Right. A warm welcome to everybody here in the room at Penser Bank for the Capital Markets Day held by Egetis Therapeutics. Also, a warm welcome to all of you, 50+ or so, which I'm very pleased with, that joining us via the live stream. For those I haven't had the privilege to meet before, my name is Nicklas Westerholm, and I'm the CEO of Egetis Therapeutics. I have a background in chemistry, and before I joined this company five years ago, I had the privilege to spend close to 17 years within AstraZeneca amongst a number of different international business areas, such as late-stage development, finance and Investor Relations, global manufacturing, but also heading up AstraZeneca's business in Japan.
We have a very exciting agenda today, where we're gonna cover, amongst everything, a strategic overview by myself and really illustrate the long-term direction and the ambition we have for Egetis Therapeutics. We're also very pleased to have with us today two world-leading clinical key opinion leaders in their respective field. We have Dr. Edward Visser from the Erasmus Medical Center joining us to talk about our lead candidate, Emcitate, for the treatment of MCT8 deficiency, where we will be elaborate on the disease, the clinical phenotype, the unmet medical need, as well as the clinical experience we've seen year- to- date with Emcitate. We then move on to talk about the development pathway up until regulatory approval for Emcitate, both in Europe but also in the U.S. We will then break and leave ample time for questions and discussions.
We'd really encourage the audience to ask a lot of questions here to ensure we have a dialogue. Subsequently moving on, considering the global plans for commercialization in U.S. and Europe, but other parts of the world as well, and focusing in on the commercialization in the European market. We'll have a break subsequent to that, and then we will focus on Aladote for the prevention of acute liver injury caused by paracetamol poisoning. Here again, we have Professor James Dear from the Edinburgh University that's gonna walk us through paracetamol overdose, the incidence levels, and the clinical manifestations of the same, as well as the experience of using Aladote in the treatment of this patient population.
We're gonna move towards the development path for Aladote, up until regulatory approval in Europe and U.S., and finish off with the commercial opportunity for Aladote. We're then gonna move on to the summary of the day and also some closing remarks by our Chairman of the Board, Thomas Lönngren. Starting off with the company then. Most of you know that Egetis Therapeutics is a fairly new and recently created company. The company was actually created in quarter four 2020 from the merger of the previously listed company called PledPharma and the privately- held company called Rare Thyroid Therapeutics. As part of the establishment of this company, we are very clear with our long-term ambition to build a sustainable orphan drug company. The vision for the company is also very clear.
It's to bring unique treated therapies to patients with rare diseases to extend and improve their quality of life. In order to measure our journey towards our vision, we also have stated some very clear objectives covering the short term, midterm, but also the long term. The first one to call out is, of course, to successfully develop Emcitate for the treatment of MCT8 deficiency and Aladote for the development and registration in prevention of acute liver injury caused by paracetamol poisoning. Approvals are expected in 2024 and 2025, 2026 respectively for each candidate. Furthermore, which we'll hone in on, is the commercialization of Aladote and Emcitate through an in-house focused commercial organization in Europe and in U.S., and also clearly stipulating that we will be looking for partnerships in the rest of the world.
An important aspect for a company like ours that have passion for rare diseases is, of course, ensuring fast and broad access for these patients suffering from these conditions. Another aspect that we really have as an objective is also looking at additional assets. In order to build a sustainable rare disease company, we will continue in identifying further assets in the rare disease space where we can optimize a development pathway up until regulatory approval. By doing so, we really believe that we are well-equipped and set up for the future to create long-term shareholder value. One can also ask ourselves, so when we came together, PledPharma and R T T, creating Egetis Therapeutics, why the orphan segment? Why do we focus on rare diseases? It's a simple answer to that.
We really believe that the attractive features in the orphan space really cater to our setup. We are a small biotech company on our way to internationalize ourselves, but we don't have unlimited funds. We truly believe that the features you see here on the slide really cater to us in the sense of shorter development timelines to market approval. Fewer patients are required in the clinical trials, which of course then considers a lower cost base. There are generally, which is very important, higher probability of success. Of course, looking at risk- reward from an investor's perspective, probability of success is very important. That in combination with premium pricing in the orphan drug space or in the rare disease space is very, very attractive and makes the case, in our humble opinion, as creating our corporate strategy and the optimum way of operating in.
One also very important area worth mentioning is the efforts we have made in attract, recruit, and retain a very competent team. We have recruited now an organization with global experience and proven track record on designing late-stage clinical studies, executing late-stage clinical studies, analyzing them, navigating the complicated regulatory pathways in their different jurisdictions, but also be able to commercialize them. To pick up some examples, we have Kristina Sjöblom Nygren, our Chief Medical Officer that joined us last year, who has experience as a chief medical officer in other small biotech companies like Santhera, but also experience from Sobi. Our Head of Development, Christian Sonesson, very experienced in late-stage development from AstraZeneca, being globally leading development programs for large assets, the likes of Forxiga and Brilinta, and also being part of leading oral explanations and advisory committee meetings with FDA.
Our recent hire, Sara Melton, who joined us in June this year, brings substantial experience in commercializing orphan drugs in the rare disease space in the U.S. We also have a CFO in Yilmaz Mahshid, who has a seasoned and experienced in the life science sector with a scientific background, but also been working as a equity analyst in the healthcare sector, as well as an investment manager. We have Henrik Krook, our Head of Commercial, who's actually have a proven track record from Alexion, amongst others, commercializing orphan diseases. Why do I say this? This is really based on my personal experience being in the life science sector for over 20 years. People will make a difference.
By having a very strong team, a differentiated team, we are very well-equipped and set up for the future, making a success for the company. In addition to that, we have a very seasoned and experienced and engaged board. Our Chairman of the Board, who we'll hear from later, Thomas Lönngren, who amongst others, have had a tenure as the Head of the European Medicines Agency for 10 years. Gunilla Osswald, CEO of BioArctic. Elisabeth Svanberg, a very seasoned late-stage developer, both from executive positions, but also operational positions. And amongst others, she's also on the board for LEO Pharma and Galapagos, and previous board member of Sobi. Mats Blom, previous CFO of [Zealand], now, CFO of NorthSea Therapeutics, bring additional capabilities around the financial market into the organization.
Last but not least, you'll hear later from Peder Walberg, who's operating also active in the company, who's got a very interesting experience and broad background in the orphan drug space, where he amongst others, was a co-founder of Wilson Therapeutics together with HealthCap, which was then all, I guess, you know the success saga there. If you turn our attention then to the pipeline, which will be the focus of today, we have a very well and advanced pipeline. We have our lead candidate, Emcitate, for the treatment of MCT8 deficiency, where we're looking forward to a regulatory submissions in Europe first half of next year. When it comes to U.S., we're looking forward to a submission mid-2023, pending a short placebo-controlled randomized study, which Peder will elaborate further on later that needs to be completed.
In addition to that, with Emcitate, we also have another opportunity outside MCT8 deficiency in the indication called RTH-beta, or resistance to thyroid hormone beta, which is a distinct and separate patient population to MCT8- deficient patients. We also have Aladote, our second candidate for the prevention of acute liver injury caused by paracetamol poisoning. Here we are planning to start a pivotal study at the beginning of next year, and we'll hear more about the study design, the incidence levels from the team later on. With that, and no further ado, I will actually hand over to Dr. Edward Visser, and I'm sure Edward will introduce himself properly as well.
Thank you very much, Niklas. Good afternoon, everybody. My name is Edward Visser. I'm an endocrinologist based in Rotterdam, the Netherlands. I would like to talk about our experiences in MCT8 deficiency. This is my disclosure slide, and I thought it's good to actually kick off with showing a patient because there it's where it starts and also where it should end. Quite some prominent disease features are seen in this picture. For example, the lack of head control. You see the patient needs support to sit upright. He is underweight.
There's dystonia, and there are many other disease features which are not seen in this particular photograph, but certainly occur in this disease. What I would like to talk about today is first to give some background about thyroid hormone physiology. Basically a few weeks of first year medical school in a few minutes. Then I will talk about MCT8 deficiency, the mechanisms, the clinical features, and the data we have on treatment with TRIAC, also called tiratricol. Let's start with the physiology. The pituitary located in the brain produces a number of hormones, among others, TSH, and TSH stands for thyroid-stimulating hormone. It's not a surprise that it does what the name states.
It stimulates the thyroid gland to produce hormones, thyroid hormones, mainly T4 and to a lesser extent T3. T4 is a prohormone which is converted to T3, which is the bioactive form. That's released in the bloodstream, and for many hormonal systems there are feedback systems also for the thyroid hormone physiology, and that there's a negative feedback loop onto the pituitary. The hormones, they can be released from the bloodstream and enter many cells and tissues and exert their clinical effects there throughout development, but also throughout entire life. When the hormone reaches the cells and tissues, there is another kind of intricate regulatory mechanism. This represents a target cell for thyroid hormone.
This is the plasma membrane, and actually the hormone binds inside the nucleus, to a receptor called the thyroid hormone receptor. That acts as a switch to induce thyroid hormone dependent transcriptional programs, thereby ultimately inducing its effects. Inside the cell, there are a set of enzymes called the deiodinases that can either activate or inactivate thyroid hormone. As these processes occur inside the cell, the hormone needs to be transported across the plasma membrane barrier. To keep a long story short, transporter proteins at the plasma membrane are required to facilitate this process. It was only in 2003 that our group identified the most specific transporter known to date, called MCT8. Let's move to the mechanisms of disease. What are we talking about?
If MCT8 is defective, there will be a problem downstream. The first patients were identified back in 2004, basically one year after the discovery that MCT8 is an important key player in the cellular regulation of thyroid hormone, both by our group and also by another group. Another year later, it was recognized that the clinical features of this disease described in these two papers are very reminiscent of a syndrome already described in 1944 by Allan-Herndon and Dudley. The MCT8 gene is located on the X chromosome, so mainly males are affected. Basically this Allan-Herndon and Dudley syndrome was the first X-linked mental retardation syndrome ever described, and it took another 60 years before the genetic defect was identified.
In these slides, I would like to explain the underlying mechanisms of disease. Cells and tissues that are dependent on their thyroid hormone supply on MCT8, they will be deprived from the thyroid hormone. That's indicated here. The level of intracellular hormone is low, and that results in such cells and tissues being hypothyroid, which is the situation in the brain. Why the brain? Because MCT8 is importantly expressed at the blood-brain barrier and also in many neural cells. That's what we call the neurodevelopmental phenotype, which is one part of the disease. In the blood of these patients, there are very typical abnormalities in terms of thyroid function tests. T4 levels, the prohormone is low, but the bioactive form T3 is quite elevated.
That means that cells and tissues that are not dependent on MCT8, but on other transporter proteins, will be exposed to these toxic T3 concentrations in the blood. That results in many adverse effects in liver, skeletal, and heart tissue. That brings about the metabolic phenotype. Basically this disease has two parts. There's a neurodevelopmental and a metabolic component, which are indicated with the two different colors. Throughout the presentation, if the color turns blue in the title, I talk about neurodevelopmental phenotype, and when it is red, it's about the metabolic phenotype. Let's move to the clinical features of this disease. How do you study such a rare disease? What we did, we collected data from about 150 individual patients across the world through an international network.
We accrued the data on different endpoints. Biochemistry, we gathered data on neurodevelopmental outcomes, on clinical outcomes, and also on mortality. In the next couple of slides, I will just highlight some disease features. We were able to define the key presenting symptoms in this disorder, and it's mainly developmental delay and hypotonia that ultimately results in referral to physicians. This slide illustrates well the severity of the neurodevelopmental phenotype, and I will try to guide you through. This is the Gross Motor Function Measure, GMFM, in which 100% represents the normal motor capacities of a healthy four-year-old child. As you can see, all these patients, they score very low irrespective of their biological age. They have a very poor development.
What can we measure in the blood of these patients? When it comes to measuring the thyroid function tests, you can measure TSH, which is mostly normal in these patients. Free T4 concentrations can be normal but are mostly lowish. But when you measure T3, then actually irrespective of the age, it's nearly always elevated. It's certainly the ratio between the low T4 and the discordant high T3, which is a very nearly diagnostic feature for this disease. It's very important that physicians should measure T3, well, in a diagnostic process. Actually, for most common thyroid diseases, the TSH and the FT4, they do the job. It's important for this particular disease that this one is added.
This is about body weight in these patients. What is plotted here is the body weight corrected for age because all, well, children, they gain body weight anyway, so this is expressed as Z-scores or standard deviations. Normal growing children, they should be between plus and minus two standard deviations of their growth chart. What we plotted here, all the individual blue circles are of untreated patients with MCT8 deficiency. What you can get from this picture is that they are born at a normal body weight, then they deteriorate in the early phase of life, then they stabilize, and then again during puberty, they again start to deviate from their expected weight gain.
The same holds true also for body height and also sexual maturation is delayed, although ultimately normal. Some data on cardiovascular outcomes. Due to the high circulating T3 concentrations, patients have an elevated heart rate. Also, when we quantify the number of patients with tachycardia or so-called premature atrial complexes or premature ventricular complexes, they're occurring frequently in this population. Other disease features like conduction abnormalities and systolic hypertension occur in this disease. When analyzing all these data from these 150 individuals, we are able to conclude something about mortality. As you can see is that around 30%, 40% of individuals die during childhood. What are the causes of death in these patients?
From the patients, we do know the cause of death. It's either aspiration pneumonia or pulmonary infections. Also, sudden death is occurring quite frequently. What we did, we stratified the mortality for two, basically possibly representing the two main components of the disease. First, we stratified between patients who were able to keep their head upright versus those who could not. As you can see, the patients who cannot keep their head upright in early life have a much worse survival than those who can do. As you can see, it's the majority of patients who cannot keep their head upright. Perhaps as a proxy of the metabolic phenotype, we took underweight, and again, a similar picture seems to emerge.
Patients who are underweight at a young age have a much worse survival than those who do not. What about diagnosis? There seems to be quite a difference between the age of symptoms appearing versus the diagnosis. This is a graph, and please note this is a logarithmic scale on the age that symptoms start to occur after a few months of age, while the diagnosis was beyond two years of age for patients born before 2017. We did the same analysis for patients born after 2017, and what you do see is that the diagnosis, the age of diagnosis has been reduced, and we attribute that to a couple of factors, amongst others, disease awareness and perhaps also improved diagnostics.
Certainly, there is some way to go there. Perhaps for the future, neonatal screening might potentially be employed. In the Netherlands and some other countries as well, we have a T4-based neonatal screening for congenital hypothyroidism, which is designed to pick up problems with the thyroid gland itself. We were able to retrieve data in a retrospective manner from these patients, and it seemed that they were all below the threshold. Then according to the current flow diagram, it was concluded they did not have a thyroid disease, so there was no follow-up. One can imagine that, for example, adding T3 or adding another marker might have potential to diagnose these patients already at birth. Right.
Let's move to the last part of my presentation, which is about the treatment with TRIAC. When you have in mind the mechanisms of disease, hypothyroid tissues and hyperthyroid tissues. Back in the days, we had a very simplistic rationale. One should increase the T3 action in the hypothyroid tissues, and one should reduce the T3 action in the thyrotoxic tissues. One of the ways, well, possibly, at the time we were hypothesizing, that T3 analogs could do the job. The hypothesis was as follows. This is a cell in a MCT8-deficient patient. T3 and T4 are unable to enter via the normal route.
One can imagine if there is a mimic of thyroid hormone that can enter the cell via another transporter that might hold potential. Certainly if this T3 analog binds the receptor like the endogenous T3 would do and is also degraded. We tested this hypothesis by using TRIAC. TRIAC is, as you can see from these structures, very much similar to the T3 molecule. It's only this, the alanine side chain, which is replaced by acetic acid. It's very similar to T3. Actually, the TRIAC was already synthesized back in the 1950s by Dr. Pitt-Rivers, the person who also discovered that T3 was the main bioactive form.
Ever since, this molecule has been kind of searching for its application, and it seems that, well, that might be the case for MCT8 deficiency. I have only one slide with preclinical data, but we had years of preclinical data where we tried to tackle each of these requirements in the lab. This shows the data in animals. This is a normal, a control, a wild-type animal. These are Purkinje cells in the brain. This is what a normal brain development looks like. This is what happens to a mouse model mimicking MCT8 deficiency. It's clearly disturbed. If you start treating these mice immediately after birth, it completely restores the brain development.
There are also data that they functionally come back to normal control mice. This was done in collaboration with Heike Heuer in Germany. When having all these preclinical data available, we reasoned how might this work in human patients. It might work as follows. This is the normal situation. If T3 is administered, it would via the negative feedback loop reduce TSH, thereby leading to a reduction in the stimulus of the thyroid gland. The endogenous hormones decrease. Actually in the bloodstream, the TRIAC is able to exert the T3-like effects in all the tissues, whether MCT8 is defective or not. This was the hypothesis before moving to a trial.
We started a trial called the TRIAC Trial I, and the primary outcome, actually, the main idea was to see whether we could alleviate the metabolic component of this disease. The primary outcome was a reduction in the elevated T3 concentrations. As secondary outcomes, we had measures like body weight, heart rate, blood pressure, and also a number of biochemical markers. We had a number of exploratory markers and safety outcomes. As said, mainly the metabolic phenotype, and we had a number of tests that in which we scored the neurodevelopmental phenotype. Again, the trial was not designed for it, but we thought it was a unique opportunity, we just took it along.
The trial ran in nine different countries, with the idea having extensive baseline visits, treating them for a year, and then extensive end- study visit. We enrolled 46 patients, of whom 40 completed the trial. In the next slide, I would like to discuss the main findings in this trial. This is the primary outcome. These are the T3 concentrations plotted for the individual patients, with the red balls being the baseline condition and the arrows representing the reduction over time, after a year of treatment. As you can see, actually in all patients, it's reduced and actually bringing back in the normal range as expected.
We also noted that TSH and free T4 concentrations were also reduced, very much compatible with the mechanism of action of TRIAC. This is one of the secondary outcomes, the body weight, again plotted as Z-scores. As you can see, patients were far off their expected normal body weight. What you do see is that there's an improvement in the majority of patients. It's important because it's not very intuitive, perhaps, these Z-scores, but this can translate to many kilograms in individual patients, dependent obviously on their age. Also heart rate elevated in the majority of patients improves, in particular in those who had an elevated heart rate at the beginning.
Also premature atrial contractions, which are very unusual in children, were present to a very high extent, but subsided in the far majority of the patients and were reduced in the others. One slide on some biochemical markers, reflecting the activity of thyroid hormone in different tissues, SHBG and cholesterol for liver and CK for muscle. Again, you do see a similar pattern, so an improvement of the thyroid state in these tissues. This is one slide on one of the exploratory outcomes. This is again this GMFM score, this motor score, with 100% being a four-year-old healthy kid. As you can see, all the patients score very low.
On the group as a whole, there is no change, but we noted that those individuals that seem to respond were all at a younger, in the younger age range. We are very cautious how to interpret this. This was exploratory. The study was not designed for it. At least for us, it was reason, together with this preclinical data in animals, to proceed with a second trial to see whether this other part of the disease, the neurodevelopmental phenotype, can be alleviated as well. I'd like to finalize this presentation by showing some real-world data. Currently we are guiding like 70, 80 individual patients across the world. What happens is that physicians are mostly caring for one or maximum two individual patients. They're sending information and blood to us.
We measure the bloods and send the advice back to these patients on TRIAC dose. We were able to collect data via this way. This is not a trial, this is real-world evidence. This is the age distribution in the trial, and this is the age distribution in the real-world cohort, having many more patients of a younger age included. Together, this also results in a very long follow-up, up to six years of age, in quite a few patients. I would like to show you the main outcomes, primary, secondary, as also in a trial. Again, the T3 concentrations were reduced and back to normal in all, basically all individuals.
Actually mimicking the effects we saw in the initial trial. Again, here we have this complicated body weight graph. I try to guide you through. This is what normal healthy children should be. The gray dots are the individual patients untreated, and then the dashed red lines indicate the confidence intervals. The blue lines are the individual patients that are treated with TRIAC over a varying duration. What you do see is that most of the patients, they deviate from the natural course of the disease, so they are either stabilized or improved compared to the untreated patients. The same holds true for heart rate, which also improves in the far majority of patients.
To me, actually as a physician, I think this real-world data, it's much less controlled, but I think the very fact that we do see actually exactly the same as in a very controlled situation, speaks to me, very much. One slide on safety. It seems that TRIAC is a very safe drug. We have had only transient signs of some thyrotoxic symptoms like agitation or perspiration that subsides after a couple of days. There are no clinical signs of hypothyroidism, and we haven't seen any drug-related adverse events. To conclude my talk, I think it's important to realize that this disease has two components. There's a neurodevelopmental and a metabolic component.
For now, I think we can conclude that TRIAC is able to alleviate the metabolic part of this disease, and it seems that TRIAC can also be administered in a safe way to individual patients. I would like to highlight the main individuals behind the work I've shown you, Stefan Groeneweg and Ferdy van Geest of my team, and I feel very pleased and humbled to collaborate with a very large international network of very dedicated doctors who seek the best for their patients. Thank you.
Thank you, Edward.
Yes. Hi. I'm Peder Walberg. As Nicklas mentioned, I was the founder of Rare Thyroid Therapeutics, which merged with PledPharma and brought in the asset, Emcitate. I'm now on the board of the company, and I'm also the major shareholder. My background, I'm a physician by training. I spent a couple of years in big pharma, and then spent 15-20 years within orphan drugs, searching for and identifying products and bringing them to market for rare conditions and in companies such as Swedish Orphan, also co-founded Wilson Therapeutics, Medical Need, which is now called Immedica, and now Rare Thyroid Therapeutics, which is now Egetis.
I'm going to talk a bit on how to bring this product to the patients, to the market, and starting off with some of the key regulatory features we have with the product. I mean, orphan drug legislation, we've been through a bit. I mean, just it's a framework for making sure that it's worthwhile to investigate and commercialize products which are aimed for very small populations. This is a legislation which you have in both Europe and the U.S., and of course, Emcitate is designated as an orphan drug in both jurisdictions, and this gives a couple of benefits, closer dialogue with the authorities and so forth. I mean, most importantly, it also gives us market exclusivity.
We will have a market exclusivity in Europe of 10 years and in the U.S. of seven years from approval. For the U.S., we also have Fast Track designation, which is a system they have for therapies where they address unmet medical needs and show promising results. This makes us eligible for a faster than usual approval process. We will, provided everything goes as it should, I mean, enjoy a process of six months review time in the U.S. We also got what's called the Rare Pediatric Disease Designation, which is another way of stimulating research into rare pediatric diseases. What this does is, upon approval, we are eligible to receive what's called a priority review voucher.
This voucher can then be used for a different product, another product, to accelerate the timelines for approval for that product. That voucher can either be used by the company itself or it can be sold. For a company like ours, I think it's fair to assume that we can sell this, we plan to sell this voucher. Recent trades are in the area of $100 million-$110 million, which then would be an income for us sometime, I mean, shortly after approval in the U..S. Looking at the actual approval, we have all clinical data at hand in Europe, so we are targeting an MAA during the first half of next year. I'll come back to this.
For the U.S., we are performing a small controlled study. I'll give you more details on that as well. We are targeting a submission during mid next year. But with the review times, both of these lead to a potential launch in beginning of 2024. On top of this, we also have an orphan drug designation for the distinct condition, which is called resistance to thyroid hormone beta. This is not linked to a transporter of thyroid hormone. This is linked to the actual receptor for the thyroid hormone, and the beta receptor being mutated, which causes a set of problems which is not too different from MCT8 deficiency, but it's a distinct disease, so there is no overlap between those populations.
We have orphan drug designation for that also in the U.S. and in Europe. Looking at the different components then, I mean, we saw Edward talk about the TRIAC Trial I, which is the controlled trial in 46 patients, which was concluded in 2018 and published in 2019, which will be an important part of the submission package. We have the EMC Cohort Study, which Edward also described, with treatment periods for up to six years, also involving a completely new cohort apart from the TRIAC Trial I, which gives us additional comfort and strengthening the scientific evidence. We also have the natural history cohort, which of course is important. I mean, both the trials are not controlled, so we need something to compare it to.
Natural history is really important to understand how these patients would look and feel without therapy. For Europe, these three components are what will be included in the clinical package. We've discussed that with the EMA and they agree. We have all the clinical data necessary at hand. For the U.S., we need this small controlled study, which will be started any week now, and we have 16 patients, and I will come back to the design of that trial. On top of this, we have the TRIAC Trial II, which is running, where we recruited 22 patients. We fully recruited sometime during Q2 this year. It's running for up to two years, 96 weeks. We expect the data to be available sometime around the H1, H2 in 2024.
That will actually be post-approval, provided everything goes according to plan. Looking at the dossier, you may wonder, why don't we file in Europe right away if we have all the clinical data available? As you may know, this is a schematic of what's called the eCTD document, which is the basis for all approvals for a drug. It's essentially the same in the U.S., in Europe, and in other jurisdictions. It might be structured slightly different, but the components are there. That's composed of non-clinical data. You have some general overviews. You have the clinical data, but then you have also the manufacturing control and chemistry part, the CMC. For that component, we are not yet ready. We are waiting for stability data for our drug to mature.
We need to wait for a sufficient time to pass before we can actually add that data and include it in the dossier. Unfortunately in Europe, you're not able to submit an incomplete dossier. In the U.S., they give you an option of a rolling submission, but that doesn't exist in Europe, so we will have to wait. Coming into the small randomized controlled trial we are performing in the U.S. We had a lot of discussions with the FDA. They, according to the legislation, I mean, you should have some controlled data.
We thought that we have really compelling data, and that having a placebo-controlled trial at this stage in the clinical development for a very severe disease, where we also know that we have some very statistically significant and clinically relevant outcomes, is complicated. We had a lot of discussion back and forth, how will it be possible for us to, at this stage in the product's development, conduct a placebo-controlled trial? I think we ended up in something which is quite okay. We just published this on clinical trials, the design. We will actually have patients who are primarily part of our named patient or early access program, who are on stable therapy with our product. Basically, this means that the patients are already identified.
We have a pool of patients who could be eligible for participation in this trial. We will have a running period to make sure they are stable, and then we will randomize to either stay on therapy or get placebo. What we expect is that the patients who are switched to placebo will very rapidly, actually, perhaps within weeks, reach their T3 levels will bounce back to their native T3 levels, and they will then reach the upper limit of normal. Once a patient reaches the upper limit of normal, we will break the trial for that patient and put them back on the active product. That's also the primary endpoint here, is the proportion of patients that reaches the upper limit of normal. We have data on this.
We know for patients who have been on drug holiday for various reasons, we know that they quite quickly, when you take away the therapy, they will bounce back to high T3 levels. Perhaps from a scientific standpoint there, this is perhaps not the most exciting trial, but what it does, it adds placebo-controlled data in a good way, which the FDA has requested and agreed to. We believe that it's a quick trial. It's a 30-day trial for 16 patients and from a population of, we have 160 patients on a named patient program already. We believe it's a trial that we can conduct fairly quickly at a low cost and with fairly low risk.
Moving to the TRIAC Trial II. This slide you already saw, perhaps formatted a bit different in Edward's slides, but really showing that we saw an interesting dynamic in the younger patients who were treated, when we look at the neurocognitive phenotype. We have this trial which is running at 10 sites in the EU and U.S., where we look at very early intervention, looking at patients below 30 months of age. Early intervention with our therapy and following them for a neurocognitive developmental standpoint, we are looking at various established scales, the GMFM, which was the scale we just saw, the BSID scale, and we are also looking at some motor milestones, and the development of that.
22 children included, and the recruitment was completed in April, and 96 weeks of follow-up. This trial will continue to run, and we will have the data, but the data will come post the approvals, and we will then add the data into the approval through a variation. Looking again at the timelines, we are running the trial starting within the coming weeks, and that will hopefully conclude then in beginning of next year and finalize the end file for EU in the first half of next year and for the U.S. in mid-next year, paving the way for approvals in 2024 in both jurisdictions. Thank you.
Thank you very much, Peder, and thank you very much, Edward. I think what you have gathered so far is focus on MCT8 deficiency, the unmet medical need, the mechanism of action of the disease, but also the mechanism of action for TRIAC or Emcitate, as we use the terminology. Also, the clinical manifestations and the severity of the disease. That in combination with the regulatory pathway Peder has just illustrated, it's about time for question and answers. Can I invite up Edward and Kristina as well for Q&A? The floor is yours.
We like that. Many questions. That's good.
Thank you. You want to know the [ReTRIACt]. Yes, Edward, most interesting question, it was interesting also to see that a large proportion of the children were diagnosed, I believe as early as 10 months. What was the median in the study shown?
I don't know by heart, but I think that will be around 12 months of age in that. I mean, in the group analyzed between 2017 and now.
Yes. You alluded to that there might be some biomarkers exploratory at this stage, I suppose. Any signs that any countries are sort of screening or intending to screen?
Yeah, it's difficult. I think it's disease awareness that. Also I think the tendency in many countries to now have genetic testing for, you know, using panels, next-generation sequencing. We do see also quite a number of patients who have a developmental delay. They're screened for a series of genes, and then MCT8 is identified.
Maybe to chip in there, Johan, 'cause I think it's a very valid question. I think you'll hear more about that in the next session, 'cause obviously a key activity within our company, together with the key opinion leaders around the world, is how do we, in a constructive way, drive patient identification, diagnosis, and confirmation? So we'll elaborate further a bit around the initiatives we have in that space later on.
Yeah. Presumably it's the mother who carries by natural reasons. Is there sort of mapping on the basis of identified kids sort of going back in families, but and to see who could be at risk?
Yeah. Obviously. Once, I think that's current practice in, well, actually all countries I'm aware of. Once a child is identified, then let's say through the female line, it's investigated whether the mother is a carrier, and then the whole family can be screened.
Finally, if I may, it's great news that the kids are so young when they are diagnosed, but the big challenge here is of course that there's a great minority that is not diagnosed, and that's a big challenge and a big opportunity, I suppose.
Yeah. What can I say to this? I completely agree with you. The only thing I see is that in general, the number of patients also relatively is increasing. I wouldn't be surprised that many patients are not diagnosed as yet. Yeah.
Hi. I have two questions for Dr. Visser also. First one is in something we have talked before in the past. It's in this study on T4:T3 ratio in the Netherlands, evaluating this ratio as a potential marker for MCT8 deficiency. Could you give us a high-level timeline on this study, and what does it have to show to be considered successful in order to incorporate this measure into neonatal screening? Would it be like a few years, five years, 10 years?
Yeah. Yeah. Okay. Actually we have been trying this for with, let's say, varying intensities over the last years. We were not successful ourselves, but actually this year, or last year, a paper from Japan emerged where they were able to measure T4, but also T3 and reverse T3 in the blood spot. We are currently collaborating with another group in the Netherlands to try and copy that, their method. And if they're able to do that in, let's say, controls, then we have a small series of neonatal cards from patients. And if we are able to distinguish with this ratio of, well, whatever combination, then we'll go back certainly to the Dutch neonatal screening program.
Actually, I've already talked with them like five years ago, and they mentioned, "Well, if you're able to show a difference between patients and non-affected individuals, we would be very happy to consider to implement this, starting with as a research program and perhaps later on as normal." Yeah. They're very open to it.
Perhaps I can add my experience. I mean, the neonatal screening, I mean, that's one criteria that you need to be able to discriminate, but it's also quite often so that it needs also to change for the patient, right? Typically it's harder before you have an approved therapy. My experience is that you kind of unfortunately first need to have the therapy approved, which is hopefully soon then. I mean, that will help with the implementation of neonatal screening. That said, I think the timeframe for implementing neonatal screening today compared to 10 years ago is much shorter because there are simply a lot more therapies around for rare diseases. It's become more of a standardized procedure compared to what it was 20 years ago. Yeah.
If I can add, I mean, I can only talk for the Dutch situation, but actually, I was discussing this argument, should we first have a therapy but w e should diagnose them first. They understood that, and they were very open to it and say, "Okay, this is a realistic story."
Okay, thank you. Thank you very much. I have a second question. About a month ago, a paper was published in Frontiers, describing the potential role of thyroid hormone and analogs such as TRIAC for the treatment of multiple sclerosis, because it has been shown that these molecules can promote the migration of oligodendrocyte progenitor cells to areas in the brain where there is demyelination happening and promote remyelination there. What is your view on this? Do you think it's a good approach to target neuroinflammation in multiple sclerosis?
This is certainly beyond my area of expertise. I should be very cautious. I've been kind of hitting this area. I mean, because of similar questions. I think oligodendrocytes. Actually, thyroid hormone is one of the key regulators of oligodendrocytes. Multiple efforts have been in place to mimic that action. If you're hinting whether TRIAC could be, let's say, have another application, I don't know. Yeah.
Thank you very much.
Thank you. Ulrik Trattner from Carnegie. Perhaps first a question for you, Dr. Visser. We have seen the data thus far on the Emcitate and the data on the metabolic effects. They are quite compelling. You also talk about these neurocognitive effects, but these are, for now, purely exploratory. Could you just walk us through your impression on the importance of each of these two aspects? Would this be beneficial if it were only to show metabolic- positive effects? Because that would essentially prolong the life of the patient, but with neurocognitive dysfunctions over time.
The reason why I also was emphasizing that the disease has two basically components is that we shouldn't focus only on the neurodevelopmental part. I think that there is room to improve the quality of life if you alleviate the metabolic phenotype. Basically what you do in every common hypothyroidism in the general population. There you're let's say also only restoring the metabolic phenotype, but there's no doubt that any doctor would not treat it. From that point of view, I think irrespective of the age in general, there is room with TRIAC to improve that part.
Great. Just sort of a follow-up question on sort of disease awareness, and I know it's quite an uncommon disease. Your impression, how have disease awareness changed since the TRIAC Trial I was published in The Lancet? Have you seen any change in disease awareness since this data was sort of developed or taken forward, given that previously there was this disease that was quite unknown as well as there wasn't really any treatment for it? I'm guessing that the disease awareness should be rather low.
Actually, I've never looked from that point of view to that. I get kind of numerous emails, you know, every, well, every week, every month on new patients across the world. I don't know whether that's linked to this particularly to this publication. My feeling is it has been a kind of a gradual increase over time. What I do see that nowadays, if they send me an email, they're referring to the publication and say, "Hey, we found this data, and might this help for my patient?"
From a corporate perspective then, I mean, we see a clear increase in the requests for treating on an inpatient basis. I mean, that's increasing over time. We see a clear trend, increasing trend in requests. I guess on some level that's a kind of a secondary effect of increasing disease awareness, so.
Yeah. As you know, Ulrik, we talked about this before, Henrik will show it in his slides later, that the substantial increase in requests of using Emcitate under the managed access umbrella has increased by more than 50% over the last 12 months. We're now at more than 160 patients being treated. I think that's a token of the disease awareness increasing gradually. Henrik will, like, also give some examples in his presentation around disease awareness and the activities we do there. The feedback we're actually getting from prescribing physicians, pediatric endocrinologists, or pediatric neurologists starts from a low base, but it's gradually improving.
Great. Just final question, and that would be for you and Nicklas and Peder. What type of label are you looking at? Are we talking about any age restrictions when starting treatment, or will this be for the sort of entire patient population of MCT8 deficiency?
You want me to start or yeah?
Yeah. No, I mean, yes. We base the submission on the available data and both the TRIAC Trial I and the cohort study, I mean, treated all comers. We do not see a restriction in age. We think that the benefits we see are of benefit for all ages. We have quite a good age distribution when we pool these two data sets together. I mean, we have a very nice age distribution in all the pediatric groups and also in adults. We don't expect to have a limitation in age. We are also not expecting any other kind of limitation in terms of what we actually do.
I mean, what we are aiming for is a treatment of MCT8 deficiency. Full stop, right? Not going any— regardless of that. Yeah.
Oh, I have one more question. If I may, that would be for you guys as well. I might have missed this in the randomized U.S. trial. The patients that are to be included in the trial. Are these patients that are newly recruited, or are these patients that are currently on the named patient use program?
We are open for both. I mean, obviously, we have a large pool of patients who are in the named patient program and which we know and the physicians know them and are able to contact them. We believe that that will probably be the majority, but it is possible for a patient to enter into the run-in period and become stabilized and then enter into the randomized controlled fashion. We believe that that will be a minority of cases. That's also one of why we see that we are able to do this quickly. We do not need to wait for a patient to be newly diagnosed, put on therapy.
We can actually use the patients we already know, which of course is much quicker for us. Perhaps I didn't say that, but we have sites in both Europe and the U.S. for this trial as well. We are hoping to be able to recruit this very quickly.
Great. Thank you.
Thank you.
Thank you. I had one question on the neurocognitive scales. You mentioned it's quite established, but also you're looking for other scales as well. Can you maybe discuss that? How well do they capture the disease and what's your thinking on that?
Whatever you want. For clarification, Fredrik, are you talking about the GMFM88 scale and BSID-III?
The BSID-III is perhaps a broader scale than the GMFM. I mean, it has several domains. However, I mean, these children, the gross motor function is not functioning well. The BSID scale, just to give you an example, is something like, well, if I take this doll away, can you follow it with your eyes? You might hear what you say, you might want to comply, but I mean, if you can't turn your neck, it's impossible to comply with the scale. That's why the gross motor function becomes very dominant in these children. Having those kind of more advanced evaluations will not become meaningful.
The GMFM scale, I mean, the BSID scale, and the GMFM scale have both been used for drug approvals. The GMFM scale lately in the SMA setting, spinal muscular atrophy, they have used a modified version of gross motor function scale, and also motor milestones. That's something we have discussed a lot with the FDA to try and see what they did and have a look at that. Both those scales are very highly correlated with each other, of course, because they measure basically the same thing. I don't know if that was answering your question, but yeah.
Maybe to build on that, coming back to what Peder said during his presentation, that of course this trial is utterly important from a medical standpoint, from a scientific standpoint. We also need to be clear that market approval is not dependent on the results from TRIAC Trial II. Sorry, we have a question here in the front of the room. Joe, you've been raising your hand for a while now, so I'll hand over to you.
Thanks. Just for Dr. Visser. I was just wondering how many identified mutations of MCT8 are there? Is there a good correlation between the levels of inactivation of the transporter and the degree of both neurological and impairment on the hypothyroidism?
Yeah. Thanks for the question. That's actually where we are currently working on. This is all unpublished data. There are tens of different mutations. We are currently investigating in a set of, like, 350 individual patients, a correlation on actually 30 different disease features. There's a clear correlation between the impact of the, let's say, the defect of the transporter in- vitro in the lab. There are different levels of defectiveness, and that correlates with different clinical features. Yeah. Basically, we categorized patients as having a mild, moderate, and severe impact. Yeah.
Do you have any idea at the moment where the patients in the phase— in the TRIAC Trial I, the very young ones where you've shown, you know, they're creeping into the realms of there's a— They've reached a milestone, they've gone from the 10% to the 20%. Do you have any idea what mutations those patients have, and would you expect that they might naturally improve as they got older, or is that just impossibility for them generally?
Yeah. Good question. Yeah. Actually, all these mutations were severe mutations. Can you go back to your slide?
I think we have the asterisk, if that's what-
Yeah, that's the asterisk. [crosstalk] Okay. Actually, by chance, we had three unrelated patients all carrying the same severe mutations, those three. As you can see, those two were older, did not, you know, respond at all. This patient, I think it's this one actually, had an increase. Again, I mean, as a doctor and also scientist, I'm very cautious to interpret this, but I mean, these are the data. We are not kind of overstating or overinterpreting, but it was, let's say, reason enough to proceed with the second trial.
Maybe for Nick and Peder, you got Fast Track. What about PRIME in Europe? Is there a route there to shorten the review time?
I mean, PRIME, I mean, typically it's designed for something which is much earlier. I mean, now we are months or half a year away from filing. I mean, that's... I mean, it's not really... I don't think it adds value right now.
No, no, to chip in on that, I think that's a well-laid question, thinking about where we are in the development game, so to say. If we were in phase I or potentially starting a phase II study, of course one would consider that more in detail. We need to put in perspective also that we are a small, nimble organization. We need to focus our efforts in the right aspects, and then we've been focusing on a potential submission based on the data we have with EMA. We've been successful in those discussions. We believe that where we stand today, it's too late in the game to do that. It won't add too much to where we stand. You should ask our Chairman of the Board that later, by the way, in the closing remarks as a preview. Thank you. Thank you.
Just on the stability data, I mean, when did you start that work and how long has it been going, and when do you expect it? I mean, do you give yourself about-
Yeah. No, no, it's a valid question. It comes back to, I guess, to what Peder said, that we are in a privileged situation for the submission in Europe, first half of next year. Obviously in an ideal world, we would have submitted already now since we have all the clinical data at hand. What we have also done in parallel with the clinical development plan is of course upgrading the manufacturing process since that needs to meet the current standards and guideline from, well, all the different regulatory bodies. There we are in the final process, actually completing the validation batches that is now put on stability and hence why we are guiding for a submission first half of next year. We'll be ready then.
I think we have time for one more question. It's very exciting that we have a few. I think we hand over to Susanna. Sorry, Johan. You had your opportunity. We'll get back to you.
Sorry. Suzanna Queckbörner, Handelsbanken. My first question is on TRIAC II. If I follow the timeline correctly, that's after your actual submission to the EMA as well as the FDA. Can you sort of expand on how you think this will contribute in terms of possibly reimbursement? But also c ould it just be a safety net? How should we think about TRIAC II ?
Yeah, I can start. TRIAC II was initiated and then we received the cohort data. I think that changed things because we went to the authorities and we presented this. I mean, it made the situation very different because we suddenly had a lot more information. We had a whole new cohort. We saw the same thing. Now we had two trials already. That's when we engaged the authorities and discussed the possibility of submitting already on that data and that outcome was positive. That's what we're pursuing. The trial is still running. I mean, in fact, that will report sometime after, not only after submission, but after the approvals.
It will come after, but it will probably, I mean, come sometime in H1, late H1, in 2024. With approvals in earlier that year, I mean, we do not think it will delay the approvals, but it will be available for pricing reimbursement discussions in certain markets in Europe, for example. Timing-wise, it's actually quite— We believe that's quite good. We will not have to wait for it for the regulatory approvals, but we will still be able to leverage the data for pricing and reimbursement discussions. I don't know if you want to add something.
No. I think we apologize, Johan. We are running out of time. I'm a hard taskmaster today, so we need to continue. I'd like to thank Edward, Peder, and Kristina for responding to the questions. We'll have more time for questions later, Johan, so hold that thought. With that, I will hand over to Henrik to talk about our plans for commercialization of Emcitate with focus on Europe and U.S., but also focus on the key aspects that was brought up in the room today, which was around diagnosis and disease awareness. Henrik.
Thank you. Very happy to be here today. I'm Henrik Krook. I've worked for Egetis now for two years. Before that, I've been roughly 20 years in the pharma and biotech sector. Most of those years I've spent at larger international companies, so Roche, Novartis, and Alexion, for example, where I have been a part of both planning and executed several launches of pharmaceutical drugs, also including several orphan drugs. Today, I will give you the update on where we are right now with the commercialization preparations for Emcitate. First of all, I think it's really encouraging to see that we already now before marketing authorization are able to supply Emcitate to more than 160 patients in over 25 countries.
That's something that we can do thanks to this named patient use program that was discussed in the Q&A session here. It's also very interesting that we are frequently getting more requests and that patients stay on treatment. We really see that also as a confirmation that it's clear that physicians think that we are addressing an unmet medical need with Emcitate. If we look at the bar chart here, actually from the beginning of last year, we have been able to increase the number of patients in this NPU program with 50%, and it's continuously increasing. This will also be important at the time of marketing authorization because then these patients will be transferred to commercial drug.
That means that we already, the first months, after marketing authorization will get a number of patients on commercial drug. There are some very favorable conditions with Emcitate and the setting here that I would like to stress before going more into how we plan to execute on this launch. First of all, and I think that was also clear from Edward's presentation that Emcitate it is addressing an unmet medical need. It's also interesting in this kind of ultra-rare diseases that the treatment normally is centralized to a relatively few number of hospitals per country and that treatment decisions also are protocol driven. That means that we do not need to have huge sales organizations to be able to communicate information about Emcitate at the time of launch.
We can do that through a relatively limited number of caregivers. Also lastly, we are the only company having an active clinical development program in Emcitate. Sorry, in MCT8 deficiency. Based on these conditions, we have now started the stepwise establishment of a small in-house commercial organization and really preparing for the launches in U.S. and Europe, 2024. At the time of launch, we plan to be in the range of 40-50 people in the commercial organization, including medical affairs. Based on the prevalence numbers, there should be roughly 2,400 patients in U.S. and 5,400 patients in Europe.
Not all of these are diagnosed as of today, and that's why we are focusing a lot on disease awareness and educational effort for the healthcare so that patients that are living with MCT8 deficiency but their parents or the physicians haven't understood that this is the actual disease, that they become diagnosed as soon as possible. We just mentioned take care of North America and Europe ourselves with our own commercial organization and are planning to commercialize in the rest of the world through partners. There is quite a lot of interest from potential partner companies who clearly also have seen the opportunity with Emcitate just as we have. We have initiated this stepwise commercial organization build up during the spring this year.
I'm really happy that we have been able to attract actually some of the best people in the industry to this team. All of us have done and worked for quite some time in the big pharma setting, but then also have worked in smaller settings with less resources and managed to also use what we learned in big pharma in a smaller setting to execute good launches also with less resources.
To really make sure that we get the launch success here and we'll be able to improve the lives of both patients and also improve the life of their caregivers, we now really have laser focus on two key areas, which is identifying patients and driving and ensuring access to treatment as soon as possible after marketing authorization. If we start with ensuring access then, there we really aim for a broad access to Emcitate to the patients as soon as possible after marketing authorization. As you are aware, in this kind of orphan diseases, payers are used to reimburse prices that have somewhat a higher price tag compared to traditional pharmaceutical drugs.
This is even more so if the setting is a very severe disease and an ultra-rare indication. Emcitate fulfills this criteria, so it is very unique in this area. To be able to navigate the pricing and reimbursement landscape in the best possible way, we have kicked off now several key initiatives to be able to do this in the best possible way to get an optimal reimbursed price. Some of the key activities that we are running there is a Vignette study that we have done by involving physicians that are used to treat these patients, so that they have been grading the different health states in MCT8 deficiency.
We have also started the caregiver study where we collect information about costs and quality of life for parents. As already has been discussed, we are also focusing a lot on this disease awareness and education, and we're not alone in this process. There is also a lot of activities going on from patient advocacy groups and support by key opinion leaders. We are having exhibitions at scientific congresses within pediatric endocrinology and pediatric neurology. A couple of weeks back, I was myself at the European Society for Paediatric Endocrinology, and there had a lot of interactions and discussions with physicians. They were all extremely interested in this disease, and we received, related to this, 50 requests or more information about MCT8 deficiency.
We were in discussions about 14 different patients that were diagnosed but not yet had treatment, and 15 patients that they're based on their new learnings understood that, yeah, maybe these patients have MCT8 deficiency without that the physician was aware of it, and they would now go home and test these patients. It's clear that these activities helps to identify patients, and we will continue to be present at different congresses. We also have our more digital platform where we have our mct8deficiency.com website and the social media platforms, Instagram, Facebook, LinkedIn, where we post information about the disease. Publications, as already mentioned, is of course also an important part here. This was more of a flavor of some of the activities that we are doing in the pre-commercialization preparations from a global perspective.
All in all, I think we're really on good track here, and we have now also initiated the preparations in the major markets. To give you a little bit more information about what we are doing in the U.S., which obviously is one of the key markets, our President in North America, Sara Melton, will update you a little bit further on that.
Thank you, Henrik. Good afternoon. My name's Sara Melton. I'm the President of Egetis North America. Since this is the first time I'm seeing most of you, give a little bit of a background about myself. Been in the pharmaceutical industry for 25 years, working for both large pharmaceutical companies like Astellas and Bristol Myers Squibb, as well as small biotechs like Egetis, launching rare disease products in the United States. We are well on our way to building a presence in the United States, and Egetis Therapeutics U.S. Inc. has a new home in Naples, Florida. Our business entity was established in Delaware, and we are looking at approximately 20 to 25 full-time employees at the time of launch. We're gonna have medical affairs, market access, sales, and a fully functioning commercial organization, once we launch the product.
We've already begun recruitment, and I'm happy to announce that Kate Sulham, Vice President of Market Access and Pricing, has just joined the organization. Kate comes to us with a wealth of experience in health economics, market research, market access, and she worked for companies like The Medicines Company and Spero Therapeutics. We are going to also be recruiting and very close to hiring for our Vice President of Medical Affairs, who will be recruiting a whole team of regional medical affairs directors that will be focused on hospital center of excellence strategies. We are going to be going into about 25 centers of excellence across the United States and working with the multidisciplinary teams within them that treat MCT8 deficiency, like pediatric neurology, pediatric endocrinology, genetics, physical therapy, occupational therapy.
As we engage with clinicians who will participate also in U.S. advisory boards and functions, and they treat these patients, we have confirmed that there is a high unmet medical need for MCT8 deficiency patients. There is no approved therapy, and they're looking for something that can treat this peripheral thyrotoxicosis. They're looking for something that will help to improve the clinical manifestations like poor weight gain, disturbances in bowel function, rapid heart rate, and these clinical manifestations are very concerning to caregivers. Mortality is high, and causes of death, as Dr. Visser described, are lung infections and arrhythmias. We hear that they're looking for these novel treatments to treat MCT8 deficiency, and this one shows promise. They're looking to treat the underlying cause of this severe metabolic disease.
At Children's Hospital of Philadelphia, Dr. Bauer has now got 29 MCT8 deficiency patients that he either treats or consults on, and he thinks that that's just scratching the surface. We think that this is severely underdiagnosed. Two very important initiatives that we're gonna be focused on in North America are disease awareness, as Henrik mentioned, and patient identification. Awareness of MCT8 deficiency in the United States, even amongst pediatric neurology and endocrinology, is relatively low. When caregivers first identify something is off with their child, they're looking for a clinical manifestation like hypotonia. What we want doctors to think is, "Okay, I need to do additional thyroid testing." We're aiming to educate and advocate to add T3 testing to the standard thyroid function panel, so that we can start to uncover these MCT8 patients.
In addition, we're looking to obtain a specific ICD-10 code in the United States. This will help for us to be able to code correctly, doctors to be able to code correctly, and also get reimbursed for the drug correctly once we're launched, and we intend to submit for that to CMS by the end of the year. In addition, we would like to roll out a sponsored genetic testing program where when a physician or a patient is identified or there's a suspected MCT8 genetic malfunction, so we want to provide this sponsored genetic testing. We're pleased to report that the FDA has requested to move to an expanded access program versus the high demand for single-patient INDs, or investigational new drugs.
This new program will not only provide a simpler process for patients and clinicians to get early access to Emcitate, but patients who wanna continue Emcitate after the ReTRIACt study will easily go into this program and be able to access Emcitate through expanded access program. When we hear from caregivers of these patients, they are concerned about easily getting their children, once they're diagnosed, into this expanded access program. They're also concerned about early diagnosis. What really is concerning is the inappropriate utilization of drugs that can worsen the symptoms and cause further brain damage. We're really focused as an organization on patient advocacy efforts, and we wanna educate stakeholders like the FDA on the patient voice so that they can understand, you know, some of the unmet need from the patient and caregiver perspective.
We'll be moving forward with initiatives to be able to do that. This quote is from a mother of an MCT8 patient whose child was prescribed an inappropriate drug which severely impacted their development and resulted in further brain damage. This mom often wonders if she had a diagnosis at birth and were given an appropriate drug right away, where her child would be. The pricing and reimbursement of ultra-orphan drugs is relatively straightforward in the United States. We select analogs based on similar value drivers, in this case, epidemiology, pediatric patient population, no FDA-approved treatment options, and chronic treatment and the severity of the disease. We then conducted payer research with commercial and Medicaid payers, our two top payers that we anticipate for Emcitate. We confirmed with them that they agreed with our value drivers.
We've aligned on U.S. analogs, ranging in price from $500,000 a year to $750,000 a year, for this particular research. A proven solution for rare disease product access and reimbursement is through an exclusive distribution model. A single specialty pharmacy will act as a hub for the clinician, the patient, and the payer, and the company. When a prescription is written of Emcitate, it will go directly to the specialty pharmacy that we partner with, and they will navigate the approval process with the payer. They'll work directly with the physicians and the caregivers to make sure from a outcome standpoint that we're providing a white glove experience to any physician and any patient who wants access to Emcitate.
We'll also be working with the specialty pharmacy to implement our patient assistance and co-pay support, and it's our aim, our goal as an organization, that no family will pay out of pocket for Emcitate. In summary, significant progress has been made to establish Egetis Therapeutics U.S. and build out the infrastructure to support the North American effort. There is a high unmet medical need that's been confirmed by the conversations that we've had with doctors in the U.S. We're gonna be rolling out a sponsored genetic testing program that will support patient identification. We'll be continuing efforts working with the patient advocacy groups and the patient foundations to include the patient voice as the FDA considers our application for Emcitate.
We have confirmed the fact that there is a significant market opportunity, and the value drivers for Emcitate will have basically been confirmed and that there will be broad access and reimbursement through payers in the United States for Emcitate. Thank you. I'm gonna turn it back over to Nicklas.
Thank you, Sara, and thank you, Henrik, and I'll invite Peder up to the panel as well. It's now time for more Q&A, and you can ask any questions, of course. We have around 15 minutes for this, and then we'll take a break. Ulrik, you were quickest grabbing the microphone, so the floor is yours.
Thank you very much. I was just wondering regarding the prevalence of the disease, one in 70,000 males. What are you basing these assumptions on? Are there any sort of country-based evidence that this should be the prevalence? Anything in the literature, could this be half or what are you currently basing this on?
Do you wanna go first, Peder, or we might invite Edward to give your view as well?
Do you want to start?
Yeah. Well, actually, it was us who brought up this figure.
Sorry to put you on the spot, Edward. It wasn't deliberate.
I'm the first to say this is an estimation, but it's based on something. First it all started that at a certain stage in the Netherlands, which has a population— in which every year, like, 140,000 babies are born, like 70,000 baby boys. We had in every age category one child. We thought, well, that should be the order of magnitude. There have been three cohort studies in which patients with X-linked mental retardation have been screened for MCT8 mutations. Actually, I've done one of these studies, thousand individuals in the Netherlands with unexplained mental retardation. You can do some math, so how frequent the X-linked mental retardation occurs in the population.
Even if I took all, let's say, assumptions on the conservative side, again, we reach, like, one in 50, like one in 100,000 individuals. As a last example, we got aware of 12 new German patients identified in the last 20 months or so, all below one and a half, two years of age. In the German population, 400,000 male individuals are born. Again, if that's, like, five, six per 400,000, then this is so—I think from three different directions, it all comes down to this order of magnitude.
Great. Thanks for the clarification. Just on the pricing, did I hear you right that the price was to be based on your discussions with payers to be between $500,00 and $750,000 per patient in the U.S.?
Maybe I can start 'cause I think it's important. Of course, pricing for Emcitate in particular, both in Europe and U.S., it's a bit premature to speculate on the exact price. I think what we're trying to illustrate is that pricing, of course, is set based on through established guidelines and so on in the respective jurisdictions, both in the U.S. and as well as in Europe. What we try to illustrate here on the screen is more around similar type of analogs with disease severity and prevalence in the U.S. They are priced in the ranges on the screen. Let me be clear, that's not what we see them to try to put Emcitate price that will be 'cause it's a bit premature to discuss that. Sorry, Sara, you might wanna comment a bit on the drivers in the U.S. and how it's priced.
Yeah. I mean, you pretty much handled it, Nicklas. I would agree with that. It is premature to discuss price. We do an analog analysis first, and then we do payer market research to understand at what levels, you know, and what value drivers payers see. We confirm that the value drivers are resonating with payers, which is a good thing, but we have not landed on a price yet.
If I were to rephrase my question, your best guess is that it's going to be priced between $500,000 and $750,000.
It's good effort, Ulrik, I have to give you that. As I said, no, honestly, we're not gonna speculate on the price here. What we try to do is really to calibrate how we see the value proposition, and then, of course, the pricing will be set at such a level, which I think is important, and Sara mentioned that as well, that the families shouldn't be paying out of pocket. We have the local guidelines and established processes in order to do that. The U.S. is different to Europe. Within Europe, there are different guidelines in different countries where some jurisdictions, like the U.K., requires in-depth, detailed health economic data, and others doesn't. It's gonna be on a case-by-case and country-by-country basis.
Just one more. Sorry to sort of be stuck on the pricing point here, but it tends to be quite important when valuing a biotech company. Just how important is it for you to show these are clear benefits of the neurocognitive functions in order to obtain this price? As well, Henrik, given your focus, and your focus on the European market, what would be the sort of major hurdles to have sort of Emcitate being priced at sort of a very, very high price point above EUR 100,000 per year?
Yeah. First of all, I think echoing Niklas here, it's too early to really comment on the price for us. I mean, you know, in Europe, the situation is very different in different countries how prices are assessed. We know that we have a very strong— because we have also performed payer research in Europe, that they really recognize the value that we already have demonstrated with the metabolic part of the disease that Edward shown.
We also know that in an ultra-rare setting, easier to get reimbursed, also with higher price levels. The more rare the disease is and the more efficacy that can be demonstrated, the better in those cases.
Just then back to the one on neurocognitive and metabolic effects. Given that, I think, the awareness of this disease is that it has a dual effect, and price point must differ if you can only show benefits for metabolic even though it's the only option there is out there, right?
Maybe I can start, Henrik, and I think this is a very important and valid question. I'll come back to, I think, what we have generated so far and how we see the submission in EMA based on the clinical data we have generated from TRIAC Trial I, the EMC Cohort Study, et cetera. It's a strong value proposition. I think from our perspective in discussion with payers and then reimbursement authorities, it's gonna be a dialogue based on the established processes. We really showcase our value proposition, and then it's a negotiation. With the key aim, of course, again, that families shouldn't be paying out of pocket. 'Cause at the end of the day, there's no point having a drug that is priced extremely high without being reimbursed, right?
Great. Thank you.
Thank you, Ulrik.
Thank you. Gonzalo Artiach from ABG Sundal Collier. I have a question. I mean, you are describing now a quite intense period in front of you. Based on this, combined with your current cash position, how can we think about or what can we assume in terms of the study in RTH-beta to start realistically? Could it start before the approval of Emcitate for MCT8 deficiency or after?
Thank you, Gonzalo. That's a very, very good question. I will come to the financial situation and the cash runway towards the end in my summary remarks. When it comes to, I hope we will get an answer there. When it comes to RTH-beta, I think Peder touched upon it, we see that as a very exciting opportunity. But we also need to recognize that we don't have unlimited resources today, as well as further need to investigate the feasibility in a clinical study in that setting. As you probably know, the RTH-beta indication is much more heterogeneous patient population.
We have some work to do internally, and of course, in the discussions with Erasmus Medical Center, how would a clinical trial look like design-wise in this setting? When we have established that, together with, of course, looking at the pros and cons of doing it, we'll communicate to the market.
Okay. Another question in this indication in RTH-beta. Well, I guess that probably you don't know yet, but how hard will it be or easy to expand the label of Emcitate? It would be possible to do with one study, a big, good study, or it could be done with two? Yeah.
I mean, in general terms, again, remains to be carved out in more detail. I mean, in general terms, the second indication, I mean, then you need to add efficacy in that indication. You don't have to add everything else. In a scenario where we are already approved, the hurdle, of course, is lower to gain an indication for the second indication. I mean, exactly how a trial would look like for an approval of RTH-beta as a follow-on to MCT8, I guess we just have to come back to you.
I think it's a valid point, and hence why I was a bit vague in my answer to you. That obviously from our perspective, and again, we truly believe that we have a differentiated capability within the whole organization. It's really spending some time in considering a design, because the optimum approach would of course be just one single pivotal trial up until and then approved.
Thank you very much.
Thank you. Johan, the time is yours.
Thank you. Yes. Two questions. The first to Sara. This early screening, genetic screening then, is that directly towards the 25 specialist centers of excellence? And how likely is it to be in place, and what within what sort of timeframe after approval?
Yeah. We're in the process right now of evaluating partners to be able to implement this program. We have to get out there in those centers to start talking about the disease and start to raise awareness to even offer this program. Once we get the regional medical affairs directors on board, which we're targeted hopefully by the new year to be able to get them on board and in these 25 centers of excellence, we anticipate that we'll start to get requests for the sponsored genetic testing right starting in the new year.
The mechanics there, like the specialist, was it [Bern]? Professor [Bern] and 25 patients, I think, on the slide. He alluded to that it was only the most severe cases. I guess parents will start to be worried already after a couple of months. Is that when you would hope to screen?
Yeah. I mean, the earlier the better. In combination with our disease state awareness efforts, if they're doing the thyroid screening that we're suggesting and they're noticing an elevated T3, among other criteria like hypotonia and some of the other clinical manifestations that maybe sometimes are missed, then, you know, we're educating, we're talking about MCT8 deficiency and then offering them a resource like free genetic testing. Because in the U.S., even though genetic testing has really become the standard of care, there's still some financial barriers to some of the families being able to have it done. For us to be able to offer this is just. It's not just a benefit to us because we'll be able to capture the data, identify more data, but it'll be a benefit to the patient as well.
A related question to Dr. Visser again. Early screening and discovery seems to have a very good effect on neuro side, and preclinical, it could be extremely good. But what about the physical metabolic side? Is it a similar dynamic, or can you make a significant improvement if you are diagnosed sort of more typically to age two or three or four or five or whatever?
I'd like to emphasize that I'm not over-interpreting my own data on the, let's say, the neurodevelopmental side. Actually, what I do believe, however, and I think there's also the data supporting that, is that the metabolic phenotype can be alleviated irrespective of the biological age. Basically this first study, the TRIAC Trial I study, had numerous adult patients included, and we did see similar effects.
Excellent. It was a sort of very disturbing proportion that was actually dying early on. Could that be sort of hopefully related then to metabolic improvement, even if you're diagnosed later?
Hopefully, but any answer would be true speculation. Yeah.
Thank you. We have time for one more question, and it's break then. Johan, please. Niklas, if you don't mind passing the microphone.
Thanks. It's just on the early access program. So you've got about 160 patients or more than 160 patients at the moment. Just wondering, because I know that the bottleneck you've spoken about before in the U.S., individual INDs per patient. How many patients out of the 160 plus are from the U.S. at the moment? When you kind of get to this, you know, more broadly regulated program where it's easy to include patients, how does that change the dynamics of U.S. patients in there? How many more immediately go in there? How can it grow? Can you give us any idea, any numbers?
Maybe I can start. We actually have quite a substantial number in its teens of patients already under the umbrella Named Patient Use program or managed access. Those patients, all of them comes from the single patient INDs, which is very cumbersome for physicians to actually write and apply, et cetera. We are actually very pleased that the FDA, it's the FDA who requested us to submit an application for an early access program, because obviously there is a bit of a hassle for the FDA as well to sign off all these single patient INDs. We don't know exactly how many patients there are. Sara quoted a number that Professor Bauer at Philadelphia at CHOP has identified 29 patients or diagnosed 21 patients, that he actually are aware about.
Not all of them are under treatment today with Emcitate. We would expect, and I won't speculate in numbers, but of course the number will go up, no doubt.
Thank you. With that, I think, it's time for a break. 15 minutes break and coffee. Thank you.
Thank you very much, and welcome back to the last part of the agenda. What we have today or what we have for the remaining of the afternoon is really slightly shifting gear. Starting to look at our second orphan drug candidate, Aladote, for the prevention of acute liver injury caused by paracetamol poisoning. We have the same setup as before the break. We'll start off with an overview of paracetamol overdose, the clinical manifestations, as well as the clinical experience of using Aladote for the same. We will then move on to the development path for up until approval in both U.S. and Europe, and summarize the commercial opportunity for Aladote, again, with focus on Europe and U.S., and then wrap it up with a Q&A. We'll then move on to a summary of the day.
We're gonna summarize what we have heard during the afternoon, but also considering a bit about the strategy going forward and how we're gonna plan to execute and implement that. Ending up today with some closing remarks from our Chairman of the Board. With that, I'm very pleased to hand over to our second key opinion leader for the day, Professor James Dear. Thank you.
Thank you very much, Nick. Thank you for the invite to come and speak. My name's James Dear. I'm from University of Edinburgh in the United Kingdom. It's very nice to be in Europe, and I wish I could stay quite a lot, actually. I'm gonna talk about paracetamol overdose and our experience to date with Aladote. I mean, the first message really is that paracetamol is the world's most used drug, and that's really one of the basis of why overdose is a problem. Paracetamol across the Atlantic is acetaminophen. I've never managed to give a talk where I've not had an acetaminophen slip into the slide, so forgive me. Paracetamol overdose is common. It's geographically variable, but it is a common phenomenon. Particularly common in the United Kingdom.
On this slide, we are there with about 100,000 people attending emergency departments every year following a paracetamol overdose. That's one every five minutes, and it's the same as having a heart attack. Now in other countries it's less common, and it tends to be more common in Northern European countries and get less common as you go to the south of Europe. It's also common in America, although, as you can see, these are absolute numbers, and so per population, actually, the U.K. is very high. As you see, it gets much less in Germany, France. It's relatively common. Of the people who come to hospital having overdosed, about half need treatment, and of those half, about 1/4 of them don't, at the moment, have a fully effective treatment for reasons we'll come on to. It still kills people.
In the U.K., it probably kills about 200 people a year. These are young people, typically, with no other comorbidity. And also it's the commonest cause by far of drug-induced liver injury and the commonest cause of needing a liver transplant to prevent death in somebody with acute injury. A substantial public health concern. Let's put it in context of a few other giants of emergency medicine. These are data for England. You see paracetamol is about the same as breaking your hip. About the same as having heart failure. Depends how you code it, but as I said earlier, it's about the same as having a heart attack or having COPD. These giants of attending hospital as an emergency, paracetamol overdose is certainly one of them. American data we already mentioned, it's around 82,000 emergency department visits following... See, I've got it there, acetaminophen overdose.
The problem with paracetamol is liver damage. You probably all know this. It's the liver is the organ that gets damaged, that kills people if we don't treat them. I'm not gonna go into too much of the science here. It's after coffee. I don't want you all to nod off. We understand the mechanism of paracetamol toxicity. We have mouse models that faithfully represent or faithfully replicate the human. When you take a paracetamol tablet in a safe dose, predominantly it's conjugated and excreted. A small amount goes by the P450 enzymes to a metabolite, and it's this metabolite, NAPQI, that causes the problems in the liver. In a normal dose, glutathione conjugates the NAPQI, and it's safely detoxified. If we go on to the overdose setting, these safe pathways become saturated.
You produce more of the toxic metabolite, which then exhausts the glutathione and covalently binds to proteins in the hepatocyte. The key thing here is this causes oxidative stress, and that oxidative stress pathway leads to liver cell death and, if it's not treated, acute liver failure, patient death. We have a treatment. We have one treatment only, and that's acetylcysteine that I'll come back to. Acetylcysteine works by replenishing the cell's glutathione stock. I just wanna sort of to paint a picture of what we do, talk a little bit about who gets treatment and then how do we treat them now and where does Aladote fit in and what data do we have? Who gets treatment? I mean, perhaps actually the first question should be who are these patients?
80% roughly of the patients, this is an act of deliberate self-harm. Deliberate self-harm is common in all societies. It's actually fascinating. It's equally common in all societies. Deliberate self-harm is an expression of how angry you are at somebody. I'm so annoyed at you, Nick, I take an overdose to tell you how annoyed I am. That's what deliberate self-harm is. It differs by country in how you do it. For instance, in South Asia, people take pesticides because they've got pesticides in their house. In Britain and in other countries, paracetamol is the world's most used drug. That's what people reach for to take. 20% of people, it's accidental, and that is, "I've got the flu classically, and I've taken too much paracetamol, plus I've taken another product that's got paracetamol in.
I didn't realize, and then suddenly I realized, and then I went to hospital." They're the patients. As you imagine, deliberate self-harm typically are people who are younger. How do we assess somebody when they come into hospital? Just give you a picture of what happens. Now, as with most things in the U.K. these days, we do it differently and, you know, this is being recorded, so I can't really get away from it. Everyone else does it better. We say to the patient, "When did you take the tablet?" Then we measure the blood paracetamol concentration, and we have a line. That line, it doesn't really matter where it is, it's a slightly different position in Europe and in Britain. If you're over that line of time from overdose to the amount of paracetamol in your blood, you get treatment.
Certain problems with that. Let's take the example of, let's call them Mr. Black and Mrs. Red. Mr. Black's just over the line, has got a normal liver. Mrs. Red is way over the line, is presenting later, and has already got liver injury. At the moment, we treat them both the same because we've got no other treatment, and we give them the same dose of the only drug we've got, acetylcysteine. As you can see in America, actually, Mr. Black would be under the line, so he wouldn't get treated at all. Just showing that the U.K. is a little bit more conservative. One of the things we've been working on that I'm not gonna touch too much on, but just because it feeds into the Aladote data, is identifying new diagnostic markers, new biomarkers.
'Cause what we do now, ask the patient, get the history. Naturally, the history could be uncertain. We risk stratify based on the paracetamol concentration, and then we treat, and we have to wait until the liver enzyme tests that we use to say, is there liver injury or not, have either been proven to be normal or have become abnormal. What we need is a new blood marker that can push us that way, that we can identify patients quicker. I'll bring this marker up because it comes up in the trial later. That's a marker called [cytokeratin-18] that ourselves and multiple other groups have shown is a more sensitive and specific marker of liver damage. The details about the protein don't really matter other than to say it's liver- specific and is released by necrotic liver cells.
Let's give you an example of how this could be used. This is a true story. 25-year-old man took a large overdose of paracetamol. For anyone who knows Edinburgh, he took it at the top of Arthur's Seat and then walked down to the hospital. It took him about four hours to get to the hospital. Here it was assessed about 4.5 hours after the overdose. He'd put a message on Facebook, saying when he took the overdose. We had some collateral history of when it was. He had no risk factors. His paracetamol level was 100. He was below the line. He was seen by the doctor at the time, assessed, correctly assessed and discharged. He came back because he was unwell. He came back. Paracetamol's now gone down as it should. Time's gone. He's metabolized it.
Now he's got substantial liver injury. The ALT, which is the sort of gold standard liver test, should be less than 50. It's now 11,000. He's got substantial liver injury. The INR, which is a measure in this case of liver function, has gone from 1 to 2.1. This patient's in a lot of trouble. If we had measured the early biomarker, K-18, we would have seen clearly that at the first time point, it was eight times the limit of normal. Would have clearly identified him as a patient who was at risk. K-18, before we move on, is also endorsed as a regulatory marker by the FDA and the EMA. That's a little bit about who the patients are and how they're currently risk- stratified. How are they treated and where would Aladote fit in?
Well, the only treatment we have is acetylcysteine. Acetylcysteine is an infusion given typically over 21 hours. It causes quite a few side effects, but the most important thing for today's talk is it's only optimally effective if it's given soon after the overdose. Which makes sense because once the metabolite's been formed and the oxidative stress has happened and the liver cells are dying, you've missed the window. This paper from the New England Journal of Medicine shows it very clearly. This is the delay to treatment from taking the overdose to starting acetylcysteine. What you see is between four and eight hours, it's very effective. Then after eight hours, it started to lose efficacy. In fact, acetylcysteine probably doesn't work at all after about 20 hours delay. Then there is no treatment.
We treat them with acetylcysteine because there's nothing to lose, and it may reduce the risk of encephalopathy. These patients then are monitored, go to ITU, may have to have a transplant, may die with no treatment option. That's the gap that we're trying to fill, and we're trying to fill it with Aladote, calmangafodipir, which is a superoxide dismutase mimetic. Essentially, it acts on the oxidative stress that is downstream of the toxic metabolite. Here's a nice figure from a review, essentially showing this is calmangafodipir here, but essentially showing that it's acting on the mitochondria where the oxidative stress is particularly critical for this disease. We understand the pathophysiology very well. That's its action. Its action is downstream of NAC.
Therefore, it should, and animal data shows, that it works later than NAC at a time when NAC or acetylcysteine is no longer active. This resulted in doing the clinical study, the first clinical study with Aladote in paracetamol overdose. This is a phase I clinical trial that we completed and published just before COVID. Just to go over it, it's a study of Aladote at three different doses in addition to standard care with acetylcysteine, and there were three cohorts. The first cohort, six patients got Aladote 2 umol/kg and NAC or just NAC alone. There was a DMC review, and then it was dose escalated to the next cohort. These were randomly allocated to five, six patients or to NAC alone, DMC review, dose escalation, randomly allocated 10 umol/kg of Aladote and NAC or NAC alone.
What we ended up with were six patients in four groups, NAC alone and then three different doses of Aladote. The patients were patients who had taken a paracetamol overdose who needed treatment with NAC, and the primary endpoint was safety, tolerability as a phase I study, but we obviously collected efficacy data, including the biomarkers we talked about. Here's a little bit more of an overview. Acetylcysteine was given, and then essentially Aladote or nothing. There wasn't a placebo. There was nothing. There was blood sampling, as you'd imagine. There was safety assessments, as you would imagine. What did we find? We look at the primary outcome of safety. There were adverse events in all the patients. These are patients who've taken an overdose, will be vomiting, will have symptoms. However, there was no AE or SAE related to Aladote.
Essentially the safety endpoint was reached. There was no safety signal of concern. Was there any evidence of efficacy? These are predefined outcomes, all of these in the protocol, of looking at the increase first in ALT, which is the classic gold standard liver injury marker. If we look at people who've got a 50% increase, a 100% increase, greater than 100%, greater than 100% at 20 hours, we see with NAC alone, we see some injury that we don't see with Aladote. Only [N=6] per group. I'm not gonna overstate this, but there's a signal, a suggestion of a signal with ALT. If we go on and look at the more sensitive marker I introduced earlier, that being [cytokeratin-18], we see a significant signal.
We see with NAC alone a rise in K18 and an isoform of K18. For this talk, they don't matter too much, but they both show the same thing, which is reassuring. This is what you'd expect. When we give Aladote, we see a significant decrease. We don't see a rise, in fact, would be the best way of describing it. There's significant signal in this marker that even with just six patients, there's activity. Okay, I don't want to overstate it. It's a phase I study. I'm just gonna sum up with some key points. Paracetamol overdose is common. The current treatment is inadequate. We know there's only one drug, and if your window of opportunity, a narrow window of opportunity. If you're outside that window of opportunity, we don't have a treatment.
Because of new markers, we can sort of galvanize the research a bit by being able to identify more subtle signatures of activity. From the phase I study, we saw that Aladote had no safety concern, and there's a suggestion of activity both on ALT, the gold standard marker, and on more sensitive markers, which we can take forward into the next study that I think the next speaker's gonna talk about. Thank you.
Thank you. Hi. Hello, everyone. I'm Kristina Sjöblom Nygren. I'm Chief Medical Officer and Head of Clinical Development at Egetis. I've been working at Egetis for a little bit more than a year. I have over 25 years' experience from clinical development, global, international, mainly late-stage clinical development, and I worked with several pivotal studies and had many regulatory interactions on development pathways. The last 15 years, I have worked with only rare diseases and that's really my passion, so I'm very happy to be here at Egetis. Now I'm going to talk about the development path for Aladote in Europe and in the U.S.
I think you heard clearly that there's a huge unmet medical need for treatment for late presenters of paracetamol overdose, with several hundreds of patients dying every year or getting damages to their livers. I think it feels really good that we now have a study in this indication, and we are planning to enroll patients that have been overdosed with paracetamol and that present more than eight hours after their overdose to the hospital and that requires NAC treatment. In the protocol, we will add our treatment to the standard of care 21-hour NAC treatment protocol. We will evaluate four different groups, so three different dose groups, low, middle, and high dose and versus placebo. Then we will select one dose and continue with one dose versus placebo.
The aim is to treat patients as soon as possible as they reach the emergency room, but within four hours so that they will get an IV bolus of the investigative drug calmangafodipir. As I mentioned, we will do an interim analysis when we have reached 35 patients per treatment group. We will do a futility analysis, a dose selection, and also we will look at the size of the study. We plan to enroll 250 patients. We will have approximately 20 sites in Europe, U.K., and U.S. I'm happy to say that James Dear, Professor James Dear, will be our coordinating investigator in the study. The primary endpoint will be a combination of ALT and INR, that's liver biomarkers.
We will also assess number of patients who need extended NAC treatment after 21 hours. We are assessing length of hospital stay. Of course, we are assessing all the exploratory biomarkers that Dr. Dear mentioned, like K18, miR-122, and GLDH. Here is a schematic of the study. We call it the Albatross study. It's Aladote phase II-B/III study design. As I mentioned, there will be four study groups, and we are looking to have 1 umol/kg and NAC, 5 umol/kg , 10 umol/kg , and NAC and placebo, and 35 patients per arm. When that is reached, we have 140 patients for the interim analysis, and we also have a data safety monitoring board that will assess safety and that will work with us with the interim analysis.
We will assess futility at this time point, and we will also decide which dose is most effective of those three doses, and then continue. We can increase then the number of patients for the best dose, so there will be 55 patients in the active arm and 55 in the placebo arm, so that we finally reach 250 patients. We are finalizing the study. The primary endpoint, as it reads in the protocol, we are looking for patients then without hepatic injury that would have INR at 1.3 or less and ALT below 50. Or it's also possible to have INR less than 1.3 and ALT more than 50, but not increased by more than 10% up to 20 hours. That's the primary endpoint.
I have a last slide, and it's the timelines. I'm happy to say that we are really gearing up to get started with this study, and we are now submitting the clinical trial applications, and we plan to start early next year. We hope to, during 2024, to do the interim analysis, the 140 patients, and to complete the recruitment and present the top line results, which will lead us into 2025 for regulatory submissions in Europe and U.S., and hopefully have an approval in this very high unmet medical need indication to prevent acute liver failure. It will be the first treatment approved in this indication then. We will also perform regulatory submissions in the rest of the world.
I also would like to mention that we do have orphan drug designation in both the U.S. and EU, and we have a composition of matter patent that expires in 2032. That's all for clinical development for this time. I hand over to Henrik.
Thank you. A few words about the commercial opportunity for Aladote now. It's clear that bringing another antidote for the treatment of POD would have a huge benefit both for the patients but actually also for the society since it is related with quite some costs. For example, in the U.S., the annual cost has been estimated at more than $1 billion to treat the patients with POD. The POD emergency department and inpatient costs is approximately $13,000-$40,000. We also all are aware of that the cost for liver transplantations are significant. Bringing an antidote that works well to this field would really add benefits both to patients and the society.
If we look at the conditions then in this setting, just as for the setting in Emcitate, we see that we have the possibility to commercialize Aladote in a really cost- effective way. This is really based on the conditions here. It's clear that we are looking at an unmet medical need here, so those patients coming in late to the hospitals where the current treatment not is sufficient. We are working with Professor James Dear and other experts in this area to develop Aladote, and we will continue to broaden this KOL base. With antidotes, there are actually this kind of national emergency treatment guidelines.
That means that while getting into those antidote guidelines, hospitals store these antidotes, and that means that one doesn't have to visit and target every single hospital, but we can work through these medical experts being involved in this guideline. Therefore also here, we don't see a need for a significant or a large sales force organization. Also here we are the only company having an active clinical development program for POD. If we then also look a little bit on different antidotes, and there we have, for example, those drugs that are used to reverse anticoagulant treatment, like Praxbind and Andexxa, and they are priced in the range of $3,500-$50,000.
Also interesting when looking at the sales uptake of these analogues is that it's quite impressive already the first year after regulatory approval. That is really thanks to these national emergency hospital stocking guidelines. Getting in there, the drug is available at the hospital and is being used when needed. We believe that we will be able to actually work with a quite lean organization to also take care of the Aladote commercialization. Just as with the Emcitate, we are focusing our efforts in Europe and North America, and we are planning to commercialize through partners in other regions of the world.
If we look at the number of patients, and James already touched a bit on this, so these are the numbers that are hospitalized for POD treatment in U.S. and Europe respectively, and also get treatment, so today NAC. About 1/4 of these patients are late arrivals. That's where we definitely can hopefully make a big difference with Aladote. To conclude, I just had a few minutes here, but it's really clear that there are a number of patients that would benefit from a new antidote in the POD setting. We see really the possibility to commercialize Aladote with a very lean and cost-effective organization. Thank you.
Thank you very much, Henrik, and thank you, Kristina and James. I would like to invite all of you up here, and we'll start the Q&A session with focus on Aladote. Samir, you were the first one raising your hand. You will have one in a second.
Thanks for the presentations. I'm just wondering a couple of things on, I think Professor Dear, you talked about 100,000 in the U.K., 50,000 that get treatment. I'm just trying to. You didn't mention a timeline in terms of the study. Is there a specific timeline after which patients can only get Aladote in the clinical trial? 'Cause it seems as if it's taking you quite a while to do this study when the incidence is clearly quite high. Is this trial gonna be stratified by the degree of overdose the patient has taken?
Yeah. Sure. I'll answer that. You're quite right. The trial will recruit people who are greater than eight hours after the overdose. That's the unmet clinical need, the late presenter. It will also take people who are over— You remember those two lines? It'll take people over the 150 line, which is the line used in Europe and America. That's higher than the English or U.K. line. It'll take people who've taken larger overdoses later.
If you were then just to estimate from the 100 to the 50,000 to the over eight hours and meeting that barrier, what sort of proportion of patients do you think that is?
We know that of the 50,000, around 25% are late presenters. Let's say we call that 10,000-ish. And then of that, probably around 8,000 in the U.K. would fit that kind of criteria.
Just on stratification by overdose. Assuming if you have 80 g of paracetamol, you're gonna have much worse INR data than somebody who's had 35 g.
Yeah. What we do is we'll take people who are over that line, and then we can also take a line, say, at 200 and analyze those as well. Because you're right, the risk factors for doing badly, as you'd imagine, are having a high paracetamol level and coming late, and actually already having liver injury when you come in. That's the other factor that we look at.
Kristina, do you wanna add?
No, I just wanted to add that we are not stratifying, but that we are, of course, analyzing it as James said.
Thank you. Fredrik?
Thank you. I was wondering about the statistical power. Have you communicated that for the phase III trial?
Yeah, I mean, the trial is powered, I think at around 85%-90% t o detect a difference of, I think it's around 1/3 reduction in the prevention of liver injury. The primary endpoint is preventing liver injury, 'cause this is why you're giving the treatment. It's going from around 75% of people not having liver injury to I think it's around 90% not having liver injury at, I think about 85%, 90% power.
I think to build on to that and as Kristina alluded to when we looked at the development pathway, there's also an opportunity as part of the interim analysis. Interim analysis is very important for efficacy and dose selection, selecting the best dose moving forward. An opportunity for a sample size re-estimation as well, making sure that we're meeting the criteria as James alluded to.
Thank you.
Thank you.
Yeah. Is the kind of format of the NAC regimen the same everywhere? In every country you look at, especially in the ones covered in the trial? Is the 21-hour regimen the gold standard? If it's not, I mean, could there be any kind of interference in the data from differential use of the NAC regimen?
The different measurements are used in different countries. That's quite right. The 21-hour regimen's chosen because that is the licensed regimen, and that is the licensed regimen in essentially all countries. All countries will use that and will recognize that. Absolutely there's variability hospital to hospital, but in the trial, we'll standardize it by using that licensed regimen.
Great. Any further questions? If not, let's move to the summary of today. Let me start off summarizing the day and where we stand as a company, more from a corporate perspective, and then narrow down into the different assets. I'm very pleased to see the significant progress we have had over the last two years, and where we need to recognize that this company has been in its existence for less than two years. We are well on the way of creating a sustainable orphan drug company. We have a clear vision of bringing unique therapies to patients with rare diseases that could extend and improve quality of life for patients.
To measure the journey, as we've heard today, the objective of successfully develop Emcitate and Aladote for market approval in 2024 and 2025/2026 respectively, well on track for that, which is very pleasing. The commercialization highlighted by Henrik and Sara, especially with focus on Emcitate, which is in the near term, is also progressing as planned with focusing on activities such as disease awareness and access. We also have an objective that you heard this morning around realizing the full potential through life cycle management. We are in the process for Emcitate, for example, on looking at feasibility for an indication expansion into RTH-beta. There, we'll come back to the market at that early next year or mid next year, looking at the potential development pathway with an optimal one study for approval.
Another key objective that's touched upon today is around the broad and fast access. You heard us speak about how we're gonna work with access, already engaging with payers and reimbursement authorities, making sure that we can do this in the most optimal way without patient paying out of pocket. The one thing on the objectives in our journey to actually creating a sustainable company is identify further assets. This has been one objective that I haven't mentioned that much in detail.
What we are doing in parallel to the intense efforts around developing Emcitate and Aladote is also Peder and myself very much focusing on identifying new assets within the orphan space where we again can add the experience and, in my humble opinion, the differentiated organization we have in place for taking a potential new asset with an optimized one additional study to market approval. Last but not least, that will of course, if we're delivering on those aspects, create increased value for shareholders. Focusing on our two assets then and trying to summarize that in a simple way, you heard an overview from both a medical standpoint, medical needs standpoint, the clinical data at hand, regulatory pathway.
Starting off with Emcitate for MCT8 deficiency, the ultra-rare condition that Edward so well described with a prevalence of 1 to 70,000 males roughly. No approved therapy, a detrimental condition, and no products in clinical development besides us. Regulatory features such as orphan drug designation, pediatric disease designation, as well as Fast Track designation sets us up very well for submissions next year in U.S. and Europe. We also have the ongoing TRIAC Trial II focusing on the neurocognitive phenotype that will read out in first half of 2024. Last but not least, of interest in Emcitate and the increased disease awareness has led to a substantial increase in patients already now being treated under our Managed Access Program. More than 160 patients in over 25 countries.
For Aladote, as you heard from Professor James Dear, paracetamol, one of the most used drugs in the world, but also one of the most commonly overdosed drugs in the world. There is an unmet medical need for patients that arrive late into the hospital. Here again, we have successfully discussed with the regulatory authorities, the EMA, the FDA, and the MHRA on a design of only one additional trial for market application. It's a phase II-B, phase III trial called Albatross, which will start off early next year. Focusing a bit more on the commercial side of things, because that was something that was fairly new today for the audience, I would say again reiterating our ambition for a fast and broad access for patients worldwide.
What I haven't mentioned is when we talk worldwide, we are looking for partnerships in jurisdictions outside the U.S. and Europe, and there one can imagine that those discussions has been accelerated or intensified over the last period, especially in those jurisdictions where potential additional work is required for approval, such as Japan or China. There we have got a lot of interest in Emcitate and are having discussions on potential partnerships going forward, again, ensuring broad access worldwide. We are in the process of establishing stepwise and responsibly a commercial in-house organization to maximize the value of the commercial opportunity we have for Emcitate. The organization is heavily focused on two areas today. It's disease awareness and diagnosis, very important for the caregivers, for the patients, but also for us as a company.
Also, in parallel, continue to generate a strong value proposition for the payer and reimbursement activities around approval. Before I move into the financials, I would also like to reiterate a very important aspect that plays a role, of course, into financials as well. As Peder mentioned, we're eligible for, or we have a Rare Pediatric Disease Designation, which means that we are eligible for a priority review voucher. Those vouchers can be sold by the sponsor at the time we receive it, i.e. approval. For a company like ours, it's highly likely that we will sell this.
The sales price, the so-called going rate for these over the last one-two years has been in the region of $100 million-$110 million, which of course will be a significant income for us being a small biotech company. Switching gear then and a brief overview of financials. I won't go through a P&L or the balance sheet because that's of course not exciting being a small biotech company. I think it's important to recognize that of course we are generating even though a little some revenue, and that is driven. We recognized SEK 11 million as revenue for the first half of 2022.
That is driven by the logistical fees we are charging as part of the named patient use program in the jurisdictions where they are reimbursed. Again, in the rest, jurisdictions where the named patient use program Emcitate are not being reimbursed, we are providing Emcitate for free. Cash position, we had a good question in the room that I promised to come back to. We reported cash of SEK 233 million, or roughly EUR 23 million and/or $23 million, at the end of quarter two. The question then was, how will the cash runway look like going forward? I would like to tie that into with the exciting upcoming milestones we have. Starting off with the upcoming milestones and then segueing into cash runway.
We see, as you heard from the speakers today, that we are looking forward to starting off the so-called ReTRIACt trial, the small placebo control in the U.S. for the new drug application, where we'll see results early first half of next year. For EMA, we are looking forward to filing based on existing clinical data, pending maturity of stability data from a CMC perspective on the first half of next year. A filing in the U.S. mid next year under the Fast Track designation that enable us priority review as well as a rolling submission. Subsequent launches then in U.S. and Europe approval and launches at the first half of 2024.
For Aladote, as Kristina mentioned, we have clinical trials applications being submitted imminently now in quarter four, with the study start in the first half of next year, and then interim analysis in 2024. How does that tie into the cash runway then and the SEK 233 million I referred to on the previous slide? What we have calibrated the cash runway to is we have enough cash to take us post the most important milestones we see as a company next year, which obviously are the submission in Europe and the submission in the U.S. We also are in a privileged situation when it comes to cash runway in the sense of we can balance.
When I say that balance, it means that we can balance or step how we stepwise invest in the establishment of the commercial infrastructure. Of course, we'll be monitoring our cash runway closely, and we can then flex up or down as we see. With that said, though, we then also all recognize, and we talked about the priority review voucher at the point of an approval in the first half of 2024. We see a gap between second half next year and first half 2024, where we need to bridge our financing. There, as you can imagine, we're looking at alternative ways of financing the business, everything from debt financing to, of course, traditional equity raises. I hope that answered your question also. With that, I will hand over to our Chairman of the Board for some closing remarks.
Shortly about myself. I'm an ex-regulator, 30 years of experience as an ex-regulator. Stepped down 11 years ago. Post-regulator, I have been working as a regulatory consultant for a Swedish company. Spent a lot of time in Boston, Cambridge, talking with a lot of biotech companies in U.S. Also a lot of orphan companies, of course, that I have been. I have had board positions, Egetis here as the chairman, but also board member of COMPASS Pathways in London. We are developing psilocybin for treatment-resistant depression. We had a Capital Day yesterday, and I was just looking at the share price. Well, hopefully, we will have the share price going up for Egetis tomorrow after this event, I hope. I have also a couple of advisory positions in companies and venture capital companies also.
2001, I took up the position as Executive Director of European Medicines Agency. The first thing I had to do was to implement the orphan drug legislation in Europe with establishment of the orphan committee, the COMP committee. That was, of course, challenging. The interesting thing with that was that the first committee in European Union Scientific Committee that had patient representatives. During my 10 years at EMA, when we developed the orphan legislation and got it up and running, to what more or less what it is today, I find the patient representatives in the committee was extremely valuable. Also how Europe developed the EURORDIS, for example, that together with EMA, was a success factor in order to get the whole legislation in Europe up and flying.
U.S. FDA was, of course, much earlier, as you know, with it. During that time, we also established the first collaboration between EMA and the FDA. That was a cluster, the orphan drug cluster, I mean, Marlene Haffner, who was the pioneer at the FDA in the orphan drug. When I left EMA, the orphan drug legislation went up and flying. We had many, many, many applications coming in and many designations of orphan drugs. I think that was one of the biggest success story when it come to regulatory reform in Europe. That's a little of my interest in orphan drugs.
When I got the question to be the chairman of Egetis, it was easy for me to take it over after Håkan, who is sitting here, to continue to work with orphan drugs, because it was a little passion for me to be involved in that, and especially also see all the patients and the good thing that we could do with patients. As you well know, there are nearly 8,000 rare diseases, and it's only a few of them, about 100 or more, that have some kind of treatment today. It's much more to do, I will say. We, Egetis, we contribute to that with two assets.
Of course, we have the ambition, of course, to continue to work as an orphan drug company and try to get more of this high unmet medical need products to the market, of course. We have two fantastic assets that you have been told about today. I think, going to the regulatory pathway, with my background, I have followed what the company are doing quite closely, and I think they have done the right way, interact with the regulators, both EMA and the FDA, in the right way at the right time, in order to go to them and propose the development program that we want to run. It's not the case that the regulators will tell you what to do.
It's up to the company to come with a proposal, how to design the clinical trial, and then get the feedback from the regulators. I think what the team really have done is have been reading the regulators in a very good way. When we have got to the regulators, we have come with very constructive proposal for how we are designing our clinical trials, and we have got very positive feedback from both EMA and the FDA. You notice there is a difference between EMA and the FDA. It look like EMA is more willing to accept real-world evidence as the basis for regulatory approval. FDA have asked for a small controlled clinical trial, as you have heard. There is a different between the regulators, even though that the regulators working quite closely together.
in summary, I think we are on a very good track in order to get a regulatory approval. We have done it exactly as it should have been done, and now it's up to see when we get the result of that little withdrawal study that we have in the U.S. and when we are filing to Europe in the next year, when we get our CMC data correct, how it goes. I quite optimistic that we will have a very good outcome, both in Europe and in the U.S. We have a fantastic strong team, as you have heard here. Nicklas, his team, fantastic team. we have a very engaged board, and we have a fantastic board with very experienced board members. Peder is here. Elisabeth and Gunilla is not here.
They represent really, really good knowledge in drug development and also in economics and commercial with Mats, who also is one of the board members here. I'm very happy about the board and the engagement of the board in the company. We got very good feedback from the management and Nicklas with all the developments going on, so that we in the board could have a real insight in what's going on. Nicklas is saying that we are building for the future.
With this strong team and this strong board, we have all the opportunity to continue to develop this company into a even greater company with not only two assets, but maybe new acquire other assets in the orphan space, using the competence that we have built up in the company in order to go into the future and maybe help to get a little more treatments for orphan disease. You know, there were 8,000, and not many of them have treatments. This is our ambition, and I think that will be the end of my little presentation. I know there is no questions after this, but you are very welcome to come to Nicklas or me if you have any specific question. I want to thank Edward especially and James for coming here.
I want to thank you who are here and you who are listening in. Thank you very much.