Good morning. My name is Audra, and I will be your conference operator today. At this time, I would like to welcome everyone to the Quince Therapeutics KOL Investor Webinar focused on addressing the high unmet need in AT. Today's conference is being recorded. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during this time, simply press the star key followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one again. At this time, I would like to turn the conference over to Dirk Thye, Chief Executive Officer and Chief Medical Officer of Quince Therapeutics. Please go ahead. Thank you very much, and good morning, everybody, or good afternoon, depending on where you're at. Thanks a lot for joining our webinar today. We've got a special guest. I get asked quite frequently in my investor meetings whether there's an expert that they can speak to regarding the technology. Today we have Mary Kay Koenig, who has more experience with this technology than just about anybody else in the world, certainly the most in the United States, one of two sites in the whole world with over, I think, 1,000 infusions at their site. Today we're going to give you a lot of background on the disease of ataxia telangiectasia. We'll review our technology. We'll cover some of the basics for those of you that don't know the story very well. Let's go ahead and get started. As you heard, my name is Dirk Thye. Most of you have—many of you have met me before. I'm the CEO and the Chief Medical Officer, joined by Mary Kay, who's a Professor and Associate Vice Chair for Clinical Research at UT Houston. As I said, one of the world's experts in this technology with a tremendous amount of experience, both in this disease and other pediatric neurologic diseases for which this technology could potentially be used in the future. We'll talk a little bit about that later. We also have on the line with us my colleague, Brendan Hannah, who's the Chief Operating Officer and the Chief Business Officer here at Quince Therapeutics. This is my typical disclaimer slide. All of you are familiar with the content in the slides, so we'll be making forward-looking statements during the course of this presentation. Just as a general overview of Quince Therapeutics, for those of you that don't already know, we have a technology that we call autologous intracellular drug encapsulation. You'll hear a lot about it, but it's a machine by which you can encapsulate molecules into a patient's own red blood cells and then re-infuse those red blood cells, which dramatically changes the pharmacokinetics, pharmacodynamics, and biodistribution of that particular molecule. Right now, we're in phase three for ataxia telangiectasia with our lead compound, which is dexamethasone sodium phosphate, encapsulated inside the patient's own red blood cells. We have a fair bit of historical data in this particular indication, and we have a long history, many years of chronic safety data as well, which we'll describe during the course of the presentation today. We'll talk mostly about ataxia telangiectasia, but we also have a strong interest in Duchenne muscular dystrophy, which will be the next indication that we pursue with AID. From a business and cash perspective, things are going well right now, and we have cash into 2026, which we anticipate is enough cash to get us to data for this pivotal trial in AT. At this point, I'm going to hand it over to Mary Kay Koenig to walk you through her aspect of the presentation. Thank you, Dirk. I'm really excited to be here today and have an opportunity to talk with you all about AT. Like Dirk said, I'm a child neurologist by training, and I work in Texas at the University of Texas, caring for children and young adults who have genetic neurodegenerative disease, one of which is ataxia telangiectasia. I focus on clinical trials research, and it's always really exciting when we find a new therapy that's available that can help either slow the progression or improve the symptoms in a patient with one of these conditions. We're going to talk today about ataxia telangiectasia, or AT. This is a pretty complex disorder. It was first recognized about 70 years ago by Bodor and Sedgwick. It was first described as a progressive ataxia associated with telangiectasias. If you're not familiar with that term, telangiectasias are a small collection of blood vessels that occur on the skin, producing these little teeny-tiny visible red lesions. Originally, they also noticed there were some endocrine abnormalities, problems with the ovaries and the thymus. Over the next 10 years, the clinical picture started including problems with the immune system and an increased risk of blood-borne cancers like leukemia and lymphoma. They also began to recognize that this was inherited through an autosomal recessive fashion. In 1998, they localized the chromosome to 11, the genetic defect, and by 1995, they had actually identified the genetic defect as a protein that was named ataxia telangiectasia mutated protein, and the gene was called ATM, ataxia telangiectasia mutated. The question arises, which is how—and this is always a problem in neurodegenerative diseases—how does a single gene cause such a global problem? Over the years, we've started to recognize how this gene works. The ATM gene is really critical in repair of something called double-stranded DNA breaks, or DSBs. Each human cell acquires about 25 double-stranded DNA breaks per day. This is when the DNA inside the cell, the double-stranded DNA, breaks. This happens during a lot of normal cellular processes. During regular cell division, meiosis, it can happen. It's very common in the immune cells. As the immune cells are recombining through a process called variable diversity joining to create these immune cell receptors that are required to recognize pathogens, double-stranded breaks occur pretty commonly. It also happens through generation of reactive oxygen species through normal cellular metabolism. It can happen up to 25 times per day per cell in the human system. ATM is integral for repairing these breaks. It also happens at an increased rate after exposure to things like ionizing radiation, certain chemicals, and ultraviolet light. If you are not able to correctly repair these double-stranded breaks, it produces cellular death and chromosomal rearrangements that lead to cancer. Repairing these double-stranded breaks as they occur is critical to normal health and well-being of the whole body, but particularly the neurologic system. It also plays a vital role in multiple signaling pathways. We know that ATM interacts with over 700 other proteins. We do not necessarily know the role of all of its interactions, but we do know that it is involved in regulating cell cycle and apoptosis. We know it is involved in insulin signaling, epigenetic regulation, and that it plays a role in intracellular vesicular transport. Decreased ATM activity has been noted not only in ataxia telangiectasia, but also in a lot of other neurodegenerative diseases, things like Alzheimer's, Parkinson's disease, and also Huntington's disease as well. I think that the ATM molecule itself is really pivotal for a lot of neurodegenerative conditions. We know that AT, ataxia telangiectasia, occurs with some frequency in the United States. It's a rare disorder, but there are 4,600 patients who have been diagnosed in the United States who are linked to or affiliated with a healthcare professional and being treated. What's really nice about rare diseases like this is that often these communities are very tight-knit. They have groups or nonprofit associations where the patients receive a lot of support, and the community becomes very tight, and they get really affiliated with their physicians. They are very close and easily accessible. We're aware of 4,600 patients in the United States that are affiliated with this organization. There's probably more than that that are out there. One of the things that we see commonly with rare diseases like this is that there are a subset of patients when they're diagnosed where there is no treatment option available who stay kind of locally with their local physician because they have no need to affiliate themselves with a clinic. Once a treatment becomes available, patients start kind of coming out of the woodworks because now they hear about these new treatments that are available. A lot of times when you're aware that there's a larger patient population, you do start picking them up once treatments become available. What does AT look like? The typical or early onset classic form of AT is childhood onset. It usually onsets before the age of five years. The first thing you notice is typically a cerebellar ataxia. The term ataxia really focuses on an inability to coordinate smooth movements. When we think about our movements, our ability to reach out and pick something up, our ability to walk, there's a lot of neurologic processes that are involved in allowing that to occur. Your brain has to talk to all sorts of different muscles and motor functions to coordinate how this occurs to make it happen seamlessly. When someone has ataxia, that coordination aspect of that doesn't work right. These movements can seem jerky, off-balance, or staggering. What it leads to is an impaired motor control and a decreased ability to move. Other symptoms that are pretty commonly seen are immunodeficiency, which leads to decreased ability to fight infections. Very commonly, this is seen as pulmonary disease. There's also a high increased risk of malignancy because of these double-strand breaks that occur and an increased sensitivity to ionizing radiation. There is a significantly reduced life expectancy in the classic form of this disease, usually secondary to either pulmonary failure or malignancy, and patients often don't live beyond the age of 30. In the first five years of life, what do you see? You see the onset of ataxia, immunodeficiency, an increase in infections, particularly sinopulmonary infections, and then you see the lymphoid or blood-borne cancers. As children get a little older, between 5 and 15, they start having more and more trouble with speech and swallowing, which leads to nutritional compromise and problems with growth. As they get to be between 15 and 20 years, you start to see more and more of the telangiectasias, and you start to see a metabolic syndrome develop with liver disease and diabetes. As they get to be over 20 years of age, if they survive that long, you will start to see the addition of solid cancers coming in, solid organ cancers. This is, again, just another representation of that. It's really difficult in the first two years of life to diagnose this disease. Everybody, when they start walking, they have this kind of staggering gait. Everybody's seen a one-year-old kind of stumble around trying to walk. When children with ataxia telangiectasia start to walk, they do the same thing. What's really striking about them is they never stop doing that. In the classic form of this, they just continue with that kind of staggering gait. When you expect a normal or healthy two-year-old to start walking more smoothly by the time they're two years old, a child with AT will continue with that kind of staggering gait. It kind of stays that way. By the time they get to be about five years old, the walking starts to deteriorate. By the time they're 10, they tend to end up not being able to walk without support anymore. At that point, they usually are requiring a wheelchair. They start having a lot more pulmonary problems. They start developing lung disease. By the time they're 15, interestingly, the neurologic features start to level out. They stop having any deterioration anymore. You are starting to get into the infections, the nutritional problems, and problems with the cancer. This is a really nice slide, and I really like this slide. It shows you the neurologic progression of ataxia telangiectasia by age. What it shows you, again, is that the symptoms do really onset in that early age, under the age of five. That really critical age for decline is six to nine years. You see the slope of decline between six and nine years of age is pretty steep. Children go from being able to walk at age five to really most of them being wheelchair-bound by the age of 10. The progression of their neurologic symptoms is pretty striking between the age of five and 10 years of age, with them plateauing in their neurologic phenotype without a lot of worsening beyond that age. Unfortunately, there is currently no curative or disease-modifying therapy available for AT. Really, the therapies that we have are mostly supportive. We are able to modulate some of their symptoms. We try to manage risk factors for their immunodeficiency. We optimize vaccinations. Everybody with AT is given all available vaccinations. We also provide prophylactic antibiotics as indicated, and immunoglobulin replacement therapy is a mainstay of therapy. That does help with immunodeficiency. It helps with the recurrent pulmonary infections and also the interstitial lung disease. In addition to that, inhaled corticosteroids are often used as well as systemic corticosteroids. Unfortunately, systemic corticosteroids, although they can help with the interstitial fibrosis, can worsen the overall immune function. It is kind of this balancing act trying to keep patients safe while helping with the lung disease. From an oncologic standpoint, we know these children are at really high risk to develop lymphoid cancers and blood-borne cancers early on. I've been part of a large working group where we're trying to develop some sort of consensus on screening for these cancers and also how do we treat them. Treatment of the cancers is much more difficult in children with AT. A lot of the agents that we use to treat cancers induce double-stranded breaks. Unfortunately, that makes it a little more complicated because these children can't heal those double-stranded breaks. You can't give them radiation therapy. That's absolutely contraindicated. Some of the drugs that we use are neurotoxic. They can induce nerve damage or cerebellar damage, which is going to make their neurologic symptoms even worse. On top of having this terrible neurodegenerative disease, you have difficulty giving them even therapy for the cancer when they develop it. Unfortunately, there's still really limited treatment available for ataxia. A lot of things that we have tried in the past haven't worked. There has been some limited evidence initially showing that corticosteroids do help with ataxia. We're going to go through that in just a minute. The studies that have been done prior to the studies with EryDex have been limited due to the side effects of the corticosteroids. We're going to talk a little bit about these two studies or this one study, these two publications that have recently come out, one in The Lancet in September of last year and one in Neurology in January of 2025. These are both papers based on the ATHEST clinical trial using the Auradex system that Dirk mentioned earlier. I was the PI for our clinical site on that study. The early evidence for corticosteroids providing some neurologic benefit in patients with AT was actually apparent observation. As I mentioned, a lot of children with AT have a lot of sinopulmonary and pulmonary involvement. One of the mainstays of treatment for pulmonary symptoms, particularly pulmonary inflammation, is to provide oral corticosteroids or systemic corticosteroids. There was a child who had some pulmonary symptoms with ataxia telangiectasia, and their doctor prescribed them some oral betamethasone. The parents commented his ataxia got better when he was receiving the oral betamethasone. Some doctors in Italy did some small studies looking at small cohorts of patients, providing them with oral betamethasone, and noted that there was significant improvement in the ataxia symptoms when they were receiving the betamethasone. Unfortunately, these studies were quite limited by the fact that oral corticosteroid treatment or systemic corticosteroid treatment leads to pretty significant side effects: adrenal insufficiency, weight gain, growth suppression, it can cause diabetes, could go on and on about the ills of oral or systemic corticosteroids. The other problem is that once this treatment was discontinued, all of the symptoms came back. The neurologic stabilization or improvement associated with the systemic corticosteroids in these patients was only there while they were receiving the steroids. Once the steroids were withdrawn, the neurologic deterioration returned. This is what led to the concept that perhaps if we could find a better way to administer corticosteroids to patients with ataxia telangiectasia, we might be able to see some long-term improvement in the neurologic symptoms. The ATHEST study was a phase three clinical trial using the EryDex system that Dirk described, where you encapsulate the corticosteroids within a patient's own red blood cells and readminister those to the patient for a slow release over time. The ATHEST study was a phase three study in ataxia telangiectasia patients followed by an open-label extension. The original double-blind placebo-controlled study enrolled 175 patients. They were randomized one-to-one-to-one with low-dose treatment, high-dose treatment versus placebo over six months and treated with the EryDex system. Everyone who completed that study was eligible to roll over into a 12-month open-label extension. 104 patients rolled over. The primary endpoint for that was something called the modified ICARS, which I'm going to show you in a second. The secondary endpoints were a clinical global impression of change along with a QOL and something called a Vineland Adaptive Behavioral Score. The study observed that in ataxia telangiectasia patients between six to nine years old, so remember, this is the group showing that steep decline, that there was a slowing of their neurologic deterioration. Additionally, the 12-month safety data showed that this therapy, as opposed to systemic corticosteroids, this therapy was well tolerated with no serious safety concerns that you typically see with chronic steroid administration. Let's look at the ICARS here. There are three scales that we're going to briefly go over. One is the full ICARS, one is something called the modified ICARS, and one is the rescored modified ICARS. That's something the FDA came up with. The full ICARS, this is a scale that was developed for rating ataxia, not specifically in ataxia telangiectasia patients. Remember, ataxia telangiectasia is a systemic disorder. It causes more than just ataxia. When you're looking at ataxia symptoms, it's a pretty good scale to measure ataxia. It has 19 items, and it scores up to 100 points. It's something that is well validated in lots of different types of ataxia. It's used frequently in clinical trials, and it's something that a lot of neurologists are very familiar with performing. It has four domains. One has to do with posture and gait. One has to do with kinetic functions. One has to do with speech, and another has to do with oculomotor or eye motor functions. What you do is you have the patient walk, and you watch the way they walk, and then you have them stand. You watch how well they're able to stand, whether or not they're able to put their feet together, whether or not they can close their eyes with their feet together, and how much they sway. You have them sit in a chair and see how well they can sit. You have them do some simple tests like, can they take their finger and touch their knee with it? Can they go back and forth? And how much do they tremor when they do that? You have them move their arms back and forth and see whether or not they're able to do this without swerving or moving their elbows around. You have them speak, and you assess how well they're able to speak and how well they're able to control their eye movements. The modified ICARS scale was developed specifically for the ATHEST study. This was one that was designed more to focus down on the ataxic symptoms that are seen in patients with ataxia telangiectasia. This is what was used as the primary endpoint for the ATHEST study. It eliminated some of these finger-nose tests and some of the movement tests with the arm, as well as the eye tests, which are not necessarily predominant symptoms seen in ataxia telangiectasia. The FDA came up with something called the rescored modified ICARS, which was also looked at in the ATHEST data and is what is being used as the outcome for the NEAT study, which is what's going on now. It is a little bit more specific for the ataxia telangiectasia patients. As I'm going through some of this stuff, you may hear me talk about the ICARS, the modified ICARS, and the rescored modified ICARS. These are three scales that are all based on an original scale, and each one has gotten more specific, looking specifically at symptoms that are seen in ataxia telangiectasia patients. This is the original results of the original ATHEST phase three study. This is if you included the entire cohort. The entire cohort for the original study did not limit age. This study allowed enrollment of all patients for all age ranges, looked at everybody no matter what their age. If you recall, once you reach the age of 10, 12, 15 in particular, the rate of deterioration in AT really slows down. If we're looking here, let's just look at the placebo arm. That's this light blue arm on the top. What we're seeing is here, this is the baseline ICARS score or the baseline modified ICARS score. What we want to see is how much did it change over the treatment period in six months? It went down about two points. Okay? It didn't really go down that much. Remember, the higher the score, the worse the ICARS. Let's go back here. If you look here, we're looking at the modified ICARS. The higher you score on each of these, the worse you did on your ICARS, which means the more severe your ataxia is. Okay? A patient here on placebo, they had about a two-point worsening or a two-point increase in their ICARS score over this time period. Okay? This is taking into account everybody that was on this study, any age, no matter what. There were quite a few patients that were over the age of 15, even over the age of 10, who really aren't deteriorating all that much because we know there's a plateau at this point. We look at the patients. This green is the high dose, and this dark blue is the low dose. What we noticed is that compared to placebo, there was a one and a half point less worsening of the ICARS score or the modified ICARS score over time over the six-month period. Clearly, it made a difference, but this wasn't statistically significant. I'm going to show you. The next thing that we did was we pulled out the six to nine-year-olds. These are the people that we know are getting the worst the fastest. If you look at this group here, the blue line is the placebo for the six to nine-year-olds. This group had a five-point, almost five-point, 4.8, almost five-point worsening in their ICARS, their modified ICARS score over the six-month treatment period. I'm sorry, it was almost a four-point worsening of their modified ICARS score. What you see here is that the people on treatment, both the low and high-dose group, had almost a five-point difference in their modified ICARS score compared to the placebo group. This was a statistically significant improvement. When I look at this data, to me, what I see is that given enough time here, you would have seen more of a separation. We did not really have enough time. The reason you see such a big separation here in the six to nine-year-old age group is because of the rapidity of the decline in this group. W e were able to reach a statistically significant change here. What we were able to do with this data was really help design the next study. Now the NEAT study is being run. The NEAT study is using the rescored modified ICARS as the primary endpoint, which is more specific for this patient population. It is also focusing on six to nine-year-olds. We are able to look at the age group that we know is declining the most rapidly. We are able to make the most impact in their score with this Auradex system. I believe that this therapy is working for everyone. Given enough time, we would see this improvement in everyone. I guess I can't say that because we don't have the data that proves that at this point. We are able to see it, and we're able to prove it over a six-month time period in the people aged six to nine. At least that's what the ATHEST data showed us. The other thing that was shown really clearly in the ATHEST data is that with this open-label extension at three-plus years, we've had no serious safety concerns with this therapy. Unlike systemic corticosteroids that are administered through conventional means, we're just not seeing these typical corticosteroid side effects: diabetes, aggression, weight gain, adrenal insufficiency. Those things are just not occurring in the patients who have been on the EryDex system long-term. This is a little bit more detailed information about the adverse effects that we're seeing in the initial treatment period as well as the 12-month open label. You can see just looking at any treatment adverse effects, these numbers are very similar across the board between low dose, high dose, and placebo, as well as patients with serious adverse effects. There were two patients in the high-dose group that had some steroid-related treatment emergent adverse events, some pain and pruritus, and some pyrexia and tachycardia. Overall, it was very well tolerated with no serious safety concerns. This is just a slide to let you see what the competitive landscape is right now, so what other things are being tested or treated. There are a few compounds in phase one and phase two trials. Most of these are some antioxidants, some other novel therapies. There is one that is in a phase three trial, the N-acetylleucine, and Dirk could probably tell you more about these than I could. I am, with that, going to turn things back over to Dirk. Thank you. Okay. Thank you very much. I'll walk you through some additional details related to the technology and our past data, and then we'll open it up for questions. I'll move through this fairly quickly. This is a picture of the machine on your right, and it sits at the patient's bedside or in the lab or on a tabletop or on a cart. It is potentially mobile. Each site has preferences on where they want it to go. It's about the size of an old-fashioned desktop computer. It's fully automated. There's a 17-step process that basically takes place once you hit the start button on that touchscreen you see there. Essentially, what happens is that you take a small amount of the patient's blood in a syringe, 50 mL. That's about a double shot of espresso worth of blood. The patient is not hooked up to the machine. You take their blood, you hook it up to the machine, and over the next 90 minutes, while the patient does whatever they want, the kids go play or they go to lunch, the blood is processed automatically through that 17 steps using hypotonic and hypertonic solutions plus some excipients to slowly swell the cells to make them porous, then incubate them with the cargo of interest, in this case, dexamethasone sodium phosphate, and then shrink the cells back down. Dexamethasone sodium phosphate, being polar, gets stuck inside the cells. It can't diffuse across the lipid bilayer until intracellular phosphatases cleave that phosphate group in a concentration-dependent manner. Once that phosphate group is cleaved, it renders the native dexamethasone, which is a nonpolar molecule, able to diffuse through the lipid bilayer. What you get is an initial Cmax as you have defosphorylation of those large number of molecules. Over the first few hours, you get a Cmax that exceeds 100 nanograms per mil, which is important. You get a long, slow decline in plasma concentrations over the course of a month. It is a once-monthly therapy. Kids come in once a month, get their blood drawn, get it reinfused after that 90 minutes. The whole process takes a couple of hours. They usually spend about a half a day at the clinic. You get that the Cmax is very important to saturate corticosteroid receptors for the non-genomic effects associated with the mechanism of action. That long, slow decline in plasma concentrations is important for long-term corticosteroid receptor occupation, which is important for the genomic effects of corticosteroids. Those two elements of efficacy are imperative for any corticosteroid dosing regimen. That is very important. Also note these dotted lines on the slide. Those represent plasma concentration thresholds that are typically associated with different types of steroid-related adverse events. The highest thresholds are associated with hyperglycemia and immunosuppression. The most sensitive one, that light blue dotted line, is associated with adrenal suppression. What you get with this PK curve is that you satisfy the two most important elements required for efficacy, but you pretty quickly get below these toxicity thresholds. Let's contrast that with typical corticosteroids. This is a PK curve of dexamethasone 6 milligrams given daily, which is a typical therapeutic dose for a variety of diseases. You could put any corticosteroid on this graph. You could put prednisone, hydrocortisone, betamethasone, whatever. These, because of their pharmacokinetics, and that's true of any existing approved formulation of corticosteroids, you have to give them at least daily. Sometimes you give them multiple times a day. This is dexamethasone given once daily. You can see that when you give it once daily, you satisfy that Cmax requirement for the non-genomic effects of corticosteroids and the receptor saturation. If you want to get persistent receptor occupation, you have to keep dosing it. If you keep dosing it at an efficacious level, what happens is you continuously trigger, you exceed these plasma concentration thresholds associated with toxicity. Because of that, if you're dosing any corticosteroid long-term at an efficacious dose, you get toxicity. It's universal. You can't dose; there is no steroid that you can dose chronically without quickly running into toxicity. You get acute toxicities, which happen over hours and days. Adrenal suppression kicks in after a week or two, and that's unavoidable with any approved steroid. We get around that by getting below these thresholds pretty quickly. We now have data on 384 patients, 68 of whom have been taking this for an average of 30 months, so about two and a half years. We actually have three patients that have been taking this monthly for 13 years now. We do not have any signs in that cohort of chronic steroid toxicity or adrenal suppression. I think our safety database with respect to this particular dosing regimen is very strong. I think the NEAT study that Mary Kay outlined for you is going to be the ultimate test of whether what I say about efficacy is true. I think if we look carefully at what is in ATHEST, she explained that the assay sensitivity for efficacy really exists in that six to nine-year-old population. When you look at that population in the previous study, it was highly effective. If you look back at studies that Aridel performed—Aridel is the company we acquired a year and a half ago that developed this technology over 20 years. If you look at their historical studies in AT and other indications, you'll find very strong signals of efficacy with respect to just the corticosteroid element. I think it's going to work, but we'll get data by the end of the year to either prove or disprove that belief. This just summarizes what I already told you about corticosteroid pharmacodynamics. If you want to get more familiar with this and dig into the details, we do have our publications listed on our website. At the end of last year, we attended a couple of scientific meetings, and we presented data on patients that had received the therapy for at least two years. Originally, there was a phase two study in AT. That is where those three kids that have been on it for 13 years come from. They did the ATHEST trial, which you have heard about. Patients in the ATHEST trial had the opportunity to roll over into an open-label extension that continued for a year. Children that completed that were allowed to go into an expanded access program under an investigator IND, and many patients have taken advantage of that. That is where this cohort of 68 kids that have received it for an average of 30 months comes from. We analyzed the safety data on that a few different ways and presented a poster at the Child Neurology Society in San Diego last year in November on that. We also had two posters at what is called the ICAR meeting, International Congress for Ataxia Research, in London. That was also in November. Okay. I think you have already talked about the study design, but I will hand it back to you for a recap. All right. Thank you. Just briefly, we'll talk about the NEAT study design. This is a pivotal study being conducted under a special protocol assessment agreement with the FDA. It's a multicenter, randomized, double-blind, placebo-controlled study with six infusions scheduled once every 21-30 days. The first patient was enrolled in June of last year, and top-line data is expected in the fourth quarter of 2025. As of February 7th of this year, 46 patients had been enrolled. The plan is to enroll approximately 86 patients aged 6 to 9 years, which is the primary analysis population. Again, I talked about why that group is so important. There are going to be approximately 20 additional patients enrolled who are 10 years and older because those patients should hopefully allow for an expansion of the label, which I personally think is crucial. The primary efficacy endpoint is going to be the rescored modified ICARS, which is mostly looking at posture and gait disturbances. There are going to be two treatment arms here, treatment and non-treatment, followed by a safety follow-up visit here. You see there is the six-month treatment period. The NEAT trial design supports the expectation of clearer top-line results. We have chosen an appropriate primary analysis population, again, focused on the 6 to 9. There is a well-defined primary endpoint. It is sufficiently powered based on the prior ATHEST study results. The inclusion of the patients 10 years and older was recommended by the FDA to allow for a broader label. The ATHEST data really was used very clearly to help with the design of this study. The anticipated impact of approved Auradex in this population, the goal would be to start treatment as early as possible to slow the deterioration. The true expectation is that this is a lifetime administration. The clinical meaningfulness of this is that it could slow or even prevent clinical decline in patients. I have quite a few patients who are still on expanded access. Some of the patients opted at some point. The original ATHEST study for those of you who aren't aware occurred in the middle of COVID, and it became quite challenging. We did lose a lot of patients either to the study itself or to the expanded access program due to COVID. We have three patients who have been being treated since before COVID. Those patients continue to come every 30 days. One of them comes from an international site on their own dollar. They are coming because they continue to see the benefits of this therapy. The patients that we have who have stopped therapy, just as was seen in the very original studies, the benefits of the therapy waned pretty quickly, and the neurologic deterioration returned. We have gotten, as Dirk said, pretty experienced with administering this therapy. We can do it in three hours, in and out in three hours. That involves all the blood draws, all the safety checks, all the vital signs, making sure everything is going well, placing IVs. We are very capable and confident. I think that it is a relatively easy procedure. In neurology, there are lots of people who get monthly infusions for lots of different indications. This is no different than that. This here says that the first study patient rolled over into OLE. We had our second, actually, I think our third rolled over yesterday. We are well on our way to getting this trial completed as well. We are very excited about seeing the top-line results from this study as well. Okay. We can open it up for questions. Thank you. We will now begin the question and answer session. If you have dialed in and would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one again. To submit a question via the webcast, locate the question and answer box in the lower left corner. Type in your question and click submit. We'll take our first question from Elimer Peros at Rodman and Renshaw. Yes. Good morning. Thank you very much for conducting this webinar. Dr. Koenig, when the FDA suggested to rescore the ICARS, if I remember correctly, they went from a range of zero to six for each observation to zero to four. It just seems a little counterintuitive that they are narrowing the range. Am I missing something there in their thinking? What was the rationale for that? For the motor function for the walking capabilities, we're only going to four because if you hit a four, you can't walk anymore. In order to be included in the study, you have to be able to walk. That's the rationale for that. I can add a little color to that as well. It's not exactly clear what was going through their head because this was done through written correspondence. This was done before I acquired the company. In the written correspondence, you'll see that over time, they moved from the full ICARS to the modified ICARS to ultimately the rescored modified ICARS, which goes from 100 points to 54 points to 29 points. Clearly, their intent was to choose a subset of the ICARS that they believed more accurately reflected how a patient feels, functions, and survives. The rescoring component of it simply puts more of those 29 points into the posture and gait domain. If you look at the ICARS versus the RMICARS, by the way, the ICARS is what's done in the clinical trial, both ATHEST and NEAT. The investigators do the full ICARS. The conversion from ICARS into rescored modified ICARS is fully programmatic. It's not a separate assessment. The rescoring just essentially even further emphasizes that gait and posture. Essentially, what the ICARS becomes largely is a measure of your ability to stand or walk. If you remember that natural history study that Mary Kay showed you, you see that the neurological function deteriorates really rapidly in the age cohort that we're studying. It turns out that, and we've looked at the different domains of the ICARS with our historical data sets, it turns out that that gait and posture domain is, in fact, the most sensitive indicator of function in these children over time. I'm not sure they knew that specifically, but they did have the ATHEST data set, and that's what they said they'd be looking at. I think they actually chose an endpoint that really does reflect how a patient feels and functions in this population. Thank you. Thank you for that follow-up. Just one last question about potential other indications, Dr. Koenig. In your practice, what sort of conditions would this treatment be also amenable, theoretically at least? I keep telling Dirk, I have 1,000 other indications. In neurology, we use steroids for everything. You could just google neurology and steroids. Chronic steroids are used very commonly for a ton of conditions. The one that he's already brought up that is the most pressing would be, obviously, Duchenne muscular dystrophy. This is something that steroids are very commonly used for. Typically, patients can only tolerate them for two to three years, and then they have to be withdrawn. Yet, there's so much efficacy data that they delay the worsening of Duchenne. Yet, patients, I mean, it just goes to show you how severe the side effects can be that even though these patients are receiving significant benefit. I'm sure that Dirk could provide you with a list of many other conditions. I don't know, Dirk, would you like me to continue to elaborate? No, that's good. Like you're right. There are many. We looked at 90. We narrowed it down to about 14 that we would really like to pursue. It's certainly enough indications to keep me busy for the rest of my life. There are probably four or five that we could tackle in the near term with appropriate funding. Right now, our funding is committed to AT only, but we're going to be opportunistic with respect to the ability to raise money. If we can do that, we'll certainly accelerate our DMD plans. We already have a study design for that that we're reviewing with KOLs in the field. There are other indications like autoimmune hepatitis, systemic juvenile lupus, pulmonary sarcoidosis, things like that that we're also very interested in pursuing in the near term. Thank you very much. We'll go next to Jon Wolleben at Citizens JMP. Hi, this is Catherine on for Jon. I have kind of a quick general question. As far as kind of the symptom burden of these patients and kind of the relief that they get from steroids versus the steroid-induced side effects, how big of a concern is it in this patient population given they're pretty severe? I mean, academically, I understand sort of this rationale, but I'm just wondering how aware are patients of the actual tolerability and safety risks of steroids? Thank you. From a cognitive standpoint, most of these patients are pretty cognitive. They are pretty aware of what's going on with them. When you talk about things like how aware they are, they're very aware. The things that we worry about in them are the potential risk for increased infections is really significant. These are children who are already immunocompromised. If you throw on top of that systemic steroids, it makes it a lot worse. The adrenal insufficiency can be really bad, the weight gain in someone who is already prone to having problems with nutrition. They're malnourished, and then you make them overweight in a negative way. In addition to that, it affects their bone health. They become prone to fractures. They develop osteoporosis. These are children who are falling frequently. If you just look at any one of those, just for example, look at the broken bones. These are kids who fall all the time. If you make their bones brittle, and then all of a sudden, now they're breaking a bone every time they fall. That causes a significant amount of pain, which then causes a discomfort that is throwing on top of them already having this neurologic condition. It is a limiting factor. It is something that prevents us from using systemic steroids in them. Just a quick follow-up to that. As far as the timescale of these steroid-induced effects, how early are these patients actually seeing them? Usually, they start within a few months. Okay. Perfect. Thank you. Next, we'll move to Sumant Kulkarni at Canaccord Genuity. Morning. Thanks for your work on behalf of AT patients and for taking my questions. I have two. The first is a two-part question on the scales, and the second is on the treatment landscape for AT. On the rescored modified ICARS scale, what would be considered a clinically meaningful point difference versus placebo? We know the rescored modified ICARS was an FDA recommendation, but does the agency have a preference between this scale and using a modified version of the SARA scale, for example? As far as the clinically meaningful difference, I don't know what the—I don't actually have access to the original remodified—I'm sorry, the rescored modified ICARS data from the ATHEST study was. What I know is the modified ICARS scores. There was that four-point decline in the patients who were between the ages of six and nine. What we saw was an almost five-point difference. For me, if you can stop any decline in these patients at all, that's significant. I would say any change at all in stopping decline is going to be clinically significant to these patients. I'm sorry, I missed the second part, but I think that. I can tackle the second one. It was about the FDA's opinion on a modified SARA score versus the ICARS. And the ICARS was developed in the mid-1990s and validated in clinical studies in the early 2000s for a variety of ataxias. It was initially used by Aridel in the phase two study for AT and then subsequently in the ATHEST study. There is a historical legacy of using the ICARS for this indication with this technology. It is very attractive because when you do integrated analyses, ultimately, you are going to want to have data with the same outcome measure. The SARA score evolved later and also is not specific to AT. There was no historical data with the SARA score in this population using our technology. The FDA has clearly stated under the SPA. This is under a special protocol assessment, which means that the FDA has a priori said if it's a positive study, it can be a single pivotal study, which is potentially approvable after their review. In that document, they specify the RMICARs as their preferred measure. There was no discussion of SARA. I think that's appropriate because of the historical data set in AT. Thanks. That's very helpful. This is more of a question on the treatment landscape. Given the similar epidemiology between AT and Friedreich's ataxia, is it mainly a current lack of establishment of safety in patients under 16 years of age that prevents the potential off-label use of a product like SKYCLARYS, which is approved for FA? Is there anything in future that might preclude combo use of that product with the EryDex system? I'm going to defer that to Dirk. Okay. You might want to comment on the idea of using SKYCLARYS in AT. I think there hasn't been a lot of discussion of that because the pathophysiology of the two diseases are different. In discussions with other KOLs on whether Friedreich's would be a good target for our technology, it's unclear. The difference is in AT, there has been historical evidence to suggest that corticosteroids could be beneficial. That's not true in Friedreich's. I'm not aware, and Mary Kay, this is where you might want to comment. I'm not aware of any physicians that treat AT patients that have considered using that drug in their population. Yeah. I'm not aware either of using SKYCLARYS for AT. Yeah. Because of that, any discussion of combination therapy would be purely speculative on my part. I don't have a good answer for that. There are no further phone questions. I'll hand it over to Brendan Hannah for any web questions. Yeah. There's a couple of questions in the chat here. Dirk, why don't you start off with this one? It's a two-part question. The first part is, is AT part of prenatal screening? The second part is, assuming positive results, do you expect the FDA would allow EryDex to be used in patients younger than six years old? That's coming from Serge Bellinger of Needham. Okay. Hi, Serge. A couple of things. One is it's not specifically included in panels of prenatal screening. If a family knows that they are carriers or if there has been a previous child in the family with AT, you can do specific prenatal tests to look for those gene mutations. With respect to just standard screening tests, it's sometimes picked up in a SCID assay, a lymphocyte assay for severe combined immunodeficiency. When that test is positive and the follow-up genomic test is negative for SCID, the central lab that did the test is supposed to suggest to the physician that AT is one of the things that they should test for. I guess that doesn't always happen. It depends on the lab, but that's how it's supposed to work. Sometimes children get picked up that way. With current technologies, there is no standard test. One of the complications is that because it's heterozygous, autosomal recessive, and heterozygous, there are about 450 different mutation combinations that account for the phenotype. That's why there is some variability in the phenotype because the different combinations of mutations affect ATM function differently. Right now, I think there will be evolution in the field, and there will be a subset of those 450 that have similar phenotypic mutations for the ATM protein that lead to bad disease. Those might be able to be added to a panel. I think that's an area that if this drug gets approved, that'll be an area that I think we could help evolve because doing such prenatal screening or adding it to panels would be definitely beneficial. The second part was testing kids less than six years old. The EMA has requested a pediatric investigational plan which would test children between 9 and 15 kilograms. In an AT child population, that equates to about one to six years of age. It would be very valuable for us to be able to study those kids and include them in a label. We are planning on initiating that study later this year in the second half of the year. The complication with those younger children is that the procedure we perform in the six and older, and this is why the lower age limit of six was chosen. W e use a 50 mL blood process. There are generally—there is some variability, but there are generally consistent guidelines on how much blood you can take from a child at a given weight over a day, a week, or a month. To remain within those guidelines, it's about 50 mL would mean that we can't really treat patients younger than six. We developed a 30 mL process instead. That 30 mL process will be used for children between 9 and 15 kilograms. That'll be a PK study. I'm hoping we can use that PK study and that 30 mL process to get label expansion or maybe even include some of that data in our NDA or all of that data in our NDA if we can finish the study quickly enough. That's the plan for the younger population. The older population, there are 20 kids included 10 years of age or older in the NEAT study. That was at the request of the FDA, specifically so that we could potentially get a broader label in the older age group. That's not enough children to show statistically significant and manage in efficacy. I think if we have a lack of safety signals in that population, it'll be a good justification to include that older age cohort in the label. If I can just add one thing, there is a lot of research that's gone on lately or a lot of examples lately where once a treatment is available for a condition like this, then it gets added to the newborn screening. I think it's very likely that if a treatment becomes available, that there'll be a big push to add it to newborn screening. Okay. Dirk, one more question from Jason Doerr of Oppenheimer. How are you thinking about opportunities for EryDex and AT beyond the phase three NEAT population? Where may there be residual unmet needs in AT? Yeah. That's probably not just for me. I'll let Mary Kay answer it in a second. I think the biggest opportunity would be to study these younger kids because with neurodegeneration, like a lot of other diseases, like infectious disease, the earlier you can intervene, the better. Since neurological deterioration is not reversible, it looks like we can slow it or maybe even halt it. It's probably not completely halting it, but we can greatly slow the neurological deterioration. By the age of six, a lot of that has already occurred. If we could intervene at a younger age, don't forget that these patients get infections and cancers, all kind of probably the same pathophysiology related to oxidative damage, double-stranded DNA breaks, and accumulation of cellular damage, which leads to problems in tissues, cell populations that divide quickly or don't divide quickly. Neurons don't divide quickly. Lymphocytes do. You get problems in both populations. If you could intervene really early at an early age, one or two years old, and continue therapy for life, there's a possibility that you could greatly delay the incidence of cancers and infections at an older age, in addition to greatly slowing the neurological deterioration. That would be my hope for the next phase of development of the drug. I'll hand it over to you, Mary Kay, to add to that. Yeah. I'm really excited about the possibility of younger kids. I think there's a lot of potential there for that. The other cohort that we're not talking about today, though, that was included in the ATHEST study that I think is going to be an important aspect of this is the older onset. We really focused on the classic phenotype today, but there is an older phenotype. There are some patients that present in their teens who really don't start showing ataxic symptoms until they're in their teens. This is a group that's a lot more mild, and they're a lot less prone to the lymphoid cancers. They tend to not have as much immunodeficiency, and they tend to not have as much cancer risk. They do develop this slowly progressive ataxia that really progresses throughout their 20s and 30s. They are less defined because they have been less well recognized. I could go all day about why that is, but I will not. I think that this is a population that did not necessarily show the dramatic benefit in the ATHEST study because their decline is so slow. We do have one patient who has stuck with the therapy. She enrolled with us in the ATHEST study, and she has continued on therapy. She has been on it now for more than three years. Her decline has really been, if at all, very, very minimal. I think that is a population that is underdiagnosed, underrecognized, and has a really good potential for benefit from this therapy in the long term. I think that is one that I am pretty excited about potential for. We will take our final question on the phone line from Kumar Raja with Brookline Capital Markets. Yeah. Thanks for taking my question and also for this informative session. I just had two questions. One on the two patients who have been on the drug for like 13 years, what age did they start the trial, and what age are they right now? For Dr. Koenig, I have a question with regard to the deterioration. Compared to what was seen in the trial and in the published paper, what do you see in the real-life setting? Thank you. Okay. I can tackle the one about the three children on the original phase two. I think when they enrolled originally, they were on the order of 9 or 10 years old. Now they're all in their early 20s. Okay. As far as the real-life situation, we had, I want to say, 15 patients enroll in the original ATHEST study. We have, I do not even know our numbers today, like 10 patients enrolled in the NEAT study now. From a standpoint of the therapy, and I can talk very clearly about the ATHEST study, that data's all been published, it's a pretty easy therapy to administer. Once you start, the first time, it takes a little bit. Once you get used to doing it, our team, my team is very experienced, and it's pretty easy for them to do. It's no different than any other infusion therapy that's prescribed. Those are very, very common in neurology for us to prescribe infusion therapies. They're actually very common in lots of other conditions as well these days. From a standpoint of the experience that I have with its benefits, as far as adverse effects, we just don't see them. When you start doing infusions in children who are six years old, it's amazing how tolerant they become of them. I remember some kids who initially just were very, very resistant to the blood draws and very resistant to the IVs who now, it's no big deal. They just come in and stick their arm out. They're so used to it at this point. Other adverse effects, they just don't have them. We're just not seeing adverse effects. As far as benefits, the biggest benefit is the lack of deterioration. I say that over and over again. When you see a kid with AT who is still walking after years, that's just striking to me. I'm seeing that, and I love it. I'm a believer. I've been really pleased with what we're seeing with this therapy, both with the ease of administration, the lack of side effects, and the efficacy that we see in these patients who've been on it for a long time. Very helpful. Thank you. This does conclude the question and answer session. I will now turn the conference back over to Dirk Thye for closing remarks. Thank you. Sorry we went over, but I'm glad we were able to address people's questions. Thanks, everybody, for joining today. I hope it was helpful and informative, and you know where to find us for any future information. We'll see you on the next one. This concludes today's conference call. You may now disconnect.