Quince Therapeutics, Inc. (QNCX) Earnings Call Transcript & Summary

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 A-T. Today's conference is being recorded. [Operator Instructions] 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. And 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. So 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. So 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 is a Professor and Associate Vice Chair for Clinical Research at UT Houston. And 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 this slide. So we'll be making forward-looking statements during the course of this presentation. So 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 reinfuse those red blood cells, which dramatically changes the pharmacokinetics, pharmacodynamics and biodistribution of that particular molecule. Right now, we're in Phase III 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 AIDE. 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 A-T. So, 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 A-T. Like Dirk said, I'm a child neurologist by training. And so 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. And 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. So we're going to talk today about ataxia-telangiectasia or A-T. So this is a pretty complex disorder. It was first recognized about 70 years ago by Boder and Sedgwick. It was first described as a progressive ataxia associated with telangiectasias. And if you're not familiar with that term, telangiectasias are 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. So 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. And so over the years, we've started to recognize how this gene works. So the ATM gene is really critical in repair of something called double-stranded DNA breaks or DSBs. So each human cell acquires about 25 double-stranded DNA breaks per day. So this is when the DNA inside the cell, the double-stranded DNA breaks, and this happens during a lot of normal cellular processes. So during regular cell division, meiosis, it can happen. It's very common in the immune cells. So 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. So again, it can happen up to 25 times per day per cell in the human system. And 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. So 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 don't necessarily know the role of all of its interactions, but we do know that it's involved in regulating cell cycle, in apoptosis. We know it's 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. So I think that the ATM molecule itself is really pivotal for a lot of neurodegenerative conditions. So we know that A-T, ataxia-telangiectasia, occurs with some frequency in the United States. It's a rare disorder, but there's 4,600 patients who have been diagnosed in the United States, who are linked to or affiliated with a health care 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. And so they're very close and easily accessible. And so again, 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 physicians because they have no need to affiliate themselves with the clinic, but 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. So 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. So what does A-T look like? So the typical or early onset classic form of A-T is childhood onset. It usually onsets before the age of 5 years. The first thing you notice is typically is cerebellar ataxia. So the term ataxia really focuses on an inability to coordinate smooth movements. So 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, motor functions to coordinate how this occurs to make it happen seamlessly. And so when someone has ataxia, that coordination aspect of that doesn't work, right? And so these movements can seem jerky, off balance or staggering. And so 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. So in the first 5 years of life, what do you see? You see the onset of ataxia, immunodeficiency and 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. So this is again just another representation of that. It's really difficult in the first 2 years of life to diagnose this disease. So everybody, when they start walking, they have this kind of staggering gait. Everybody's seen a 1-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. So in the classic form of this, they just continue with that kind of staggering gait. And when you expect a normal or healthy 2-year-old to start walking more smoothly by the time they're 2 years old, a child with A-T will continue with that kind of staggering gait, and it kind of stays that way. Then by the time they get to be about 5 years old, the walking starts to deteriorate. And so 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. And by the time they're 15, interestingly the neurologic feature start to level out. They stop having any deterioration anymore. And now you're starting to get into the infections, the nutritional problems and problems with the cancer. So this is a really nice slide, and I really like this slide. It shows you the neurologic progression of ataxia-telangiectasia by age. So what it shows you again is that the symptoms do really onset in that early age, under the age of 5. But that really critical age for decline is 6 to 9 years. So you see the slope of decline between 6 and 9 years of age is pretty steep. And children go from being able to walk at age 5, to really most of them being wheelchair bound by the age of 10. So the progression of their neurologic symptoms is pretty striking between the age of 5 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 A-T. Really, the therapies that we have are mostly supportive. We are able to modulate some of their symptoms. So we try to manage risk factors for their immunodeficiency. So we optimize vaccinations. Everybody with A-T has 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, they can worsen the overall immune function. And so it's 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 A-T. A lot of the agents that we use to treat cancers induced double-stranded breaks. And unfortunately that makes it a little more complicated because these children can't heal those double-stranded breaks. So you can't give them radiation therapy. That's absolutely contraindicated. And 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. So on top of having this terrible neurodegenerative disease, you have difficulty giving them even therapy for the cancer when they develop it. And 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. But the studies that have been done prior to the studies with EryDex have been limited due to the side effects of the corticosteroids. So 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 test clinical trial using the EryDex system that Dirk mentioned earlier. And I was the PI for our clinical site on that study. So the early evidence for corticosteroids providing some neurologic benefit in patients with A-T was actually a parent observation. So as I mentioned, a lot of children with A-T have a lot of sinopulmonary and pulmonary involvement. And one of the mainstays of treatment for pulmonary symptoms, particularly pulmonary inflammation, is to provide oral corticosteroids or systemic corticosteroids. And so there was a child who had some pulmonary symptoms, ataxia-telangiectasia, and their doctor prescribed them some oral betamethasone. And the parents commented, his ataxia got better when he was receiving the oral betamethasone. And so 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, if you 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. So 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. So, this is what led to the concept, 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. And so the ATTeST study was a Phase III clinical trial using the EryDex system that Dirk described, where you encapsulate the corticosteroids within a patient's own red blood cells and re-administer those to the patient for a slow release over time. So the ATTeST study was a Phase III study in ataxia-telangiectasia patients, followed by an open-label extension. The original double-blind placebo-controlled study enrolled 175 patients. They were randomized 1:1:1 with low-dose treatment, high-dose treatment versus placebo over 6 months and treated with the EryDex system. And then 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 Vineland Adaptive Behavioral Score. So the study observed that in ataxia-telangiectasia patients between 6 to 9 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. So, let's look at the ICARS here. And there's 3 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. So 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. But 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, and 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 4 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 ocular motor or eye motor functions. And so 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. And then 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. And then 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 ATTeST study. This was one that was designed more to focus down on the ataxic symptoms that are seen in patients with ataxia-telangiectasia, and this is what was used as the primary endpoint for the ATTeST 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. Then the FDA came up with something called the rescored modified ICARS, which was also looked at in the ATTeST data, and is what is being used as the outcome for the NEAT study, which is what's going on now. And so it, again, is a little bit more specific for the ataxia-telangiectasia patients. So 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. Again, these are 3 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. Okay. So this is the original results of the original ATTeST Phase III study. This is if you included the entire cohort. So the entire cohort for the original study did not limit age. So this study allowed enrollment of all patients for all age ranges, looked at everybody no matter what their age. And if you recall, once you reach the age of 10, 12, 15 in particular, the rate of deterioration in A-T really slows down. So if we're looking here, let's just look at the placebo arm, that's this light blue eye on the top. So what we're seeing is here, this is the baseline ICAR score or the baseline modified ICAR score. And what we want to see is how much did it change over the treatment period in 6 months. Well, it went down about 2 points, okay? So it didn't really go down that much. And remember, the higher the score, the worse the ICARS. So let's go back here. So if you look here, we're looking at the modified ICARS, the higher your score on each of these, the worse you did on your ICARS, which means the more severe your ataxia is, okay? So a patient here on placebo, they had about a 2-point worsening or a 2-point increase in their ICAR score over this time period, okay? So this is taking into account everybody that was on the study, any age, no matter what. So 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. And then we look at the patients, this green is the high dose and the dark blue is the low dose. And what we noticed is that compared to placebo, there was a 1.5 point less worsening of the ICAR score -- with the modified ICAR score over time over the 6-month period. So clearly, it made a difference, but this wasn't statistically significant. So I'm going to show you. The next thing that we did was we pulled out the 6- to 9-year olds. So these are the people that we know are getting the worst, the fastest. And so if you look at this group here, so this group here, the blue line is the placebo for the 6- to 9-year old. This group had a 5-point -- almost 5 point, 4.8, almost 5-point worsening in their ICARS, their modified ICAR score, over the 6-month treatment period -- I'm sorry, it was almost a 4-point worsening of their modified ICAR score. And what you see here is that the people on treatment, both the low and high dose group, had almost a 5-point difference in their modified ICAR score compared to the placebo group. So this was a statistically significant improvement. So 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, but we didn't really have enough time. The reason you see such a big separation here in the 6- to 9-year old age group is because of the rapidity of the decline in this group. And so we were able to reach a statistically significant change here. And so what we were able to do with this data was really help design the next study. And so now the NEAT study is being run. And the NEAT study is using the rescored modified ICARS as the primary endpoint, which is more specific for this patient population. And it's also focusing on 6- to 9-year olds. And so we're able to look at the age group that we know is declining the most rapidly. And so we're able to make the most impact in their score with this EryDex system. So I believe that this therapy is working for everyone. And 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. But we are able to see it and we're able to prove it over a 6-month time period in the people aged 6 to 9. At least that's what the ATTeST data showed us. So the other thing that was shown really clearly in the ATTeST data is that with this open-label extension, at 3-plus years, we've had no serious safety concerns with this therapy. So, 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. So 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 2 patients in the high dose group that had some steroid related treatment emergent adverse events, some pain and pruritus and some pyrexia and tachycardia. But overall, it was very well tolerated with no serious safety concerns. So 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 I and Phase II trials. Most of these are some antioxidants, some other novel therapies. There is one that is in a Phase III trial N-acetyl-L-leucine and Dirk could probably tell you more about these than I could. So 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 touch screen, you see there. And essentially, what happens is that you take a small amount of the patient's blood in a syringe, 50 mls, that's about a double shot of espresso worth of blood. 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, and incubate them with the cargo of interest, in this case, dexamethasone sodium phosphate, and then shrink the cells back down. So 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. And once that phosphate group is cleaved, it renders the native dexamethasone, which is a nonpolar molecule, able to diffuse through the lipid bilayer. So what you get is an initial Cmax as you have dephosphorylation of those large number of molecules. You get -- over the first few hours, you get a Cmax that exceeds 100 nanograms per mL, which is important. And then you get a long, slow decline in plasma concentrations over the course of a month. So that it's a once-monthly therapy, kids come in once a month, get their blood drawn, get it reinfused after that 90 minutes. So the whole process takes a couple of hours. They usually spend about half a day at the clinic. So you get that -- the Cmax is very important to saturate corticosteroid receptors for the nongenomic effects associated with the mechanism of action. Then that long slow decline in plasma concentrations is important for long-term corticosteroid receptor occupation, which is important for the genomic effects of corticosteroids. So those 2 elements of efficacy are imperative for any corticosteroid dosing regimen. So that's very important. But 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 and then the most sensitive one, that light blue dotted line, is associated with adrenal suppression. So what you get with this PK curve is that you satisfy the 2 most important elements required for efficacy, but you pretty quickly get below these toxicity thresholds. So let's contrast that with typical corticosteroids. So this is a PK curve of dexamethasone, 6 milligrams, given daily, which is a typical dose for therapeutic dose for a variety of diseases. But you could put any -- just corticosteroid on this graph, you can 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. So you can see that when you get it once daily, you satisfy that Cmax requirement for the nongenomic effects of corticosteroids and the receptor saturation. But if you want to get persistent receptor occupation, you have to keep dosing it. And if you keep dosing it at an efficacious level, what happens is you continuously trigger, you exceed these plasma concentration thresholds associated with toxicity. So, 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. And then adrenal suppression kicks in after a week or 2, and that's unavoidable with any approved steroid. So we get around that by getting below these thresholds pretty quickly. And we now have data on 384 patients, 68 of whom have been taking this for an average of 30 months, about 2.5 years. We actually have 3 patients that have been taking this monthly for 13 years now, and we don't have any signs in that cohort of chronic steroid toxicity or adrenal suppression. So 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 was in ATTeST, she explained that the assay sensitivity for efficacy really exists in that 6- to 9-year old population. And when you look at that population in the previous study, it was highly effective. So -- and if you look back at studies that EryDel performed, EryDel is the company we acquired 1.5 years ago that developed this technology over 20 years. If you look at their historical studies in A-T and other indications, you'll find very strong signals of efficacy with respect to just the corticosteroid element. So 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. We do -- 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 have received the therapy for at least 2 years. Originally, there was a Phase II study in A-T. That's where those 3 kids that have been on it for 13 years come from, and then they did the ATTeST trial, which you've heard about. Patients in the ATTeST trial have the opportunity to roll over into an open-label extension that continued for a year. And then children that completed that are -- were allowed to go into an expanded access program under an investigator IND, and many patients have taken advantage of that. So that's where this cohort of 68 kids that have received it for an average of 30 months comes from. And we analyze 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. And then we also had 2 posters at what's called the ICAR meeting, International Congress for Ataxia Research in London. That was also in November. Okay. I think you've already talked about the study design, but I'll hand it back to you for a recap.

All right. Thank you. So just briefly, we'll talk about the NEAT study design. So 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 6 infusions scheduled once every 21 to 30 days. The first patient was enrolled in June of last year, and top line data is expected in the fourth quarter of 2025. So, as of February 7 of this year, 46 patients have been enrolled. The plan is to enroll approximately 86 patients aged 6 to 9 years, which is the primary analysis population. And 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's going to be 2 treatment arms here, treatment and nontreatment, followed by a safety follow-up visit here. So you see there's the 6-month treatment period. The NEAT trial design supports the expectation of clearer top line results. So we have chosen an appropriate primary analysis population, again, focused on this 6 to 9. There's a well-defined primary endpoint. It is sufficiently powered based on the prior ATTeST study results. And again, the inclusion of the patients 10 years and older was recommended by the FDA to allow for a broader label. So the ATTeST data really was used very clearly to help with the design of this study. So the anticipated impact of approved EryDex in this population -- the goal would be a start treatment as early as possible to slow the deterioration. And the true expectation is that this is a lifetime administration. So the clinical meaningfulness of this is that it could slow or even prevent clinical decline in patients. So I have quite a few patients who are still on expanded access. Some of the patients opted at some point. The original ATTeST data, for those of you who aren't aware, occurred in the middle of COVID. And it became quite challenging. And so we did lose a lot of patients, either to the study itself or to the expanded access program due to COVID. We have 3 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, and they're 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. So we've gotten, as Dirk said, pretty experienced with administering this therapy. We can do it in 3 hours. So, in and out, in 3 hours, and that involves all the blood draws, all the safety checks, all the vital signs, making sure everything is going well, placing IVs. And so, we are very capable and confident. I think that it is a relatively easy procedure. In Neurology, there's lots of people who get monthly infusions for lots of different indications. This is no different than that. This here says that the first NEAT study patient rolled over into OLE, we had our second, actually, I think, our third rolled over yesterday. And so we are well on our way to getting this trial completed as well. So we're very excited about seeing the top line results from this study as well.

Okay. We can open it up for questions.

[Operator Instructions] We'll take our first question from Elemer Piros at Rodman & Renshaw.

Yes. Dr. Koenig, when the FDA suggested to rescore the ICARS, if I remember correctly, they went from a range of 0 to 6 for each observation, to 0 to 4. It just seems a little counterintuitive that they are narrowing the range. And -- but am I missing something there in their thinking? What was the rationale for that?

So for the motor function for the walking capabilities, we're only going to 4. Because if you hit a 4, you can't walk anymore. And so in order to be included in the study, you have to be able to walk. And so that's the rationale for that.

If I could add some -- I could add a little color to that as well. I mean it's not exactly clear what was going through their head because this was done through written correspondence. But if you -- and this was done before I was -- before I acquired the company. But in the written correspondence, you'll see that over time, they moved from the full ICARS, to the modified ICARS, to ultimately the rescore 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. And the rescoring component of it simply puts more of those 29 points into the posture and gait domain. So if you look at the ICARS versus the RmICARS, by the way, the ICARS is what's done in the clinical trial, both ATTeST and NEAT. The investigators do the full ICARS. So the conversion from ICARS into RmICARS is fully programmatic. It's not a separate assessment. So the rescoring just essentially even further emphasizes that gait and posture, so essentially what the ICARS becomes largely is a measure of your ability to stand or walk. And if you look -- 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. So it turns out that -- and we've looked at the different domains of the ICARS with our historical data sets. And it turns out that, that gait and posture domain is, in fact, the most sensitive indicator of function in these children over time. So I don't -- I'm not sure they knew that specifically, but they did have the ATTeST data set, and that's what they said they'd be looking at. So I think they actually chose an endpoint that really does reflect how a patient feels and functions in this population.

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?

So I keep telling, Dirk, I have 1,000 other indications. So, in Neurology, we use steroids for everything. And you could just Google Neurology and steroids, but 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. So this is something that steroids are very commonly used for. Typically, patients can only tolerate them for 2 to 3 years, and then they have to be withdrawn. And yes, there's so much efficacy data that they delay the worsening of Duchenne, and 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. But there are probably 4 or 5 that we could tackle in the near term with appropriate funding. Right now, our funding is committed to A-T only, but we're going to be opportunistic with respect to the ability to raise money. And if we can do that, we'll certainly accelerate our DMD plans, and we already have a study design for that, that we're reviewing with KOLs in the field. And then 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.

We'll go next to John [Owen] at Citizens JMP.

This is [Catherine] on for John. Just kind of a quick general question. 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?

So from a cognitive standpoint, most of these patients are pretty cognitive. So they're pretty aware of what's going on with them. So when you talk about things like how -- where they are, they're very aware. So 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. And then 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, so they're malnourished and then you make them overweight in a negative way. And then in addition to that, it affects their bone health, and so they become prone to fractures. They develop osteoporosis. These are children who are falling frequently. So, if you just look at any one of those, just for example, look at the broken bones. So these are kids who fall all the time. And if you make their bones brittle and then all of a sudden, now they're breaking a bone every time they fall. And that causes a significant amount of pain, which then causes discomfort that is throwing on top of them already having this neurologic condition. So it is a limiting factor. It is something that prevents us from using systemic steroids in them.

A quick, quick follow-up to that. As far as the time scale of the steroid-induced effects, how early are these patients actually seeing them?

Usually, they start within a few months.

Next, we'll move to Sumant Kulkarni at Canaccord Genuity.

Thanks to your work on behalf of 80 patients. I have two. The first is a 2-part question on the scales and the second is on the treatment landscape for A-T. So on the rescored modified ICAR scale, what would be considered a clinically meaningful point difference versus placebo? And 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?

So as far as the clinically meaningful difference, so 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 ATTeST study was. So what I know is the modified ICAR scores. So there was that 4-point decline in the patients who were between the ages of 6 and 9, and what we saw was an almost 5-point difference. So, for me, if you can stop any decline in these patients at all, that's significant. And so I would say any change at all in stopping decline is going to be clinically significant to these patients. And then I'm sorry, I missed the second part, but I think...

I can tackle the second one. It was about the FDA's opinion on modified SARA score versus the ICARS. And the ICARS was developed in the mid-90s and validated in clinical studies in the early 2000s for a variety of ataxias. It was initially used by EryDel in the Phase II study for A-T and then subsequently in the ATTeST study. So there is a historical legacy of using the ICARS for this indication with this technology. So it's very attractive because when you do integrated analysis, ultimately, you're going to want to have data with the same outcome measure. The SARA score evolved later and also isn't specific to A-T. And 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. And, in that document, they specify the RmICARS as their preferred measure. So there was no discussion of SARA. And I think that's appropriate because of the historical data set in A-T.

That's very helpful. And this is more of a question on the treatment landscape. Given the similar epidemiology between A-T 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? And is there anything in the future that might preclude combo use of that product with the EryDex system?

I'm going to defer that to Dirk.

Okay. Well, you might want to comment on the idea of using Skyclarys in A-T. I think there hasn't been a lot of discussion of that because the pathophysiology of the two diseases are different. And in discussions with other KOLs on whether Friedreich's would be a good target for our technology, it's unclear. The difference is in A-T, there has been historical evidence to suggest that corticosteroids could be beneficial, and that's not true in Friedreich's. So I haven't -- I'm not aware -- and Mary Kay, this is where you might want to comment. I'm not aware of any physicians that treat A-T patients that have considered using that drug in their population.

Yes. I'm not aware either of using Skyclarys for A-T.

Yes. And because of that, any discussion of combination therapy would be purely speculative on my part. I don't have a good answer for that.

And there are no further phone questions. I'll hand it over to Brendan Hannah for any web questions.

There's a couple of questions in the chat here. So Dirk, why don't you start off with this one. It's a 2-part question. So the first part is, is A-T part of prenatal screening? And then the second part is assuming positive results, do you expect the FDA would allow EryDex to be used in patients younger than 6 years old? And that's coming from Serge Belanger of Needham.

Okay. 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 they -- there has been a previous child in the family with A-T, you can do specific prenatal tests to look for those gene mutations. But with respect to just standard screening test, it sometimes picked up in a skid assay, a lymphocyte assay, for severe combined immunodeficiency. When that test is positive and the follow-up genomic test is negative for skid, the central lab that did the test is supposed to suggest to the physician that A-T 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. So sometimes children get picked up that way. But there is -- 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, and that's why there is some variability in the phenotype because the different combinations of mutations affect ATM function differently. So, 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, and those might be able to be added to a panel. But I think that's an area that if this drug gets approved, that will be an area that I think we could help evolve because doing such prenatal screening or adding it to panels would be definitely beneficial. And then the second part was testing kids less than 6 years old. So the EMA has requested a pediatric investigational plan, which would test children between 9 and 15 kilograms. In an A-T trial population, that equates to about 1 to 6 years of age. It would be very valuable for us to be able to study those kids and include them in a label, and we're 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 6 and older -- and this is why the lower age limit of 6 was chosen. We use a 50 mL blood process. And there are generally -- there's some variability, but they're 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. And to remain within those guidelines, it's about 50 mL would mean that we can't really treat patients younger than 6. So we developed a 30 mL process instead, and that 30 mL process will be used for children between 9 and 15 kilograms. That will be a PK study. So I'm hoping we can use that PK study in 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. So that's the plan for the younger population. The older population, there are 10, 20 kids included 10 years of age or older in the NEAT study, and that was at the request of the FDA, specifically so that we could potentially get a broader label in the older age group. We're -- that's not enough children to show statistically significant advantage in efficacy. But I think if we have a lack of safety signals in that population, it will be a good justification to include that older age cohort in the label.

And if I can just add one thing. There is a lot of research that's going on lately or a lot of examples lately where once the treatment is available for a condition like this, then it gets added to the newborn screening. So I think it's very likely that if a treatment becomes available, that there'll be a big push added to newborn screening.

Okay. Dirk, one more question from Jason Dorr of Oppenheimer. So how are you thinking about opportunities for EryDex in A-T beyond the Phase III NEAT population? And where may there be residual unmet needs in A-T?

Yes. That's probably not just for me. I'll let Mary Kay answer it in a second. But I think the biggest opportunity would be to study these younger kids because with a lot -- with neurodegeneration like a lot of other disease, like infectious disease, the earlier you can intervene, the better. Since we're not -- 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. But, by the age of 6, a lot of that has already occurred. So 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 cellular or the 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 1 or 2 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. So that's -- that would be my hope for the next phase of development of the drug. But I might -- I'll hand it over to you, Mary Kay, to add to that.

Yes, I'm really excited about the possibility of younger kids. So 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 ATTeST study that I think is going to be an important aspect of this is the older onset. So 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 there are a lot less prone to the lymphoid cancers. And so they tend to not have as much immunodeficiency and they tend to not have as much cancer risk, but they do develop this slowly progressive ataxia, that really progresses throughout their 20s and 30s. And they're less defined because they've been less well recognized. And I could go all day about why that is, but I won't. But I think that this is a population that didn't necessarily show the dramatic benefit in the ATTeST study because their decline is so slow. But we do have one patient who's stuck with the therapy. She enrolled with us in the ATTeST study, and she's continued on therapy. She's been on it now for more than 3 years. And her decline has really been, if at all, very, very minimal. And so, I think that, that's a population that's underdiagnosed, underrecognized and has a really good potential for benefit from this therapy in the long term. And so I think that, that's one that I'm pretty excited about potential for.

And we'll take our final question on the phone line from Kumar Raja with Brookline Capital Markets.

I just had 2 questions. One on the 2 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? And 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?

Okay. I can tackle the one about the 3 children on the original Phase II. I think when they enrolled originally, they were on the order of 9 or 10 years old. So now they're all in their early 20s.

Okay. And as far as the real life situation, so we had, I want to say, 15 patients enrolled in the original ATTeST study, and then we've got -- I don't even know our numbers today, like 10 patients enrolled in the NEAT study now. So from a standpoint of the therapy from -- and I can talk very clearly about the ATTeST study, that data has all been published. It's a pretty easy therapy to administer. Once you start, it's -- the first time, it takes a little bit. But 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 and those are very, very common in neurology for us to prescribe infusion therapies. And 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 6 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. And 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. And I say that over and over again. When you see a kid with A-T who is still walking after years, that's just striking to me. And I've seen that, and I love it. And so I've been -- 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.

And 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.

And this concludes today's conference call. You may now disconnect.