so long. And one of the things that we are proud of as a company is that we have focused on trying to bring down that diagnostic delay. In Joshua's case, it took over 12 months for him to be properly diagnosed. So the question really comes to me and to all of us, what is Egetis doing in this space? Well, we're doing a number of things. And some significant things have happened this year alone, the gene for the condition has been included on a number of national panels. So you'll see at the bottom of the screen there, the generation study by Genomics England, we are now -- we've now got that gene in that panel. So babies as they're born, the gene will be picked up earlier. And we are seeing more and more of these genes be included on these panels as a result of more awareness from both us and from the parents. We're doing other really important things like the caregiver study. So you'll watch the film. But sometimes, many payers don't have the opportunity to get as close as you will to Joshua. And so understanding the burden of the disease is critical to beginning to understand how society might want to pay, how we might want to make sure that proper recognition of the value of treatment is given. One of the other things we're trying to do, of course, is through our patient journey studies is look at the hurdles that these patients and their caregivers have in the hospital, at home and other places and just map that so that when the treatment is available, we can minimize those treatment delays and blocks. And of course, another really, I think, a significant thing that we've done is the feeding tube study. So making sure that we can understand how this treatment can be given long term, the best way because this is a lifelong treatment. So some really, I think, significant things that we're doing as a company as we begin to build out. Of course, we also recognize that we are a relatively small company. We think we're doing great things as we're small, but we are small. But what we're doing is beginning to partner with other advocacy groups -- patient advocacy groups to make sure that the awareness of this condition is heightened and made more widely known. And so we're proud, for instance, of our engagement with the patient groups as we designed the study to make sure that things like home nursing was integral to that study. And you'll see a list of -- I really think are opportunities for us to work with patient groups, things like life cycle management. So not many patients or their caregivers sometimes understand the issues about access, the time it takes deeper pricing. And sometimes, they may ask us difficult questions. Well, part of our role is to help them understand that part of drug development. Of course, payers don't just want to hear from us. They want to hear directly as you can see from the patients as to the value that this technology might make to people's lives. And so caregivers understanding how to speak and being able to speak to payers is a critically important component. Patients and their caregivers, of course, are experts themselves. And so giving them a platform, making sure that the pamphlets and the videos that they appear in are widely distributed is also really important because they can tell just the -- their own story in a very compelling way, if it's made widely available. And then, of course -- and lastly, making sure that they know how to meet with and engage with political stakeholders. So one of the joys that I had actually was working very closely with the Batten's Disease Association and going hand-in-hand with them, not quite hand-in-hand, but going with to Parliament going to the European Union to actually show to political stakeholders that actually pharmaceutical companies and patients can work hand-in-hand for the same name which is about access and awareness of the disease. So this is something really important, I think, that we need to do. So we're doing as we grow, we are, I think, building a larger and more impactful patient voice. And what we've done in the last year or so is identified 3 categories of different patient groups that we can engage with. They're the MCT8 disease-focused groups, they have the thyroid groups and the more broadly rare disease groups. And all of these have a role to play in building awareness. And I just wanted to give you one example. I -- the TFI, the Thyroid Federation International is an international global patient group interested in thyroid disorders. They have 35 affiliated groups to them. And before, they haven't really focused on MCT8 deficiency. But as a result of us engaging with them this October for Awareness Day, they put out a post to not only to their members, but also to their affiliated members. So we're working, we're making sure we're partnering. We're working to broaden that voice and that awareness. So in closing, I wanted to give you a picture really of a company, I think that is committed to making sure that we bring this therapy to market that we engage actively with patients. We listen to them, that we understand it from their point of view and that we give them the platform to advocate and speak for its reimbursement and awareness. Thank you very much indeed. Thank you. At this stage, I'm going to hand over again to my colleague, Peter, who's going to talk a little bit about the market campaigning and awareness in further detail. Thank you, Peter.

Thanks, Nigel. Good afternoon, everybody, and good morning, everybody online. My name is Peter Verwaijen. I'm the Global Head of Marketing as well as the General Manager for Iberia and Benelux. I'm from the Netherlands, hence the funny accent and I've a track record only exclusively in rare diseases, working for companies as Actelion [indiscernible] before it was acquired by Roche and last but not least, Santhera. The objective of my talk is to tell you a little bit about the model that we're applying to raise disease awareness. We heard Dr. Bauer talk about the importance of raising disease awareness. We've heard about the delay, the diagnostic delay between first symptoms and these patients being diagnosed. So really, the need to make sure that this disease is more well known. I will talk a little bit about how we took insights from patients and other stakeholders into developing a campaign that is highly emotive as well as to the point and easy to remember in an ultra-rare disease. I'll talk a little bit about maximizing the touch points we have with the different stakeholders. And then finally, I spend some time on talking about patient-finding initiatives. So first of all, I would like to focus on the patient-centric engagement model. And I know that patient centricity is a buzzword but I've never seen it live so much as within again this. And it goes from home visits during the ReTRIACt trial to the patient-centric videos we made with Joshua but also took including 190 patients in a Managed Access Program. It really shows how much we are committed to these patients. And I think if you look at the left-hand side of the slide, we are also really engaging with them to learn from them, what are the problems in the patient journey. When did you first encounter symptoms? What did you do next? What are the bottlenecks that we can identify and that we can act up as a company to improve the care for these, mostly boys. I think we've done market research. Nigel already briefly alluded on the patient journey research we conducted to really talk to doctors as well as caregivers about birth first symptoms to diagnosis and beyond. Again, to really learn where we can improve. Patient and advocacy engagement is something that Nigel talked about. We interviewed a lot of patients as well as caregivers, but also doctors like Dr. Bauer to really understand this disease to the maximum. And then I think where we also have a lot of engagement is at the international congresses and that led to the development of materials that we've developed on the right-hand side that are really aiming to make sure that patients that go online or caregivers that go online or physicians that go online to try and find information about disease can find the information, but also they did know the disease explained in a simple, but easy to understand way. We have a social media campaign linked to it to drive awareness to our website and also to make sure that we increase awareness as much as possible. I think the final point on this slide is the Medscape eCME. I don't know if you're aware, but Medscape is the market leader if it comes to medical education. Doctors need to collect points in order to keep their license and Medscape is the party that we've selected to work on, on a disease awareness program for 2024 about MCT8 deficiency. If we then look at the campaign that we've developed, and this is mainly focusing on healthcare professionals. It is about making sure that we shorten the time from first symptoms to the diagnosis. But how do you do that? There are 7,000 rare diseases out there. Does it make sense to focus on just one disease. We don't believe so. And I think the way we've eloquently, I must say, done it is not focused on the one disease, but make sure that doctors recognize the phenotype when they walk at a congress, see the booth, they will recognize this patient. Patient doesn't have specific symptoms for MCT8 deficiency, but the doctor will also recognize T3. And like Dr. Bauer said, this is really a problem and a challenge we're facing. T3 is not normally included in the thyroid function test. TSH, T4 are done. We are trying to make sure that if this phenotype is recognized, automatically, T3 is included in the testing. And we mentioned MCT8 deficiency. We mentioned it at the end. It's not the incentive. We don't want doctors to first think about MCT8 deficiency and then realize, oh, I need to include T3. No. You see this phenotype. It can be a mix of diseases. Make sure you include T3 in the test that you would do anyway. This is a busy slide, and please don't get stuck in the details. I will try to summarize the most important part, but if we talk about the patient journey and looking in close detail to the patient journey also as Dr. Bauer described, it informed us where to focus. And it's really pediatric neurologist, pediatric endocrinologist and metabolic physicians followed by the geneticist. Why? On the top left-hand side, you see the newborn segments. These are the patients that are not symptomatic yet. Dr. Bauer explained the difficulties with newborn screening. T3 is naturally high, including T3 in newborn screening doesn't make sense. However, there are many follow-up protocols out there. These patients are being tested for hypothyroidism. And if TSH, T4 come back abnormal, there's a follow-up protocol. T3 can easily be included in those protocols. And that's really an opportunity to identify and diagnose patients. The other thing that Nigel already alluded to is newborn sequencing programs. So a lot of programs in different European but also U.S. countries, focused on including newborn sequencing into the -- our new pilots related to newborn sequencing, focusing on newborn screening through genetic screening. And by making sure that the SLC16A2 gene is included in those programs, we also hope to find many patients. And again, it was a simple phone call to Genomics England that ultimately led to the inclusion of the gene into the pilot. And we are aware in conversation with other parties in Europe and the U.S. to make sure that the gene is included in those pilots. Then if we know what we want to communicate, to who we want to communicate, how do you know where they are. And I think this is where the International Congress has really come into play. So on the left-hand side, you see a compilation of the 23 International Congresses, Egetis has attended to in 2023. And I think I'm proud to share that overall, we became aware of 135 patients during conversations at these congresses. Now not all of them are treatment naive. Some of them are already on treatment. Others, we already knew through other programs. But I think it shows that if you go to a congress, you don't -- in a rare disease like this where you usually have to find your patients. In this case, actually, the doctors with the patients came to us. So a great opportunity. On the right-hand side, you see the materials we're using at the congresses. And really, the message here is that we're developing materials for all kinds of customers. There are the scammers, the ones walking by, they really need to understand phenotype T3 testing, that's all they need to know. But there are also peddlers, deep divers, the ones that come to the booth and really want to understand more about the disease. And you can see that we've got a lot of detail for them as well. Then something less focused on the healthcare professionals, but more on the general public. Also, parents that have a child that becomes hypertonic, unable to hold his head up, they will try to find answers on the Internet. Dr. Google is everywhere. So what we're trying to do here is, one, make sure that we have a central hub that patients, caregivers and healthcare professionals can land on. This slide is mainly focused on the patient advocacy groups that Nigel was already mentioning, the ones that are focusing either on rare disease. So on February 29, we will have a rare disease day this year in May, on the 25th, there is thyroid day. And then on the 8th of October is the MCT8 deficiency day. And making use of the networks that those patient advocacy groups have access to, collaborating with them and developing assets for those days. We're really trying to reach out to the maximum audience. And I think the key there is to create emotive videos like the one with Joshua, but also stuff that is really highly shareable to reach out to as many of the general public as possible. Again, a busy slide and not intend to understand all the details. But what I want to try to show you here is that we've got one central hub in our disease awareness campaign, which is called mct8deficiency.com. And we've got sections on it for healthcare professionals as well as for the general public. It's completely SEO, SEA optimized. So even people that go to ChatGPT to understand about the symptoms or the disease can find the information here. And it's really about activating them and making sure that they will go to their doctor to specifically ask for T3. In case of an increased T3, ask for a genetic information and know where they need to be referred to next. On the right-hand side, you will see a couple of traffic drivers that are nonpersonal. On the left-hand side, you will see the interactions we have with the different stakeholders in a face-to-face manner. Finally, a couple of comments on patient finding initiatives, and we already spoke briefly about making sure that we've got our gene, the SLC16A2 gene available on the different pilots that are available in countries if it comes to newborn sequencing, it's really focusing on making sure that T3 is included after the first newborn screening has taken place and the T3 -- sorry, the TSH or T4 values come back abnormal, and that is really to identify the newborn segment. And remember, these are patients that are asymptomatic, but the ones that we want to catch as early as possible, as Dr. Bauer alluded to. So I think we're in a very good place to identify those patients. Then if you look at the other segments, it is a first segment where parents and doctors are really keen to get the diagnosis right. This is where the campaign comes into place. And then if you look at the older segments, it's really about doing the key pilots in populations that have a higher likelihood of having misdiagnosed or uncovered MCT8 patients. For instance, cerebral palsy is something that comes back in the patient journey, study a lot as one of the misdiagnosis of these patients. So making sure that we engage with cerebral palsy patient advocacy group to know where the patients are to do a simple T3 test with them. And then in case of an elevated T3 value, we can follow up with the genetic confirmation. It's really an elegant way to identify patients also in the other patient segments. Anny -- in the next presentation, we'll talk a little bit about the gene initiatives that are going on in the U.S. as well because in the U.S., they're sitting on a wealth of data with commercial gene companies. Finally, a brief summary, just to demonstrate that I believe that we're in a very good place as Nigel and others already said. I think that the disease awareness initiatives are paying off, doctors coming to our booth at the International Congress is coming to tell about their patients, the number of patients we have identified, the close collaboration with the PAGs as well as with the doctors out there to develop materials that really address the needs that are there in this disease and the huge outreach that we've reached last year or this year. And then I think the pilots that are in place to increase the diagnosis rate. With that, I would like to hand over to the President of North America, Anny who was zooming on the commercial activities in the U.S. Thank you.

Good afternoon, good evening, everyone. Can you hear me, just checking. Great. Thank you. Thank you so much for the opportunity and for the interest in Egetis and all the work that we've been doing. I'm Anny Bedard. I'm the President of North America. I joined the company a year ago. And my background is in the rare disease space, where I've been for over 30 years. And I've had the opportunity to work at companies like Shire and Sarepta to bring their rare disease to market. I'm also based in Boston in Massachusetts in the U.S. So today, I wanted to give you a brief overview of the work that we've done in the U.S. in order to prepare for the commercialization of Emcitate. And as you heard from my colleagues, increasing disease awareness and education, finding patients, understanding the patient journey and optimizing our pricing and access strategy are really important for the success of Emcitate and that's the same situation here in the U.S. In addition, of course, as we get closer to the launch, build a high-performing team, which is also very focused on patient-centric approach to bringing these drugs to market. So this is what we have been focusing on until now. And this will also be the areas that we will be focusing more and more until we approach the launch of our products. Next slide. Thank you. So in 2023, an important part of our resources was dedicated to amplifying the disease awareness and improving diagnosis. In addition to leveraging all of the activities that were also presented by my global colleagues, we've also been present at different conferences in the U.S. And I'd like to just mention 2 of them which are the Child Neurology Society Meeting and the Pediatric Endocrinology Meeting, which are 2 specialties that are the most likely to identify the patients with MCT8 deficiency. And at talking with multiple physicians at those conferences, it was really clear that physicians are not familiar with MCT8 deficiency. Some had MCT8 deficiency patients, but were not aware of our development program. And also T3, as mentioned by Peter and other colleagues was not a measurement that was part of the standard test that they do for the thyroid function. So it really highlights once again that the disease awareness is really a big need and education, and that this is also critical for our success. And also, what's really interesting to highlight that the elevated T3 testing that Peter talked about was really an effective way and an important message that resonated with the physicians. We've also held different advisory board meetings, including some that were with physicians who already have patients on therapy. And by having these types of conversation, we gain a lot of valuable insights into how these patients are going through their journey, the challenges that they go through. And this provides us really valuable insights in order to then develop the right approach and focus in the areas where we can make the most impact in order to accelerate the diagnostic journey for these patients. Another area where we were really excited with the output is in the partnering with the genetic testing laboratories. In the U.S., there is multiple commercial genetic testing laboratories and pharmaceutical company can partner with these laboratories in order to acquire some data that has, of course, been de-identified and where patients have provided their content. So we can do a lot -- we can perform a lot of analysis on these data and identify patients who have already been confirmed with diagnose of MCT8 deficiency and then get some really helpful information in order for us to go and talk to the physicians who are taking care of these patients and then, of course, learn about these patients and share more information with those physicians. And for us, this has been a really helpful tool in order to be really effective in immediately targeting the physicians who are the right ones specifically with the resources that we have at this time in the launch. So all in all, the -- some of the activities that we've been conducting have allowed us to identify more than 50 patients that we did not know of prior to starting all of these initiatives. So this is, of course, a great foundation for our capacity to continue to identify patients in the future. And in 2024, we will continue to focus on disease awareness, patient identification and also we will invest in expanding our medical affairs team so that we can engage with a broader audience of physicians. Next slide. So we've talked about -- or Henrik has talked a bit about our Managed Access Program and many patients that were already able to receive access. This is also a really important step in preparing for the commercialization in the U.S. and back in October 2022, to the request of the FDA, Egetis has submitted a protocol for an Expanded Access Program for MCT8 deficiency patients. In the U.S., just so -- which is a little bit different than in Europe, an Expanded Access Program requires a protocol that is approved by the FDA and then each site are required to have this protocol approved by the IRB. However, once the site is onboarded and the IRB is approved, physicians can then include our enrolled patients into the Expanded Access Program with limited efforts. So we're making with this EAP program that we've implemented, we are making it much easier for physicians who wish to put their patients on therapy to do so. Prior to that, patients -- prior to our EAP patients could get access to therapy, but physicians had to do a lot of paperwork, regulatory administrative work for each patient in order to get them to therapy. So now again, we're making the process really simpler, and this will allow us to collect also some important data, real-world data in order to support some of our communications with the payers and the regulatory -- regulators moving forward, but also will help us gain a lot of insights so that we can then facilitate the transition of these patients to commercial drug once it is available. Today, we're working with 10 centers. We -- this morning, we added one center to the list that we're working with, and we're looking forward to increase the number of centers across the U.S. so that we can serve as many patients as possible and for them to have limited distance to travel in order to get access to therapy. Next slide. Thank you. So in the -- we've talked a bit about the pricing in -- before and in the U.S., the rarity of the disease, the severity of the disease and also the absence of treatment option allow us to achieve considerable pricing level. And as we've shared in the past, we've also -- our pricing strategy in the U.S. is really informed by different analogs that Henrik has showed in his presentation. And from these analogs, we get a lot of insights on what is acceptable in terms of pricing. And we've also informed our strategy and continue to do so by getting a lot of input from payers and also performing different types of behavior-based analysis. During the year 2023, we've also engaged with a lot of payers to continue to confirm and verify our pricing strategy and also to further expand our understanding of the payer mix. We expect in the U.S. that the payment for MCT8 will come mostly from insurance -- from government insurance, which is Medicare and Medicaid. In terms of the distribution channel, we're also considering a distribution channel that will help us also work in the most effective way through government payers where we still believe that a special -- exclusive distribution network through a specialty pharmacy will allow us to provide the best service to physicians, patients and caregiver, but will also provide us with important expertise in negotiating with the insurers providing a personalized service to our customers and helping -- providing services in order to help the patients through the access program -- along the progress of the access. And also, it will provide us with opportunities to better manage the net price of our product. So in 2024, so we'll continue to work on refining the price. Finally, in terms of course, to execute on all this work, we need to build a high-performing team. We've established the U.S. headquarters in Boston, where I am located. As most of you might know, Boston is a really important hub for biotech and in this location, there is a large pool of talent, particularly in the rare disease space that we will be able to tap into as we build the organization, collaborating with our colleagues in global and leveraging the work that's been done there is really important so that we continue to be as efficient as possible as we grow the organization. We'll continue to invest as well in external resources in order to get the expertise that we need when we are not ready or it's not needed to build internally. One of the examples of that is working with our novel or specialty pharmacy to implement our Expanded Access Program. And also, as we move forward into 2024, we will continue to invest in building our team particularly our medical affairs in order to continue to drive the disease awareness that we've been talking about, and we'll start building further our market access team in order to refine our value proposition and start with the implementation process. So we believe that with a team of 20 to 25 people in the U.S., we can successfully deliver on the commercial opportunity for Emcitate. So going to the next slide, I just wanted to recap the section from the U.S. and also from the commercial presentation. Overall, we believe that we're really well positioned to realize the opportunity for Emcitate. Our disease awareness activities are already demonstrating benefits and concrete outcome of our efforts by identifying many more patients and engaging with a lot of the stakeholders who are more and more interested in learning about the opportunity. We're continuously expanding as well our market -- our Managed Access Program, which really highlights that there is a high unmet medical need out there and patients are in need of a solution to help them. And also given our unique position in terms of ultra-rare condition, high unmet medical need and no alternative product in the market, we believe that we will be able to achieve reimbursement at a high price in the majority of the markets, particularly in the U.S. And being in an orphan space with all the expertise that we have in the company. We believe that we can remain a small nimble company and execute successfully on the launch of Emcitate with 40 to 50 employees across Europe and the U.S. and as clearly demonstrated by Henrik, when we look at the analogs for rare conditions and ultra-rare conditions, the uptake of these drugs is quite swift, and we anticipate that it will be the same for Emcitate. So once again, we feel that we're in a strong position, and we're really excited about the opportunity to prepare for a successful launch of Emcitate. So thank you very much for your attention.

Okay. I would like to extend my gratitude to the team, Anny, Henrik, Peter, Nigel, a great overview provided on our global commercialization plans with the flavor on the U.S. as well, getting further insight into the disease awareness initiatives. The value proposition behind Emcitate and the ability to generate data supporting the same as well as getting further insight through a very exciting presentation from your experience, Nigel, in the patient journey. So with that, it's time for the second batch of questions, and we open up for questions here in the room.

It's Alexander Krämer from ABG. And I have 2 questions on the commercialization and especially the disease awareness more specifically in Japan with your new partner, Fujimoto. My question here is like who's going to, like, in this partnership, like what are the responsibilities and roles about disease awareness in Japan? Is Fujimoto going work there also in the framework of the development agreement that you have there? So that was my first question. And then my second question is about the Anovo in the U.S. So this is a specialty pharmacy. And the question about Anova is if they are -- if they have experience with the endocrinology space, and in general with this kind of space. And if they -- if for the other drugs that you have brought up with case examples, if these case examples when they were launched in the market, if they had similar programs and similar commercialization plans.

Thank you very much, Alex. I hope I remember all the questions you asked. I'll do my best. I'll start off with Japan, and then I hand over to Anny and Henrik to elaborate further on the Anovo distribution setup and the value that brings as well as some further insights into the commercialization. So starting off with Japan, I think it's a really, really good question. And I think the important thing when we actually entered into the license agreement, we had quite a few several interested parties, was to choose a partner who actually have both the experience, capability and capacity in driving a broad range of activities in Japan because being -- again, a small biotech company originated out of Sweden, it's very important that in remote countries like Japan for us, we have a very solid partner. So the structure around the deal is that they are responsible for all the development activities, including a development plan, including the engagement with PMDA and so on and so forth. And in addition to that, of course, responsible for the commercialization. So driving disease awareness, driving the value proposition and have the reimbursement discussions, of course, with the MHLW. And I think there, one important thing is as part of the joint steering committee is, of course, sharing experience. So that has been very clear from the outset that we're not just leaving them alone and doing our thing. It's more around how do we in partnership develop very optimized development plan that we take to the PMDA together for approval and then subsequently execute it. And the same goes for the commercial space that learning from the incredible work the team has done so far and will continue to do when it comes to driving disease awareness, the Managed Access aspect of things as well as the market access and value proposition. And there, I think one of the additional reasons in Japan is that why we decided to enter that agreement already now is that -- there is a couple of key opinion leaders, amongst others, Professor [ Eva Yama-san ] and Professor Kubota from Osaka University that have done some natural history digging in Japan alone. And there was a publication out in 2021 summer from Professor [ Eva Yama-san ], stipulating that they have already diagnosed 36 patients in Japan. And then on top of that, Kubota-san had a publication in -- last year, 2022, illustrating 68 patients in total have been all identified. So I think the awareness is there, even though starting from a low base, but the opportunity will be huge working together going forward. On the Anovo side, I will hand over to you, Anny, and explain a bit more about the Anovo setup, the value proposition and how they can actually add value to our business.

Thank you. So yes, in the U.S., there are several pharmacies that specialize in distributing high-cost rare disease drugs. And Anovo is one of them and what they will be able to help us with the expanded access program, first, leverage their strong track record in implementing expanded access program for rare disease and be able as well to communicate effectively with the treatment centers and the patients to orchestrate the process to capture all of the data and also to be able to provide the drug easily. This is a part of their expertise, and they've demonstrated, again, a strong track record in that area. And one of the other advantages that we'll provide is that patients that we've talked about is not -- are not easy to move from one place to another, we will be able to provide the drug directly to the home of the patient. So we believe that this will provide a lot of benefits for both the treatment sites and for the patients and families as well. You also asked about the analogs and some of the activities that these companies have done, are they similar to what we are focusing on? For the U.S., absolutely. And I have the pleasure to be part of the launch for Exondys at Sarepta and have worked with many pharmaceutical rare disease companies also from a consulting side. And those are exactly the type of initiatives that these companies have put in place. One of the key success factor is really the disease awareness and finding patients ahead of the launch. And the other factor that is really critical for that rapid increase in the commercial sales at launch is making sure that ahead of time, we really understand the deeply payer landscape and make sure that we have reduced, limited, eliminated all of the potential roadblocks for patients to get access quickly. So then the pool of patients that have been identified prelaunch and then rapidly transition. And that's one of the key success for really having that quick ramp-up in the short-term at launch.

Thank you, Anny. And I think we have a further question back in the room. Johan?

Thank you. Yes, a question. Can you remind us when we could expect more sort of data on the cognitive effect and presumably any positive cognitive effect would also be positive for reimbursement and also for the expansion of the [indiscernible] test?

Yes, of course. And as you heard myself saying at the beginning as well as Dr. Berger, we have an ongoing study investigating the effects on neurocognitive development. That is the Triac Trial II that was fully recruited during last year June, actually. There we expect data middle of next year, so mid-2024, which we are very excited about as well. And there, of course, that it could be a very important aspect of an example, adoption of adherence for the future as well as enabling or driving further newborn screening.

Thank you.

Thank you. And then I think we have a question online. Correct?

Yes, there is a question coming from the chat forum from the Redeye site. It's an anonymous question, but the question is how should we understand the opportunity in Europe for Emcitate and how fast can you actually launch after approval?

Thank you very much for a good question. And I think I'll hand over to you, Henrik.

Yes, happy to elaborate a bit on that. So as you know, Anny showed some analogs that are relevant for U.S. in ultra-rare diseases in contrast to more traditional specialists areas, the price level doesn't differ that much between U.S. and Europe. So the list price in Europe will be possible at traditional high ultra-orphan level. Then it's negotiations that will happen in each single country related to the reimbursement process. And there, there will be different kind of value drivers in different markets. So therefore, I'm not in the position today to talk about exact price levels, but what I can say is that related to the speed of when patients can get on treatment -- on reimbursed treatment in Europe. And there, we have the fastest countries being Germany, where it's possible to sell already right after the EMA approval. In France, there is also a possibility to sell during the reimbursement process. And then in most other countries, there's really a range between like 3 months in U.K. up to 20 months in some other countries. So it will vary a bit.

Thank you, Henrik. And I think we have another question in the room.

Yes. I guess, building a little bit on the last question, when it comes to what we should expect in Europe. Access to orphan drugs is not always as good as you might wish in European countries. In Sweden, I think we only reimburse about 1/3 of non-oncology orphan drugs. So out of these 190 -- some 190 patients on expanded access programs, how many of them would you say are treated in sort of high-income countries where the reimbursement landscape is favorable?

Yes, that's a really good question, and I think we have discussed this before. But out of the 190 patients, you have 80% of the patients being in Europe or in the U.S., right? And then we can argue high-income countries or not, but in the context of U.S. and Europe, and I think that's, of course, very favorable. Coming back to, as Henrik said, if you look at pricing levels, U.S. versus Europe for ultra-orphan drugs compared to traditional drugs, the difference is not that huge. Having said that, it's also important to recognize that there we're talking about list price, whereas you have on a country-by-country basis in your negotiation on potential rebates, et cetera, which will, of course, vary between the countries and are confidential. And I hope I [indiscernible].

That's fair. Perhaps just a quick follow-up. If I may say, on that note, I guess, can you say anything about the expected gross margin on the net price?

That's a really good question. We are not giving too much detail, but think about the gross margin and then again, let's move royalties to decide that we are obliged to, of course, we have 10% in royalties, just to remind the audience to the Erasmus Medical Center, and then we have 3% to the previous owners of RTT. Based on that, I think it's fair to assume that the gross margin, if you include that, will still be very, very favorable without giving you a number. And the last question from the room. Fredrik, Redeye.

I was wondering if you could elaborate a bit on the importance of health economics and what markets would it be especially important? And also how much does it differ in terms of, for example, taking account for caregivers and [indiscernible]?

Thank you, and I think you're referring to Europe here, Fredrik. And I think it's a wide range. So it's different drivers and different countries, which makes Europe very complex. But I'll hand over to you, Henrik, or maybe Peder as general managers for different parts of Europe to elaborate a bit.

I can cover a little bit in general. So it's a very relevant question, first of all. And traditionally, I mean, the most sort of early adopter to health economy is really like U.K. and the Nordics. With cost-effectiveness models that we are working on already, I mean, we have already had payer advisory boards related to those, and those will be relevant for also countries like Italy, for example. And those are the sort of clusters where it is most important to show cost effectiveness, we should be aware that also a trend now happening in Sweden that payers really accept higher cost [indiscernible] compared to traditional pharmaceutical drugs.

Just one thing I would add as well. I mean I think for some of these countries like the U.K. and the Nordics, which I cover as well, you can have these early engagement meetings with NICE and other bodies. And I think that's really helpful and those meetings are really helpful for them to understand actually the value you're bringing as well as for you to prepare as well. So I think those early engagements are particularly important.

Thank you, Henrik. And on that note, looking at the agenda, we're coming up to the break. So we now have a break for -- I would say, around 20 minutes, and we'll reconvene at 5:30 Central European Time. Thank you. [Break]

A warm welcome back from the well-deserved break. Over the first part of the agenda, you have heard us mentioning the opportunity and our key asset, Emcitate for the treatment of MCT8 deficiency. We recapped tonight on the development pathway, the regulatory pathway to approval. The commercial opportunity as well as the ambitions we have in the disease awareness space and furthermore, elaborated on our global commercial plans for MCT. But as I mentioned in the beginning, we also see other opportunities within the company in order to build a sustainable rare disease company. And that is what we're going to cover at the last part of the agenda today. As mentioned, we are considering a potential opportunity in a different disease setting, a different indication called resistance to thyroid hormone beta, and there, I'm delighted to welcome yet another external speaker and a key opinion leader in the space, Dr. Carla Moran from University College of Dublin. Carla, over to you. Thank you.

Thank you very much for the kind introduction. Let me just share my slides and hopefully you can see those well and hopefully you can all hear me. So my name is Carla Moran, and it's a great pleasure to be able to take part in this information day. I'm the consultant endocrinologist and Associate Clinical Professor in University College Dublin. I'm going to speak today about resistance to thyroid hormone beta. I'm sure you are familiar now with MCT8 deficiency, which is a form of resistance to thyroid hormone, but there are other forms and one of the forms which I research is RTH-beta. [indiscernible] I'll be speaking about resistance to thyroid hormone beta, and I may variably refer to it as resistance to thyroid hormone or RTH-beta, but I am speaking about the same condition. And now about my background. I'm a clinical endocrinologist and I've got a particular interest in thyroid disease. I got my training here in Ireland [indiscernible] and then I moved over to the U.K., and I worked with previous mentor and colleague, Professor Krishna Chatterjee and he works in Cambridge University. And I studied for my PhD there and then I stayed on for almost 10 years in total, researching resistance to thyroid hormone and looking after those patients in the clinic. I've now moved on to Dublin where I'm from, and I work in 2 sites, Beacon Hospital and St. Vincent's University Hospital, and I did my academic work through UCT, and much of my research now is still in collaboration with Cambridge University. And with others, I conduct a weekly MDT, looking after patients with rare thyroid disease. And so our multidisciplinary team consists of geneticists, researchers, clinicians, biochemists, all of whom are interested in these rare genetic thyroid conditions. Over the course of the 20 minutes or so I have today, I'll speak a little bit about thyroid hormone. I'll speak about resistance to thyroid hormone beta, what it is, how we diagnose it, the effects on patients, the treatment options that we currently have and the unmet needs that we have identified and I will also speak a little at the end about future research priorities. So to speak firstly about thyroid hormone, many of you may know this, but I think it's helpful to recap this in the setting of resistance to thyroid hormone beta. So you now that the thyroid gland makes thyroid hormones T4 and T3, and they circulate in the bloodstream and they feed back to gland in the brain called the pituitary gland. The pituitary gland makes the thyroid-stimulating hormone or TSH. And it is TSH really that mediates all the steps in the formation of the thyroid hormone. So it's a key determinant of the amount of thyroid hormone that is produced from the thyroid gland. The pituitary gland and the thyroid gland are involved together what we call a feedback loop, as is also the hypothalamus which is a gland that is situated just above the pituitary. And we sometimes term this the axis, the HPT axis, hypothalamus-pituitary-thyroid axis because all of these organs are in contact with each other via their hormones in order to make sure that the thyroid hormones are produced [indiscernible] that the levels are kept that are relevant. So if a thyroid gland were to make too much thyroid hormone, it feeds back to the pituitary and pituitary reduces its production with TSH and that in turn reduces the production of thyroid hormone and the whole system [indiscernible]. It's very common in clinical practice that we would see patients with overactive thyroid gland, what we call hyperthyroidism and those patients have raised thyroid hormones, T4, T3 and then have a suppressed TSH. And that's because this HPT axis is working normally and the TSH should be suppressed, that's a normal response to high levels of the thyroid hormone and I'll come back to this concept later on when we're thinking about the diagnosis of resistance to the thyroid hormone beta because understanding that concept is really key in identifying the abnormal thyroid hormone pressure that we see in our thyroid patients. So normally, as I say, thyroid hormone circulates in bloodstream and it has effects on numerous organs, including the liver where it controls strong metabolism, for example, the heart where it controls our heart rate and [indiscernible] heartbeats. It's very important in the development of the nervous system, but also the maintenance of normal hormone function for adults. It's important in bone maturation, bone turnover and growth in children. And it is also one of the prime determinants of our basal metabolic rate [indiscernible]. How do the thyroid hormones actually work? So to answer this question, we need to see inside the cell and think about the nucleus. So when you've learned about, MCT8 deficiency, the abnormality, as you know, is a problem with thyroid hormone entry into the cell through the cell membrane. But in patients with resistance to thyroid hormone beta, the defect here is actually in the thyroid hormone receptor. So this is a small protein that's located within the cell nucleus and this protein is normally able to respond to thyroid hormone, and in response to thyroid hormone, it usually [indiscernible]. If there's no thyroid hormone present, the thyroid hormone receptor is not activated. It doesn't result in [indiscernible] genes and the genes are switched off. Once thyroid hormone enters the cell, the active form of thyroid hormone T3 and [indiscernible] thyroid hormone receptor and typically switches genes on and that's how the actions of thyroid hormone are mediated usually through activation of the thyroid hormone receptor. A key concept in the pathogenesis of resistance to thyroid hormone beta is that we have 2 forms of thyroid hormone receptor, alpha and beta, and most tissues preferentially express [indiscernible] of the receptor. So for example, the pituitary and the hypothalamus preferentially expresses the beta form of the receptor, and the liver preferentially expresses the beta form of receptor as well. Other tissues, so for example, skeletal muscle, bone, brain, heart preferentially express the alpha form of the receptor. Now of course, in healthy normal people, it doesn't matter because the thyroid hormone circulates right in the bloodstream, and it will activate the receptor that's present in the tissues. But what happens for patients with RTH beta is that they have a defected form of the beta form of the receptor and that results in consequences, which I will explain to you. So turning our attention specifically to resistance to thyroid hormone beta. This is the same diagram we've shown you before. What I'm trying to illustrate here is that there are certain pathways to thyroid hormone action that are resistant to this condition. And so here, we see resistance to the thyroid hormone action in the pituitary, and the hypothalamus and the liver because as I said, the beta form of the receptor is predominantly expressed in those organs. The interesting thing about patients with RTH beta is that although we see this resistance in the axis, what that actually results in is elevated levels of thyroid hormone being produced in thyroid gland. And that's because normally, what we should say is if thyroid hormone levels are going high, the TSH signals should go low. But in actual, these patients, what happens is the TSH signal is constantly being produced, and that is constantly turning the thyroid gland made too much thyroid hormone and then the thyroid hormone levels start to go high and they act normally through the tissues [indiscernible] receptor. So how do we pick up this condition? Well, it comes back to the feedback that I mentioned earlier. So you remember that I said in the face of high thyroid hormones, it's normal for the pituitary to switch off its TSH signal. But an actual fact here, because the pituitary cannot sense this elevation in the thyroid hormones, the TSH is constantly being produced and so what we will see in our blood tests is that the thyroid hormones levels are high, but the TSH is not switched off. The TSH is persistently present [indiscernible] and that, for us as endocrinologists, is a very abnormal sign and then once we see this pressure, we would start to think whether the patient might have resistance to thyroid hormone beta and we do a number of tests to try to investigate that possibility. So the abnormal thyroid blood tests in RTH in all patients who are affected, and it's a key hallmark of the condition. So we always look for the [indiscernible] and because the thyroid hormone levels are made in access, many patients will have an enlarged thyroid gland or what we call a goiter and so 70% of patients end up with a goiter. So after we see these abnormal thyroid hormone levels, how do we then confirm the diagnosis. So we have to perform genetic sequencing. And the gene that encodes the beta form of the receptor is termed THRB. So we do specific genetic testing for THRB and in 90% of patients with RTH beta, we are readily identifying mutation that causes the condition. So in that way, it's quite straightforward usually to diagnose. The condition itself is usually inherited in an autosomal dominant fashion. So if we detect it in mom or dad with RTH, if we detect the condition in mom or dad, then we know that their children have 1:2 chance of having the condition. And similarly, if we identify the condition in a child, teenager or somebody in their 20s, his parents are still alive, we would offer genetic testing for their parents. We know that the frequency of the condition is between 1 in 20 and 1 in 40 individuals. And we know that it can occur in any ethnicity. Males and females are equally affected and it can be diagnosed at any age, and it can be diagnosed in the multitude of fashions, either because we've done genetic testing for the family after we've identified the case or because people might have gone with a number of different symptoms, which I'll explain to you. So what are these symptoms or affects of resistance to thyroid hormone beta. So this slide really summarizes decades of work in cohorts of patients with RTH patient. So as I've mentioned, the thyroid [indiscernible] and many have a goiter [indiscernible] because of the effects of the thyroid hormone on the muscle, children can have an increase in metabolic rate and because of that, they can have difficulty in [indiscernible] and they can often described as always having been very slim. That problem can also be present in adults making it difficult to gaining weight. In childhood, there can be a delay in their growth. And some children can have short stature and they can come to medical attention for that reason. In adulthood, people can have a reduced bone mineral density, so they have an increased frequency of osteoporosis. Children can be affected with ADHD, so attention deficit hyperactivity disorder and even if they're not formally diagnosed with that, their parents or teachers often comment that they can have poor attention and concentration in school. They can have reduced IQ up to 30% [indiscernible], they can have some anxiety or hyperkinetic behavior, which can impair their schooling. There's an increased frequency of ENT infections. So that's ear, nose, and throat infections and they can also have the hearing impairment. Many patients will complain of palpitations, and that's a very common symptom. And there are other cardiac effects, which I'll explain to you in the next couple of slides. We've shown relatively recently that patients can have liver problems related to this condition. So the liver is relatively resistant to the action of thyroid hormone in this condition. And so patients can have a high cholesterol level, they have insulin resistance and so they may have an increased risk of high blood sugar levels or an increased risk of diabetes. It hasn't been shown until relatively recently, whether these patients have a normal life expectancy or not? And that's because, although there have been a number of cohorts that have been studied, they've also been studied in a cross-section that are being followed up [indiscernible] and so this is a study that I was involved in and that was published this year. And if we looked at patients in males with confirmed resistance to thyroid hormone beta and matched them to age and sex matched controls. In total, there are 55 patients included, which doesn't seem like a large number, but for a rare condition like RTH beta, this is a really very large number. And it's estimated that we were able to capture the majority of patients who have RTH beta in males. And what was identified by my colleague, Dr. [indiscernible] was that patients with RTH beta have increased all-cause mortality. The hazard ratio for death was significantly increased to 2.84. The risk of atrial fibrillation was also significantly increased. Atrial fibrillation is a condition where the atria, so the 2 chambers at the top of the heart don't beat in a normal fashion. And these patients have increased risk of blood clots and they have increased risk of stroke. Atrial fibrillation occurs relatively commonly in the general population, but we now know it occurs much more commonly in patients with RTH beta, and the risk is tenfold compared to healthy adults. The risk of heart failure has also increased. So we have documented a number of cases where heart failure occurred. But we never quite know until the study, whether it genuinely was an increased risk or whether there was a referral bias to our center. And so what we were able to show in this study was that the heart failure risk has genuinely increased sixfold. And it was also clear that patients with RTH beta have a significant burden of disease. So for example, we were able to calculate that the median age of the first event -- the first event being an adverse cardiovascular event or death occurred at 56 years of age in patients with RTH beta, about 67 years in the controlled group. So a significant burden, I think, on their health in middle age. So what treatment options do we currently have for RTH beta. So there are a number of treatment options that we can currently consider, but all of them are suboptimal. So we have lots of treatments that we can use for a conventional overactive thyroid gland. For example, we can use a drug to lower thyroid hormones, we can remove the thyroid gland or we can do formal treatment [indiscernible] for conventionally overactive thyroid gland. But that doesn't work with RTH beta because these patients have a combination of so many organs that need a lower exposure to thyroid hormones, and they have some organs that need a greater exposure to thyroid hormone. And so using these blunt instruments, we will be lowering their thyroid hormones, but we'll be doing that in all organs and that would not be the best way to restore the inbounds that we see in thyroid hormone exposure in these patients. It's generally not recommended that we use those, unless the patient is extremely unwell. So what we're doing at the moment is we try to treat the effects that we see. So if somebody has a high cholesterol level, we use a cholesterol medication to lower those. If somebody has palpitations, we use beta-blockers to lower their heart rate, and if somebody has reduced bone mineral density, there are lifestyle measures that can be adopted to optimize bone health, we use calcium with vitamin D and specific medication that we can use to try and improve the bone health. But again, these treatment options really are not ideal for the patient. The medication that we have been using for a number of years in patients with RTH beta is Triac. So Triac, as you know, it is Emcitate, Triac is short for triiodothyroacetic acid and is also called tiratricol, but I'll refer to it as Triac. So Triac is actually a thyroid hormone analogue and the advantage of Triac for these patients is it preferentially stimulates the beta form of the receptor. So it activates the receptor that is not working very well in these patients. So it activates the receptor within the HPT axis, and it should also activate the receptor in the liver. It lowers TSH and it lowers thyroid hormone, so it's quite effective for patients who are symptomatic from symptoms of over-exposure to thyroid hormone. We have used Triac in combination with a conventional antithyroid drug and in some cases of severe resistance to thyroid hormone. So this is a boy from Saudi Arabia, who's treated in Cambridge [indiscernible] was treated with carbimazole and Triac over the course of 2 months. And he was treated because he had [indiscernible] heart failure and he had a sibling who had a similar form of RTH, had actually died from heart failure [indiscernible] so we treated him with Triac and carbimazole and what you can see here in the [indiscernible] over the course of treatment [indiscernible] his weight increased and cardiac function improved. It's possible to use Triac alone as monotherapy. And we have used Triac in a number of patients, both in Arlington and the U.K. and we found that their symptom score for hyperthyroid symptoms improved and their energy expenditure also improved. So what kind of research priorities do we have for patients with RTH beta. We recently had a webinar for an information [indiscernible] for patients with RTH beta. We are keen to understand their own priorities in terms of research for their condition. And it was held in October in conjunction with the [indiscernible] and the things that we were particularly interested in looking at actually were more gratifying and the patients were also interested in. So I think that would be of interest to patients and [indiscernible] health registry so that we could gather information and perform [indiscernible] that I think would inform us on additional aspects of RTH beta of which we might not be fully aware at the moment. The patients are interested in novel or investigational treatments for the condition. And they are also quite concerned about their heart health, and they were keen to be involved in studies that might potentially help inform us a little bit more about what happens to the heart and RTH beta and treatments that would potentially benefit them [indiscernible] so that's everything I have to share with you today, and I thank you for your attention, and I'm very happy to take any questions.

Thank you very much, Dr. Moran, for this very enlightening presentation, illustrating a potential opportunity within the resistance, the thyroid hormone beta disease setting. So with that, we're more than happy to take any questions from the audience in the room or online.

We have one question, Fredrik, in the back of the room. Thank you.

Yes, from Egetis perspective, what would the development plan look like if you were to expand to this indication?

Yes. I think as Dr. Moran illustrated, this could be a potential opportunity for MCT8 or tiratricol or Triac in this setting. And I think the next step is really to engage closer with a key opinion [indiscernible] Dr. Moran to consider how does a clinical development program in this setting look like. I think we all heard the devastating condition of this disease, but recognize that it's a very heterogeneous patient population. So one key consideration for the team and as part of our strategy will be to engage with the likes of Dr. Moran to consider during next year the feasibility of a clinical study in the best possible way. Because obviously, we have already extensive experience from using MCT8 or Triac in a different setting. We have a robust pool of safety data generated over a number of years, et cetera, et cetera. So it's more of how do we find a good set-up from a clinical trial perspective with the right endpoints that we can engage with the regulatory authorities and subsequently execute on it. That is the key step for us as a company. I don't know if you have any views, Carla, from your perspective when it comes to the future development in this space.

So I mean, we would be very keen to conduct a trial and looking at why the Triac is really beneficial in patients with RTH beta. And we -- there's a number of different endpoints that we might potentially look at, but I think the study that I showed you that was published this year [indiscernible] clearly shows that from a cardiac point of view, these patients, I think, are really disadvantaged. And the thing that was really interesting to me in that study was that I suspect the majority of patients are disadvantaged. So not everybody has symptoms of RTH beta, palpitations are very common, but not everybody has so. And the [indiscernible], even amongst families with the same mutation, it varies over time. And so we definitely consider the condition to be very heterogeneous. But the message that comes to me from [indiscernible] paper is that an actual effect, I think the majority of patients with RTH beta even if they don't have symptoms are probably disadvantaged from cardiovascular point of view. So it would be interesting, I think, if we were to use Triac to see if it would potentially improve some surrogate intermediary endpoints for cardiac disease and that would have to be decided very carefully. But I think that would be very interesting from a patient point of view.

Excellent. Thank you, Fredrik. Any further questions from the room or online? If not, I would like to extend my gratitude on behalf of Egetis and the people in the room, Carla, for taking time out to elaborate on the very exciting opportunity and devastated condition, of course, of RTH beta. So very much thank you, and I fully appreciate you have a busy day today since I understand that you're also in the clinic. So thank you very much for taking time out, and happy holidays. Thank you. So on that note, that leads us into concluding remarks, and thank you for your attention during these 3 hours in the afternoon. We much appreciate that. So to wrap this up then, Egetis Therapeutics, a company focusing on late-stage development for registration in the orphan drug space with the ability to commercialize in Europe and U.S. The ambition from a strategic perspective is to build a sustainable rare disease company by bringing unique therapies to patients with rare disease that improves and extends life. I think here, we have made really good strides, especially as illustrated here on this slide in delivering upon our strategy with a couple of key transformative milestones communicated over the last 2 months. First, the submission to the European Medicines Agency for our lead candidate MCT8 as the potential first treatment for the devastating condition, MCT8 deficiency. We secured long-term financing, making sure that we can continue to invest in our development programs and preparing for the commercial opportunity at the point of market approval. Furthermore, as part of our strategy in broadening the access to patients outside Europe and U.S., we have signed our first license agreement for the development and commercialization of MCT8 for MCT8 deficiency in Japan. So in that sense, to summarize where we stand, being a newly created company and newly within caveats since we've been established for 3 years now, we really believe that we're somewhat flying under the radar. We are developing the first therapy for the devastating genetic disorder of MCT8 deficiency. A key enabler for that, both now and going forward is building a strong team. And as we've heard, with a strong track record and proven experience in developing rare disease treatments, get them registered and being able to commercialize them. For MCT8, as you've heard Dr. [indiscernible] elaborate on, we have very strong and consistent data for MCT8 in the clinical trial setting, demonstrating significant effects on key clinical icons. This is, of course, as well supported by a very strong mechanistic rationale and also data from the preclinical setting. We believe that we have a high likelihood of reaching our first approval in 2024, the company asset is being derisked in the sense that it's already passed most of the typical drug development risk with the submission to the EMA and the pivotal study ReTRIACt ongoing that we hope to conclude sooner rather than later, leading up to a submission in the U.S. as well. You heard the commercial team, Henrik, Anny, Nigel and Peder elaborate further on the market opportunity or the commercial opportunity for MCT8 in this setting, premium-priced orphan drugs, disease awareness and bearing fruit and enables us to identify further patients, potentially being eligible for our treatment and also verified by continuous expansion of our Managed Access program, which, of course, in addition to that [indiscernible]. From a financing standpoint, last but not least, I think it's important to recognize that for the long-term sustainability, from a financial perspective, we also are eligible for a priority review voucher, at the point of a U.S. approval, which can be sold and of course, we'll rather generate further income to actually maximize the launch post approval. So on that note, thank you very much for your attention, and incredibly great to host this Investor Day. Thank you.