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

Greetings, everyone, and welcome to our first ever Investor Day for Quince Therapeutics. My name is Dirk Thye, and I'll be walking you through the beginning elements of our presentation. We've got a full agenda for you today. I'm going to start by giving you an overview of Quince Therapeutics, our technology, our development plans and our key investment highlights. And then I'm going to hand it over to a series of departmental and technical experts that are going to walk you through the elements of the technology itself. I'll come back and talk about previous clinical studies and the development plan. We'll hand it over to Caralee Schaefer to explain to you some very interesting and compelling new data on the mechanism of action of encapsulated dexamethasone. Then we'll talk about some elements of the regulatory plan and go into some details on our commercial planning for post-approval activities. These are some of the people you'll be hearing from today. There are some additional team members on this slide. And the point here is to demonstrate that we've got a very good team of people with a lot of expertise and experience in their particular functional area. And as I said, some of the key speakers are listed on this slide as well. But let me start by going over the overview of the company and some of the key highlights. This slide outlines my disclosures. And our fundamental technology here is a machine that performs a process that we call AIDE, Autologous Intracellular Drug Encapsulation. And it's a method by which you can take a patient's own red blood cells, so autologous blood and you can treat them so that they can encapsulate a molecule, a small molecule, a large molecule, even a protein into their own red blood cells and then reinfuse those drug-loaded red cells back into the patient. Some of the highlights of our current status are that we are in Phase III. We have completed enrollment in our pivotal Phase III trial. That trial is in the lead indication of the ataxia-telangiectasia, and you'll hear a lot more about that disease and that study in the following slides. There are no currently approved therapies for this terrible pediatric disease, and it's a large and important commercial opportunity. The current Phase III trial is called NEAT, N-E-A-T. And as I mentioned, we've completed enrollment. We enrolled 105 patients, 83 in the primary analysis population, and I'll give you details about the study and its operations later in the presentation. The key here, though, is that if we are successful with encapsulated dexamethasone and ataxia-telangiectasia, we have a large list of other rare diseases we can pursue with this same drug. And next on the list would be Duchenne muscular dystrophy, which would be a really terrific disease target for this particular therapy. And then we have a prioritized list of rare diseases we could pursue thereafter. For the commercial phase, we're already planning ahead even though we don't have our Phase III results yet. But a key element of that will be our recently announced partnership with a company called Option Care, which is an outpatient infusion network around the United States with about 170 different locations in the U.S. And you'll hear from Charles Ryan more about that particular partnership. Importantly, we were successful in raising some money earlier this year to extend our runway and that extends our runway for several months after we get our top line results from our pivotal trial. So that gives us -- puts us in a good position to get results and thereafter executing additional financing and/or partnerships of some sort, following data in the first quarter of 2026. Well, let's go back to the technology. I mentioned it's a machine. This is a tabletop machine. It can sit on a cart. It can sit at the patient's bed side. It can be put in the lab. It is a mobile machine. It's about the size of an old-fashioned desktop computer, and you see a picture of it here on the top right of this slide. Over the years, it has been adapted and amended to be a fully automated system now. It's a 17-step process that uses that touch screen you see on the computer -- on the screen on the front of the machine. And essentially, what it does is you take a small volume of the patient's blood, you take 50 mls of the patient's blood, that's about a double espresso worth of blood. And it's in a bag, you hook up the bag to the machine and then you just press start on the touchscreen. Over the next 90 minutes, what that machine does is it uses a series of hypotonic solutions to slowly swell the cells. They thereby become porous and then you incubate them with the drug cargo. And then as hypertonic solution and excipients will then be used to shrink the cells back down and the drug target gets trapped inside of the red blood cell. Our lead program is dexamethasone sodium phosphate. Dexamethasone sodium phosphate is a previously approved prodrug of dexamethasone. It has a phosphate group attached to it. It's therefore ionic. And when it gets trapped inside of the cell, it cannot escape because it's a charged molecule. So I can't diffuse across the lipid bilayer. But then what happens over time is intracellular phosphatases will clean that phosphate group. It renders dexamethasone, the parent drug, nonpolar. And then that nonpolar dexamethasone can thereby diffuse out of the -- through the lipid bilayer out of the red blood cell as the red blood cells are circulating throughout the body. The key to this is to be able to facilitate the safe and chronic use of dexamethasone. So conventional dexamethasone administration looks like this. This is a graph of daily 6-milligram dexamethasone doses. And you can see because of the short half-life of dexamethasone, you get peaks and troughs. So this is 30 doses over 30 days. And regardless of the approved formulation of dexamethasone, whether it's subcutaneous or pegylated or liposomal, you still have to give it frequently enough that you're going to have these peaks and troughs many times over the course of a month. And when you do that, even at the lowest effective doses, what happens is you exceed these plasma drug concentration thresholds that lead to toxicity. You see 3 dotted lines here, horizontal dotted lines across the graph, representing plasma drug concentrations that if exceeded over time will lead to toxicity. You see one for glucose sensitivity, you see one for immunosuppression and the most sensitive one is for adrenal suppression. Adrenal suppression is, of course, the most important and the most damaging long-term toxic effect of corticosteroids. And it's associated with all kinds of adverse events that you can see listed at the top of the slide, you get growth delay, delay in puberty, you get weight gain and Cushingoid. It can lead to diabetes and behavioral issues, hypertension, osteoporosis, many, many problems. So you really can't take corticosteroids for more than a couple of weeks before you start running into these problems related to adrenal suppression. And therefore, despite the fact that corticosteroids would be just a wonderful therapeutic for lots of different diseases where chronic inflammation is a major component of the pathophysiology, you can't take them because they're just simply too toxic. And I'd mentioned DMD, Duchenne muscular dystrophy, previously. Almost every child with DMD is on chronic corticosteroids and it's a major, major problem in their life. So our technology is designed to fix that. And we do that by allowing the chronic administration of corticosteroids while avoiding these toxic drug level thresholds. And let me explain to you how that works. First of all, in order for corticosteroids to be efficacious, you need a couple of key pharmacodynamic elements to be satisfied. One is that you need an initial Cmax that is high enough to give you receptor saturation or near saturation in important tissue beds. Then what you need is receptor occupation over time, persistent receptor occupation over time. So you need long-term drug exposure. So you get that with conventional steroids, as I just showed you in that last graph by giving them frequently. But on the next slide, what you'll see, the way we achieve that is to have monthly dosing of dexamethasone that is slowly released from the red blood cell as the red blood cells are traversing your body. Initially, what happens because there's a high concentration entrapped within the red blood cell as you get a peak of concentration. And it's important to have a peak concentration of about 100 nanograms per ml or more, you get that with the encapsulated version. But then instead of it falling off quickly and having to be redosed, you get this long, slow release of corticosteroid from the RBC over time. And it pretty quickly gets below these plasma drug concentration thresholds that you saw in the previous slide and that are redrawn here at the same concentrations. Over the first couple of days, you're below the glucose sensitivity and immunosuppression thresholds. And then after about 7 to 10 days, you're below the adrenal suppression threshold. And one question you might ask is, well, you're still above that threshold for 10 days a month, is that enough to generate adrenal suppression? And the answer to that is no, we have a very strong safety database consisting of about 70 patients that had taken the drug monthly for over 3 years and had no signs of adrenal suppression and no signs of corticosteroid toxicity. And there are, in fact, 3 children that have been taking this now monthly for 13 years back to the original exploratory trial in ataxia-telangiectasia. And those 3 children have no adrenal suppression and no signs of corticosteroid toxicity after 13 years of administration. So it's pretty phenomenal. And as a drug developer, I would say that's strong evidence that we don't have a safety issue when it comes to chronic dosing of encapsulated dexamethasone given through the red blood cell. So I'm going to tell you more throughout the course of the day about ataxia-telangiectasia, about our Phase III study, NEAT. But I also want to mention that this really is a platform, a platform that can be used with lots of different diseases where corticosteroids could be really beneficial if they could be given chronically. And again, I think DMD is a good example of the problems that come with the chronic administration of corticosteroids. But this technology has been in development for well over a decade now. The first machine was developed in about 2008, and there were a variety of investigator-initiated trials starting around 2010 in ulcerative colitis, Crohn's disease, cystic fibrosis and COPD. And all of those small studies showed very interesting results with signals of efficacy and no safety issues. So we are using dexamethasone sodium phosphate encapsulated into the RBC for rare diseases, but we will pursue betamethasone encapsulated into the RBC for non-rare diseases, including some of these you see on this slide. So with respect to A-T, we'll get those results in the first quarter of 2026. And if that's positive, it really opens the door for us to pursue a variety of other rare disease indications. We'll show you a list of those later in the presentation today. As I mentioned, DMD is the first on that list. And then we will also develop betamethasone for a variety of non-rare diseases, and we'll be announcing that program in the near future. So I'm going to hand it over to Giovanni to take you through some of the technical aspects of the machine.

My name is Giovanni Mambrini, and I'm Chief Technology Officer at Quince. I'm co-founder of our predecessor company, EryDel, in 2008, and I'm pleased to be here today to provide you with insight into our journey to advance our AIDE technology and lead asset eDSP. Over the past 2 decades, we have made significant strides in advancing this innovative technology. The journey began in 1998, when an initial patent was filed and it was the first of numerous patents on AIDE technology. This moment set the foundation for future development. In 2008, the start-up EryDel was founded, marking the beginning of a dedicated effort to develop the AIDE technology. Red Cell Loader was CE marked in 2010. This regulatory approval allowed the technology to be clinically used in Europe for the first time on COPD patients. Since the company obtained IND approval in 2013, we have initiated and completed a lot of studies, bringing us closer to our goal. Phase I studies on PK and red blood cell survival in circulation in healthy volunteers. Phase II study on 80 patients, The ATTeST controlled randomized Phase III trial comparing placebo with low dose and high dose arms and the open-label extension study. In 2021, the Human Factors program was completed. And in the following year, FDA granted a special protocol assessment on pivotal Phase III NEAT trial. In 2023, Quince Therapeutics acquired EryDel and started the NEAT trial right after. More recently, enrollment completion of our Phase III NEAT study was reached in July this year, which set up for top line results in Q1 2026. It's a very exciting time for the company as we work to bring these 20 years after to fruition. Next, we thought it would be helpful to show you how our unique drug device combination works in the clinical setting. So let me walk you through our eDSP drug encapsulation process. So you can see our technology in action and what the patients experience when they come in once a month for eDSP treatment. So once you have all supplies you need, just switch on the Red Cell Loader or RCL. The RCL is super smart and fully automated with a user-friendly interface that guides you step by step. You see clear text and images on the touchscreen, making it easy to read, visualize and confirm each action. You'll always know exactly what you are doing and how long the process will take to completion. Next up, you'll install the EryKit on the RCL. For convenience, the EryKit comes preassembled with all tubing and components. There, EryKit is a sterile all-in-one system designed to handle blood, drugs and solution in a controlled way, thanks to the Red Cell Loader's automation. The EryKit's parts like lines, bags, blood separator, are set up for quick and easy installation. The tubing connects the reservoir and filter pneumatic and runner pumps and the disposable blood separator. The system contains multiple sensors to enable automation and support consistent process outcomes. EryKit is designed as a single-use sterile components that is disposed off after use, thereby avoiding any possibility of cross-contamination as the RCLs does not come in contact with blood or solutions. The system runs a self-diagnostic test during set up to test the functionality of all actuators. Tubing are automatically positioned around the 3 pumps. The process requires injectable-grade saline to wash red blood cells and resuspend them before infusion. Two specific hypotonic solutions, hypotonic solution 1 and hypotonic solution 2 are connected to the kit. They are intended to temporarily reduce the osmolarity of red cells and cause their permeability while hypertonic saline solution is used to restore physiological osmolarity after drug encapsulation. The syringe kit collects a 50 ml of blood from the patient, 2 millimeter heparin are added through a sterilizing filter. The filter is removed and the syringe is connected to the IV cannula. 50 ml of patient's blood is collected. After touching the syringe containing 50 ml of blood to the EryKit, you start the procedure via the RCL's user interface. The RCL takes care of the 18 phases of the eDSP process automatically. The procedure involves preparing dexamethasone sodium phosphate solution 25-milligram per milliliter in a syringe. As soon as dexamethasone is injected via the port, it enters by passive diffusion into permeabilized red blood cells. The entire process takes about 90 minutes from start to finish, while the patient waits nearby for the red cell loader to encapsulate dexa into their own red blood cells. At the end of the encapsulation process, the resulting eDSP is transferred to the collection bag for immediate refusion to the patient. So this is an overview of the process that the patient would experience for the once-a-month administration of eDSP. Finally, a full procedure report is available for download and printing at any time for recordkeeping purposes. We have also gathered a remarkable clinical experience behind the eDSP. Over the years, this therapy has been applied across a range of challenging conditions, Crohn's disease, ulcerative colitis, COPD, cystic fibrosis and mainly ataxia-telangiectasia. To date, that has translated to more than 425 participants who have received at least 1 dose of eDSP, including more than 240 patients. That truly stand out is the depth of our clinical exposure. We have administered more than 7,800 infusions to A-T patients alone and some of them have been treated monthly since 2012. This experience not only demonstrates the reach of eDSP, but also set the basis for safety and efficacy profile, which we must establish. Finally, it is worth highlighting that our technology is further supported by a rigorous regulatory review to date. In Europe, we have secured the CE mark ensuring full compliance across new medical device regulation. Our consumable kit reflects extractable and leachable validation that have been secured in compliance with European and U.S. regulations. We also get asked the question a lot about the stability of the system, which is insured throughout our [indiscernible] 17-step automated process that you saw in our demonstration video. The eDSP system was also designed and deeply automated for high-quality processed red blood cells, which resulted in having an in-vivo life span similar to products for transfusion. And for over a decade, we have maintained an active investigational new drug demonstrating our ongoing commitment to the high standard requested by the agency. All this to say that a tremendous amount of effort and oversight has been invested in our technology to date and gives us the confidence in our pathway forward. I hope you find this discussion helpful, and I look forward to answering any questions you might have during the Q&A session.

Hello, everyone. Dirk here again. I'm going to walk you through some of the details of our lead indication, ataxia-telangiectasia. So ataxia-telangiectasia is a tragic and terrible pediatric rare genetic disease. It's an autosomal recessive disease. Typically, one mutated allele is inherited from each parent. And typically, the parents don't know that they carry this allele. And it's a rare disease that has about 5,000 patients in the United States. It's primarily at a very young age, neurodegenerative so the children start to lose neurological function around the age of diagnosis, which is typically in the ages of 2 to 4 years. And they typically end up in a wheelchair by about the age of 10 to 12. And then during the course of their disease and into their teenage years, they develop multiple infections and frequent infections and then cancer and the life span is typically into the mid-20s. And now we'd like to show you a short video of a patient named Shane and his family, which is really illuminating and powerful story about the journey of an A-T patient and their family and what they go through. [Presentation]

So the typical pathophysiology is that when the child is born there's nothing evidently wrong that child seems normal. And typically, parents don't notice anything abnormal until later in development, maybe around the age of 2 to 3 years of age. There is no prenatal -- standard prenatal testing for this. So it's a hard diagnosis to make because it's so rare. And parents start seeking help with the diagnosis around the time they see some abnormal development. And then as the child gets into the ages of 4, 5 and 6, it's clear that they're having problems walking, learning to walk or persisting with their previously effective walking. And then as I mentioned previously, their neurological deterioration leads them to end up in a wheelchair around the age of 10 to 12, and then they get infections and cancers throughout their later years and their lifespan at their mid-20s, as I mentioned previously. So this is -- there is nothing approved for this disease. These children get physical and occupational therapy and supportive care consisting of treatment for their infections and their cancers. But there is no disease-modifying therapy ever approved. We are in the process of trying to change that with our study -- NEAT study in A-T, but the NEAT study was preceded by a study called the ATTeST study, which has been previously published, and you may have seen that publication if you're an investor in the company. It was the largest trial of A-T ever performed with 175 patients around the world. And it looked at a neurological outcome measure called ICARS, which I'll describe to you in more detail and actual modification of that ICARS score, as mandated by the FDA. And the results were good. I'll walk you through those results. But with respect to the primary endpoint, it's called ICARS. And it's one of these neurological scoring tools that is used by neurologists where you run the patient through a battery of tests, and there's a scoring system associated with each of the tests. It's a little bit like SARA or mFARS or even ADAS-Cog for Alzheimer's disease. You can see here in the left-hand column, the full ICARS score adds up to 100 points. But over the years in the company's communication with the FDA, the FDA changed their focus on which of the elements of the ICARS they wanted most emphasized to reflect the patient -- how the patient feels or functions. And so over time, they revised what they wanted to see to a subset of the ICARS of 54 points, which is called the modified ICARS and that's the primary endpoint that was used in that ATTeST study. I'll show you some of the results on that study in a moment. And the current primary endpoint for the NEAT study is the endpoint that the FDA has mandated under a special protocol assessment. We have a special protocol assessment in place for the NEAT study. So if that study is positive, it can act as a single pivotal trial for approval. And the FDA has now dictated that they want us focused primarily on posture and gait to measure how a patient feels or functions. And so that subset of the ICARS scores is 29 points out of the original 100. The good news is when you look back at the ATTeST results and you look at the RmICARS versus the mICARS versus the full ICARS, the RmICARS actually was the most sensitive indicator of change from baseline to month 6. So it's not a bad thing that we're using the RmICARS that I think of these 3, it is the most sensitive endpoint. Now the ATTeST study was technically a negative study with the P value at the end of the study of 0.07. So they didn't miss by much, but there's a good reason for that, and that's because they studied children 6 years of age and above. And here, what you're looking at is a graph of the natural history of neurological function over time in patients with A-T. And you can see that from the time of diagnosis about the age of 2 to 4, until they get to be 10 or 12, they have rapid neurological deterioration. And I mentioned a couple of times, they end up in a wheelchair by the age of 10 or 12. You can see thereafter the neurological deterioration starts to plateau out. And in the previous ATTeST trial, the enrollment ages were 6 and above in order to be inclusive and have the broadest label. But the problem in that study was that half of the patients enrolled were above the age of 10, 10 or above. And you can see from this graph that if you're studying neurological deterioration over a relatively short period of time, like 6 months, you want to study the population that's deteriorating the most rapidly. So you want to look at those years in the green shaded bar. If you're looking to the right of the green shaded bar, your probability of seeing a change in a 6-month period is much, much less. That's obvious from this graph. And that's what they saw in that study. I told you the overall P value was 0.07. So in the overall population, they're narrowly missed. But in that green shaded bar, it was highly statistically significant at 0.009 for RmICARS, the FDA mandated endpoint in the NEAT trial. And just to put that into context, that's about a 24% difference versus placebo over a 6-month time point. So that's a pretty big change over a short period of time. We looked very carefully at these results before we bought the company that performed the study, and we looked at secondary outcome measures and additional outcome measures. We looked at trends. We looked at a variety of different analyses and different subpopulations. And they all pointed in the same direction, the direction that suggests success in that younger age group. In addition to the suggestions of efficacy, we carefully looked at safety, and there were no major safety concerns from that trial. There was no adrenal suppression, no steroid toxicity in either the low dose or the high dose group from the ATTeST trial. There was a little bit of a dose response in adverse events. The low dose was pretty similar to placebo actually with the high dose being slightly higher. The major difference in adverse events between the low dose and high dose were primarily a higher number of infections that were not serious or significant and a higher rate of pruritus. But to me, that's a positive sign because it demonstrates that there's assay sensitivity with respect to adverse event reporting. So there were no safety concerns from the ATTeST trial with respect to the high dose. And that's the dose we took forward into the NEAT trial. So the NEAT trial is just high dose versus placebo. And you can get all of the details of that previous ATTeST trial by reading the previously published article in Lancet. We also have another article published in Frontiers in Neurology, which describes the long-term open-label extension safety data that emanated from that trial. So a lot was learned from that trial, and we acquired the company that performed it, and we used their work to build upon. Instead of enrolling the entire population of 6 and above, we're focusing it just to that population between 6 years of age and 9 years of age where they're deteriorating rapidly. And I think that gives us the best probability of success because as described, that's the population that is most sensitive to change over 6 months. And some bad luck that the previous company had was that they ran that study during COVID, and they ran it in places, including places like India and Tunisia, that had a lot of logistical and infrastructure problems related to COVID. And when that occurred, they had a lot of missing data and a lot of dropouts, which was adverse to their overall outcome. And we've been able to avoid that bad luck. So that makes our statistical powering and our study operations stronger than in that previous trial. This is just an outline of the study design for the NEAT trial. As I mentioned, it's under a special protocol assessment with the FDA. It's being run primarily in the United States and Western Europe, Scandinavia and one Eastern European country, Poland, with 2 sites in Poland. We've completed enrollment now with 105 patients and 83 in the primary analysis population of 6 to 9 years of age. And that gets us at least power of 90% to determine statistical significance. And on the next slide, I'll describe why it might even be higher than 90% power. But it's just high dose versus placebo. It's 6 months, 1 dose per month with then a 30-day safety follow-up thereafter. And after the NEAT trial, primary assessment visit is done, the patients have the opportunity to roll into an open-label extension trial. And so far, every patient in NEAT has elected to do so. With respect to the strength of the operations and statistics on the NEAT trial compared to a ATTeST, this is why I think we have at least 90% power to determine statistical significance. The assumptions that went into the sample size for NEAT came from ATTeST. So the point estimates of response and the confidence intervals around those point estimates came from ATTeST. And those, of course -- those confidence intervals are, of course, affected by the amount of missing data or dropouts because with larger amounts of missing data, you have to use imputation methods that lead to broader confidence intervals. Therefore, if we have fewer discontinuations and less missing data, we will have more narrow confidence intervals. With more narrow confidence intervals, you have increased power to determine statistical significance. So we use the factors in the right-hand column to determine sample size, but we're ending up with variables that are shown in the left-hand column, we have 6% missing data versus 26% in ATTeST. So that gives us a tremendous advantage and strengthens our statistical power to determine significance in this trial. So I'm feeling very good about how that's rolling out. In addition to the NEAT trial, we have initiated our PED study. It's called the PED study, P-E-D. It's a study required by the EMA for our pediatric investigational plan. And this study is going to take place in younger children. So instead of taking 50 mls of blood, you take 30 mls of blood. That results in a dose of about 12 milligrams instead of about 17.5 milligrams. And this study is going to be run in children between the weights of 9 kilograms and 15 kilograms. That will equate to an age range of about 2 years of age to 6 years of age. So this is a mandatory study required by the EMA. It's primarily a PK and safety study. But we're also using wearable devices. You can't use ICARS or any other neurological assessment physical exam tool in this population because the kids are just too young to follow the instructions. So you can't use what's typically used. What we are doing is we're using wearable monitors on the wrist and ankle so that we can explore different -- there are a lot of things you can do with this wearable device data, but we're going to explore what type of endpoint would be best sensitive and best to reflect function in this population. So that's exciting data to me that will be really informative. And I think if we can help develop such an endpoint, it would be much superior to these typical neurological assessment tools that we currently use. We are -- we've initiated our operational planning on the study, and we will be enrolling this study at the beginning -- towards the beginning of 2026. And we'll see how enrollment goes. We will -- if we finish enrollment quickly, we'll include the data in the NDA, but more likely it won't be ready in time for the NDA submission, so we can supplement our U.S. data thereafter and satisfy our requirements for the EMA by finishing this trial. We sometimes get asked about whether there are advocacy groups in this indication because with other rare disease, advocacy groups play a really important role, certainly with diseases like DMD and cystic fibrosis. They're incredibly important to the community. A-T is much less well known to the average investor, but there are advocacy groups, and we have a very strong relationship with them. The 2 largest and strongest advocacy groups are the one in the United States called the A-T Children's project and the one in the U.K. called the A-T Society. There are a variety of smaller country-based advocacy groups throughout Europe, but they work in conjunction with the U.K. A-T Society. They do a lot of things together. And so we know people at all of them, but primarily maintain relationships with everyone through A-T CP and the U.K. A-T Society. And they're instrumental in helping us find patients and communicate with the families of patients about the opportunities for being included in our clinical trials. So just with respect to our chances of success for Phase III, I'm extremely confident. I've done a lot of Phase IIIs in my time. I think I feel the best I have the highest probability of success with this particular trial. And I base that on the fact that we saw those ATTeST trial results previously, and we dug into them very carefully. And I'm convinced that they look good. We took the best elements of that ATTeST study and then we're producing it in the right population. And as I mentioned, we have a very high statistical power to determine significance. So I'm feeling very good about the results. I'm eager to see them, and we'll get them in the first quarter of 2026. But I'd like to hand it over to Caralee because we sometimes get questions about other than evidence from the ATTeST trial and just evidence about the dexamethasone mechanism of action in general, it's not obvious why dexamethasone as an anti-inflammatory would benefit a neurodegenerative disease. So we do have fascinating and compelling data from that previous clinical trial with respect to quantitative RNA sequencing and what that means for the mechanism of action. And Caralee Schaefer, Head of Nonclinical Development, is going to walk you through those results now.

I'm Caralee Schaefer, and I'm the Vice President of Nonclinical Development at Quince. I'm excited to share an overview on the mechanism of action of eDSP, and the results of RNA sequencing work that we recently completed. But first, before we get into that, I'd like to show you a short video describing the eDSP mechanism of action. [Presentation]

Before we get into the RNA seq data, I want to delve a little deeper into the pathogenesis of A-T. A-T is caused by mutations in the ATM gene. These mutations lead to a deficiency in ATM protein, which plays a central role in DNA repair, cellular stress response and immune regulation. The clinical burden of A-T is significant with these young patients experiencing ataxia, immune deficiency, recurrent infections and a heightened risk of cancer. Progressive loss of neurons is a hallmark of A-T, in particular, cerebellar Purkinje neurons. At the cellular level, the absence of functional ATM disrupts the response to DNA double-strand breaks and oxidative stress. This leads to elevated reactive oxygen species and altered redox status contributing to genomic instability. Importantly, ATM dysfunction also triggers chronic activation of NF-kappa B and then an increase in pro-inflammatory cytokines and chemokines, leading to a persistent neuro inflammation and immune dysregulation. Overall, ATM deficiency results in DNA damage and genomic instability, oxidative stress, mitochondrial dysfunction, chronic inflammation and neuro inflammation, all leading to progressive neuro degeneration. Next, I want to walk you through the design of our recent RNA sequencing project, utilizing whole blood samples that were available but had never been analyzed before. These are from the prior ATTeST Phase III trial, RNA sequencing was performed to investigate the mechanism of action of eDSP, and to identify biomarkers that may predict treatment response. ATTeST was the largest clinical trial ever conducted in A-T, featuring a 3-arm design where patients receive monthly doses of either high-dose eDSP, low-dose eDSP, or placebo. Whole blood samples were collected for RNA sequencing at 3 key time points in the ATTeST study, at baseline, immediately before eDSP infusion at month 2 and immediately before eDSP infusion at month 6. It's important to point out that the 2 and 6 month time points were collected around 30 days after the last eDSP dose. So these are considered trough samples. In total, we successfully sequenced RNA from approximately 300 ATTeST blood samples, spanning placebo, high-dose and low-dose eDSP groups. There were 29 placebo-treated, 33 high-dose eDSP treated and 35 low-dose eDSP treated patients, all with baseline 2-month and 6-month whole blood samples that we sequenced. This gives us a robust data set to investigate the mechanism of action of eDSP, and identify potential treatment responsive biomarkers through gene expression changes. Additionally, we also collected whole blood samples from 10 healthy adult volunteers to use as negative controls. We then compared the transcriptome of all A-T baseline samples from ATTeST to those healthy adult controls. This allowed us to investigate the biology of A-T and potential disease-specific biomarkers. The next slide describes the RNA sequencing workflow implemented for the ATTeST samples. We completed RNA sequencing on whole blood collected at baseline month 2 and month 6 again at trough. This allowed us to capture stable treatment effects over time. The whole blood was collected in the Pax Gene RNA tubes, which are designed to stabilize RNA for sequencing. From there, we performed RNA extraction, achieving high-quality RNA in over 96% of our samples. cDNA libraries were prepared and the sequencing was performed using the Illumina platform. The final step was bioinformatics and data analysis, focusing on differential gene expression and pathway level changes. The result is the most comprehensive RNA-Seq data set ever generated from the largest A-T clinical trial to date, giving us a very unique window into both the underlying biology of A-T and how eDSP impacts disease biology at the molecular level. With high-quality RNA sequencing data in hand, we next asked, what does the transcriptomic landscape of A-T actually look like? This slide presents a comparison between all A-T baseline samples in ATTeST and the healthy adult controls, revealing widespread gene dysregulation and offering critical insights into A-T disease biology. Comparing the A-T patients to healthy adults revealed striking shifts in gene expression with more than 6,000 genes differentially expressed. This gives us one of the clearest molecular signatures of A-T ever defined. The volcano plot on the right shows gene expression in A-T samples compared to healthy adult controls. On the right-hand side of the plot, past the hatch line, are the genes that were significantly up-regulated in the A-T samples. On the left side of the plot, past the hatch line, are genes that were significantly down-regulated. Many of these differentially expressed genes are directly tied to disease biology. Key pathways affected in the A-T samples included DNA repair and redox response, which are central to ATM function. We also saw significant reductions in immune-related genes, including those involved in B cell and T cell development, highlighting the immunodeficiency seen in A-T. There were also significant increases in pro-inflammatory cytokines and chemokines. Importantly, we also observed a marked up regulation of interferon-stimulated genes in the A-T samples, which are known to contribute to chronic inflammation and may service potential biomarkers of disease activity. Additionally, we found significant dysregulation in ion channels, neurotransmitters and mitochondrial genes. Together, this provides a landmark RNA-seq data set with the most comprehensive molecular characterization of A-T generated to date. With a clear view of the transcriptomic disruption in A-T that I just shared with you, the next slide focuses on how eDSP treatment modulated these pathways, highlighting gene expression changes that provide insights into the eDSP mechanism of action as well as potential treatment responsive biomarkers. RNA-seq data from eDSP treated patients refilled modulation of pathways directly implicated in A-T disease biology, along with the evidence of the gene expression signature that's consistent with methylprednisolone exposure. First, interferon-stimulated genes, which are typically elevated in A-T and contribute to the chronic inflammation scene were significantly down-regulated after treatment with high-dose eDSP. Down-regulation of interferon-stimulated genes are the hallmark glucocorticoid gene signature. The significant down-regulation of interferon-stimulated genes by eDSP reflects a marked impact on decreasing the inflammatory state of A-T. These genes may also serve as potential treatment responsive biomarkers. We also saw meaningful changes in immune and inflammatory pathways. There was an enrichment in humoral immune response genes and a significant reduction in pro-inflammatory gene expression indicating a shift toward a more regulated immune profile after eDSP treatment. Third, we found modulation of neuroprotective genes. For example, Wnt signaling genes, which has been shown to be neuroprotective in other neurodegenerative diseases like ALS, Parkinson's and Alzheimer's were up-regulated after eDSP treatment. Wnt activation has been shown to promote neuron survival, reduce oxidative stress and enhance DNA repair, mechanisms that are all highly relevant in A-T. Finally, ion channel genes, which are critical for neuron excitability and function were also modulated by eDSP. Since Purkinje neurons are highly vulnerable due to disrupted calcium homeostasis, this finding is very important as it ties directly to mechanisms driving neurodegeneration in A-T. The graphs at the bottom of the slide show the striking down-regulation of interferon-stimulated genes after high-dose eDSP treatment. Interferon alpha gene shown in the graph on the left, and on the right, we're showing interferon gamma genes, all down-regulated after eDSP treatment. Overall, these results reveal novel insights into the mechanism of action of eDSP as well as potential treatment responsive biomarkers. The next slide offers an overview of how high-dose eDSP impacted gene expression in ATTeST, highlighting the key pathways and their therapeutic relevance. On the left, the bar chart highlights the direction of change across these key pathways with significant suppression of interferon-stimulated genes and inflammation and up-regulation of adaptive immunity, mitochondrial function and neuroprotective genes. The robust suppression of interferon-stimulated genes is a hallmark of glucocorticoid activity while the down-regulation of NF-kappa B dependent pro-inflammatory cytokines and chemokines quite directly reduced inflammation after eDSP treatment. Mitochondrial dysfunction drives neurodegeneration in A-T and we saw up-regulation in mitochondrial genes that play roles in both restoring energy metabolism and function, which is consistent with neuroprotective effects. We also saw up-regulation of neuroprotective genes and neurotransmitters that promotes synaptic resilience and neuron survival. Excessive calcium influx leads to mitochondrial stress, oxidative damage and cytotoxic neuron death. Ion channels are known to regulate neuron excitability and calcium homeostasis. And modulation of these genes stabilize neuron firing and protect against Purkinje neuron dysfunction and death. Overall, the key takeaway here is that high-dose eDSP, not only reproduced the expected glucocorticoid gene signature, but also drove modulation of key disease-relevant pathways, including inflammation, oxidative stress, neuroprotection and ion channel biology. The next slide summarizes the key goals and results of our RNA seq project and some next steps that we're taking to build on these results. Our [ HS ] RNA seq project was designed to expand our understanding of A-T biology, demonstrate that eDSP has a measurable biological effect and show that the magnitude of those changes is meaningful compared to other traditionally administered steroids. First, we obviously succeeded in expanding our knowledge of A-T biology. By comparing A-T samples to healthy adult controls, we identified over 6,000 differentially expressed genes, providing a comprehensive data set for discovering potential biomarkers of disease activity. Next, the data revealed novel insights into the eDSP mechanism of action with the significant number of genes differentially expressed after treatment. These gene expression patterns were similar across both the 2- and 6-month time points. Notably, this activity was measured at trough approximately 30 days after the last eDSP dose, confirming that eDSP has sustained and durable biological effects throughout the 30-day treatment period. Lastly, Pathway analyses uncovered evidence of a classic methylprednisolone gene signature, reinforcing that eDSP engages steroid responsive pathways, while also revealing unique treatment responsive biomarkers. Looking ahead, we're working to correlate gene expression changes with clinical outcomes and genetic mutations in the ATTeST trial, and we're continuing to investigate potential disease-specific and treatment responsive biomarkers. Importantly, the RNA seq results that I've shared today have been confirmed using an orthogonal method, which is long-read DNA sequencing, which underscores the robustness of this data set. We're very excited to continue to pursue this work and expand upon this landmark data set from the largest clinical trial ever conducted in A-T, which we believe will be foundational for the discovery of biomarkers of both disease activity and eDSP treatment response. The final slide summarizes the synergistic mechanisms of action of eDSP including a unique and optimized PK profile that enables sustained dexamethasone exposure, while avoiding severe toxicity, improving both safety and efficacy, optimized glucocorticoid receptor occupation, maximizing exposures and improving efficacy, systemic and targeted biodistribution to the CNS. And importantly, eDSP engages both genomic and nongenomic glucocorticoid pathways, providing immediate as well as long-term anti-inflammatory immunomodulatory and neuroprotective effects. And given the compelling transcriptomic data from ATTeST, we are really optimistic about the potential of eDSP to deliver the first disease-modifying treatment for A-T, which would be an incredible step forward for patients and their families. In closing, I thank you for your time, and I look forward to answering any questions you might have during our Q&A session.

Hi. My name is Pamela Williamson, and I'm serving as Head of Regulatory Affairs for Quince Therapeutics. It's my pleasure to be able to take you through a high-level overview of our current regulatory planning. By way of background, orphan drug designation has already been granted by the U.S. FDA and the EU EMA for the treatment of A-T. As you may know, Orphan drug designation provides certain benefits in each of these jurisdictions, including, but not limited to, waiver of certain fees such as the application fee, which in the United States can be several million dollars and also affords marketing exclusivities following approval for those first to market. In the United States, we've also been granted Fast Track designation by the U.S. FDA for treatment of A-T. This affords the company additional opportunities for interactions with the FDA to move the program through more expeditiously and hopefully to approval. While not guaranteed, Fast Track designation often connotes the opportunity for priority review once the application is submitted, which allows for a shortened review clock. The eDSP system is regulated in the United States as a drug device combination product. This means that the primary center for review at the FDA will be the Center for Drug Evaluation and Research, however, they will also consult with the Center for Devices and the Center for Biologics. The eDSP system devices and the single-use treatment kit are already EU CE marked, further derisking the evaluation of the device components in the United States. Next slide, please. In the United States, the Phase III NEAT trial, which is the pivotal Phase III trial, is being conducted under a U.S. FDA special protocol agreement. The SPA includes the primary endpoint of the rescored modified ICARS tool with a primary efficacy population of the 6- to 9-year olds. The FDA has reviewed and agreed with the design of the protocol and also the statistical analysis plan. In Europe, there's also a pediatric investigational plan referred to as the PIP. In the United States, a pediatric investigational plan is not required. It's waived when you have an orphan drug designation. In the EU, we will be conducting an additional study, which is about to commence for those patients that weigh between 9 and 15 kilos, so smaller patients that are currently in the current NEAT trial. The design of this protocol has also been agreed to by the PDCO in the EU. In the United States, the regulatory pathway that we will be following for the NDA is referred to as a U.S. 505(b)(2) pathway. This allows sponsors to rely on data and findings from outside of their program in order to support FDA's review of safety and efficacy. In this particular context, because dexamethasone has been approved for many, many years and is very well characterized, we will be able to rely upon nonclinical data not generated by the company. Therefore, additional nonclinical studies are not expected to be required. Ultimately, the U.S. NDA submission is currently planned for the second half of 2026 given that the recruitment has been completed and we anticipate data readout in Q1 of 2026. I'd be happy to answer any questions that you have during the upcoming Q&A session.

Thank you. Hello. My name is Charles Ryan, and I serve as President of Quince Therapeutics. In my role, I oversee a number of functions and activities, including legal, finance, quality, day-to-day management of our Italian operations as well as working closely with the team to support our effort to prepare eDSP for commercial launch. So let me begin by talking a little bit about the commercial opportunity that we see ahead for us for our lead indication of A-T. At a high level, A-T represents a rare opportunity to provide a real benefit to patients and create a $1 billion-plus market. To ensure we fully capture the scope of this unmet need, we have completed extensive work to understand the true size of this market, both from a prevalence, physician and payer perspective. We estimate that the prevalence of A-T patients is approximately 5,000 patients in the U.S. I'll get into the details in just a moment. Assuming we have success with our final clinical study, we are also in an advantageous position as eDSP holds the potential to be first to market to meet the high unmet need of A-T as there are currently no approved therapeutics on the market. Our prospects are further supported by attractive comparables in rare disease with a number of recent launch analogs that we can look to that provide us with a good line of sight and understanding of pricing dynamics in this area. We're also in a strong position from a financial perspective, and we stand to benefit from both a highly scalable manufacturing infrastructure and a very low cost of goods. And finally, relative to exclusivity, we have an orphan drug designation, a very strong patent position and additional technology barriers that should serve us well and provide for long-term market exclusivity. And all of these factors translate into the $1 billion plus opportunity in A-T alone with more opportunities ahead for Quince. So let me talk about each of these things in a little bit more detail, beginning with existing epidemiology. Unfortunately, epidemiology in the literature is not great. And what is there is from the '70s and '80s before genetic testing was even available. Instead, we turn to third-party resources, and we partnered with IQVIA, which is one of the leading providers of work in this area, and you'll see our findings here. We worked very closely with IQVIA to go through their medical claims database. And we found approximately 4,600 diagnosed patients with A-T in the U.S. by utilizing ICT 10 codes to validate the number of diagnosed patients. And we were able to corroborate this patient finding size with a genetic prevalence study conducted at Baylor University that found approximately 6,000 patients in the U.S. using a genetic database. Comparatively, that helps to look to Friedreich's Ataxia, which has a very similar epidemiology and market size with 5,000 diagnosed patients in the U.S. So all of these factors give us confidence in this starting place for accurately sizing the U.S. market at approximately 5,000 A-T patients today, creating a very strong commercial opportunity for us. But we are also aware that because there's no currently approved treatment, there's a number of patients out there who could have A-T who don't currently present in the marketplace. To that end, we think we can increase the number of treatable patients with additional market awareness, increased testing, working with our partners at key advocacy groups and launching an approved product for A-T patients. So we believe that once we get the drug approved and it's launched, we're actually going to see some greater awareness in the marketplace, both with caregivers and patients. And this should actually help improve the commercial size of the opportunity ahead for us. The key takeaway is that we believe that this is a strong starting place as eDSP is well positioned to meet the high unmet need in A-T, quickly becoming the standard of care. Now you've heard from Dirk and others speak about the patient journey from diagnosis to rapid neurodegeneration. That's further complicated by frequent infections, respiratory issues as well as heightened risk of cancers. Unfortunately, patients really have a very challenging time in the earliest of days with this devastating disease. Our goal at Quince is to offer eDSP treatments as soon as possible, targeted at the neurological symptoms that prevail throughout the entire A-T patient journey. What that means from a commercial perspective, we will seek every opportunity to expand access to this therapy. While the NEAT study is focused on treatment effect in patients 6 years and older, you've also heard that we're beginning a pediatric study to reach smaller, younger children with the hopes of providing our treatments to kids early in their life and having them on eDSP as soon as they're diagnosed for the rest of their life. As we introduce the drug to the marketplace, we also recognize that we're going to gain a deeper understanding of the impact of our therapy for these patients. And as we collect more data with eDSP over time, we hope to see a reduction of infections in cancers and hopefully extending life, all of which will certainly help advance and support our commercial efforts. Another important factor that will underpin prospects for commercial development is to capitalize on our first-to-market potential and establish eDSP as a standard of care in A-T by matching the benefits of our innovative therapy to the clear unmet need in this space. First and foremost, A-T is underdiagnosed and the time for diagnosis is quite extensive. With increased awareness, the company's a first-to-market therapeutic, along with support from KOLs and advocacy groups, we expect to bring increased awareness and diagnosis to support early treatment. And since there is no existing therapy today, our focus will be on communicating the value of eDSP to hopefully help modify or even slow the progression of the disease, which will be the key value proposition. Another standout is our ability with a successful readout to validate not only the efficacy of steroids for the treatment of A-T, but also to dose steroids chronically and safely without toxicities, opening up another therapeutic avenue that is simply not currently available. And finally, current treatment options are really just limited to things like physical therapy and other types of supportive care with the goal of retaining ambulation as long as possible. Our hope is that our therapy will play a role in keeping kids out of wheelchairs and dramatically altering the life of patients day-to-day. Put it all together, an eDSP really checks all the boxes, a first treatment that directly addresses the key challenges patients with A-T and their families and caregivers face. Since this is a drug device combination, one thing I wanted to highlight here is the work we're doing around a number of supporting materials that are required to run the red cell loader. We've worked with a leading provider in understanding the best way to organize the materials for each monthly infusion, and that's reflected here in the eDSP EasyKit. Our goal is to launch a product that is easy as possible for physicians and infusion centers to use with no issues, while establishing clear processes that promote consistency and quality from one site to another. It's also going to improve our packaging footprint, and we'll be able to just drop ship materials as needed and help streamline supply chain overall. I'm pleased to say that we've completed this work. The final prototype is ready. We filed the patent application, and now we're working to select the commercial CDMO, so we'll be launch-ready. So now let me talk to you a little bit about other companies across the A-T landscape. Given the size of the potential commercial opportunity, the development pipeline for A-T is quite minimal. In addition to Quince, there are a few other players that are looking to provide a treatment for ataxia-telangiectasia, which are summarized here. I won't go through each of these assets. But I do want to note that we are uniquely positioned in many ways. We have the benefit of positive Phase III efficacy signals from our previous ATTeST study, which is very encouraging to us. We also have treated hundreds of patients already, and we know that our therapeutic is both well tolerated and has a very good safety profile. And for the patient, our treatment is a once-a-month therapy that delivers benefit throughout the entire course of treatment. I would point out here that [indiscernible] is the only other therapeutic in late-stage development. Our current Phase III trial includes patients of over the age of 4 and only provides treatments for 3 months, which increases the difficulty for their trial, but we'll be watching this one closely. However, as is the case with many severe diseases, our therapy currently has ability to be dosed concomitantly should one of these assets advance to approval and be available for physicians and patients. But we have a lot of confidence in the prospects of our success for all the reasons I shared. Now let me talk to you a little bit about pricing. We continue to do the work to understand our market and all of our stakeholders. Certainly, in drug development, one of the key stakeholders is the payers. To that end, we recently conducted a qualitative payer research study. This study involved qualitative research with payers that covered more than 200 million lives in the U.S., quite extensive in terms of the coverage of patients. Our initial research was both insightful and encouraging. What we learned is that many of the payers were not immediately familiar with A-T. This wasn't surprising to us as the lack of knowledge of A-T reflects the absence of sponsor engagement due to the modest product development pipeline I just discussed. However, what was encouraging is that within just a limited amount of education, payers quickly understood the graveness and burden of the disease and a significant unmet need, and that our asset really holds the potential to dramatically alter the life of patients with A-T for the better. So we really found a very supportive voice within the payer community. In terms of pricing, we have a number of comparables with other rare disease therapies that have recently come on to the market, which you see highlighted here on the right. But we certainly have more work to do in this area. After the completion of the NEAT Phase III study, we will have a comprehensive data on efficacy and safety, and now we can establish the value of eDSP and our pricing. Then we will continue with a more thorough quantitative payer research study to gain a deeper understanding of what price points would be appropriate for this therapy, and we'll keep you updated on that progress. In terms of effectively delivering this therapy, in early August, we announced an exciting partnership with Option Care Health. Option Care Health is the nation's leading outpatient infusion provider. They have more than 180 sites around the country, which will allow us to have the ease of a single contract provider while benefiting from greater geographic flexibility to match patients locations with sites strategically located throughout the U.S. So as we gain a deeper understanding of our patient community, where they're located, we want to do everything we can to make sure that we can provide our therapy in the easiest way possible for these patients. And certainly, going to an Option Care Center where you pull up and walk through the front door is much easier than navigating a large major medical center especially when these kids are not highly mobile. This strategic relationship will also play a role in improving and standardizing the patient journey with higher control and consistency across Option Care sites, while offering a comprehensive suite of enhanced capabilities to handle commercial services for us as well. Finally and importantly, Option Care will also allow us to have the ability to roll out other therapies like treatments for DMD and to leverage this partnership to execute these programs seamlessly to support our pipeline expansion. So it's a really exciting program for Quince. And we're delighted to have Option Care as a partner in providing eDSP to patients. Lastly, let me tell you about our substantial market exclusivity position and how we believe we're well protected from generic competition. Because eDSP has orphan drug designation, we automatically get 7 years of market exclusivity here in the U.S. and 10 years in Europe. This is a really significant amount of exclusivity. But in addition to that, we have an extensive patent portfolio and our patents run until 2036, with some additional extensions available. And we also have other patents that we are currently pursuing. In terms of technology barriers, as you know, this is a drug device combination, and our red cell loader has a lot of proprietary components and processes that would make it very difficult for a generic competitor to copy. For example, they would need to have extensive clinical studies and processed validation to even considering copying our technology. So we really look at our technology as having a unique position in the market in terms of our ability to have competition kept at bay. In closing, we are very excited about the market opportunity of eDSP, with the potential to be the first approved therapy for A-T, an area with no existing treatments. And we believe eDSP has true blockbuster potential. We have engaged leading consultants with proven success in commercializing rare disease therapies, and we are working closely with physicians, patients, caregivers and payers to ensure a successful and timely launch. We are confident that eDSP can deliver a meaningful impact for patients and significant value for all of our stakeholders. Thank you so much for your time, and I look forward to answering your questions during our Q&A session.

Hi, everyone. I'm Brendan Hannah, the COO and CBO of Quince. You've heard a lot of great information from our team so far today. But now I'd like to spend some time detailing how we believe our efforts will translate into driving value creation for our shareholders. Quince is very well positioned with a highly innovative asset that has potential to be the first steroid that can safely be delivered chronically. We're lining up for a very large value inflection point with Phase III data coming in Q1 of next year with a differentiated rare disease asset in an indication with no currently approved therapies. And given the profile of eDSP being a very potent, let's say, steroid, there's a large number of different indications we can go into to significantly increase the value of the product and then the company as a whole. We're in a great capital position. We finished Q2 with about $35 million in cash, which provides a runway through Phase III data and into the second quarter of 2026. We're also setting up for both strategic and financing activities following data like [indiscernible] capital all the way through launch. Now taking a look at the orphan disease landscape. Over the past couple of years, there have been several rare disease drugs launched as the first product for a disease, which we believe serves as a strong comparable for eDSP's commercial potential. These drugs are Daybue for Rett syndrome, Skyclarys for Friedreich's ataxia and Vyjuvek for DEB. These were all launched with premium pricing in the small populations and are forecast to attain at least $1 billion in peak sales. And what's interesting here is that within 18 months of launch, they were all on annualized run rates of about $400 million, either primarily or exclusively from U.S. sales. So it shows the pent-up demand for new products and indications, particularly in rare disease where nothing currently exists like that in A-T. A great case study is Reata's Skyclarys for Friedreich's ataxia. The epidemiology and market size for Friedreich's are roughly similar to that of A-T with about 5,000 diagnosed patients in the U.S. Skyclarys is the first drug approved for Friedreich's and has forecasted peak sales of over $1 billion. Both Friedreich's and A-T have very similar symptoms regarding ataxia and then moving towards non-ambulation, but A-T is actually more severe and has a shorter life expectancy. And from clinical trials, Skyclarys has shown modest efficacy in its Phase III study at 48 weeks with some significant adverse events while eDSP has shown a much larger effect 6 months in the younger population and was well tolerated. But shortly after launching Skyclarys, Reata was acquired by Biogen for over $7 billion, which just goes to show the value of a rare disease drug in a population of 5,000 patients in the U.S., especially considering Skyclarys can't be used for other indications. With A-T alone, we think there's potential blockbuster sales. But given the profile of eDSP being a potent, let's say, steroid, there's a significant number of indications we can go into. We completed a comprehensive analysis of a wide variety of indications where steroids are standard of care or would be if it wasn't for steroid toxicity. And then we assess each potential indication with a few key factors in mind. First, we narrowed down the list based on indications allowing for the same pricing as A-T, then we condensed it to chronic diseases where patients would be treated on an outpatient basis. With an eye towards commercial synergies, we also focused on pediatric indications that could be sold through a single sales force. And we only targeted orphan indications that would not trigger IRA price negotiations. Another one of the key variables was diseases with over 5,000 patients in the U.S. given that it appears to be a standard cutoff for many investors and potential partners. And then to do the final cut, we interviewed KOLs and treating physicians to understand if eDSP would be viable clinically and commercially given the current treatment landscape and development pipeline. And to give you a better idea of the disease funnel, we've reviewed nearly 100 indications at this point and narrowed the list down on epidemiology, competitive landscape, commercial opportunity, steroid usage and clinical impact. We narrowed the list down to 20 diseases following interviews with KOLs and treating physicians better understand the unmet need and commercial opportunity for eDSP. And then we did a final cut down to 12 indications based on clinical trial size, timing, cost, feasibility and probability of success. So as a result of this robust diligence process, we've selected DMD as our second indication to follow A-T. And then we prioritized rare neuromuscular, autoimmune and rheumatological diseases where patients will be willing to go in [indiscernible] for an infusion given the severity of their disease. These indications should allow for similar pricing as A-T and there is a significant commercial opportunity in each of these potentially allowing for hundreds of millions of dollars of sales per indication, if not more. And then given the wide applicability of eDSP and unmet needs in many of these indications, there is ability for it to become a blockbuster product in multiple indications. But from this assessment, DMD was the clear second indication. While it's seemingly crowded competitive landscape and commercial market, there are a significant amount of unmet needs in DMD, especially in the steroid space. Regardless of other drugs that patients are on, steroids are standard of care in DMD, they usually add 2 to 4 years of ambulation. So even a patient is on the gene therapy or an exon skipping therapy, they're still on steroids and the vast majority of toxicity, which leads to tapering dosing, intermittent dosing or fully taking the patient off the steroid. So the physicians we've talked to said that DMD is the obvious second choice for eDSP, as patients are currently losing out on efficacy while still having toxicity. So if we can provide equivalent efficacy while mitigating the safety issues, treating physicians have said that they want to try it out in the vast majority of their patients. And the clinical team has finalized 2 different clinical study designs, one in treatment-naive patients that we used for approval and the other in patients transitioning from standard steroids, which would be more of a real-world use case. Then we plan to start dosing patients in these studies next year. To provide a quick comparison of eDSP to other steroids commonly used for DMD. On the left side, you can see prednisone/deflazacort, which are standard of care and they have reasonable efficacy but a whole host of safety issues. Whereas Agamree was launched about 18 months ago by Catalyst in the U.S. and it doesn't hit the bone as much as it doesn't have growth suppression and seems to have less osteoporosis, but it still has all the other steroid-related safety issuance. So it's definitely better than the older steroids, but it's viewed as only an incremental advancement. But given the comprehensive safety data package of eDSP in over 600 years of patient safety data, we believe that eDSP has a fundamentally different safety profile that allows for steroids to be dosed safely, chronically. And moving on to finance. We finished Q2 with about $35 million in cash that provides a runway through data into Q2 of next year. We have a very capital-efficient operating model and development plan for A-T and plan to use investigator-initiated studies to get data in additional indications. And given that we own worldwide rights to eDSP, we have the ability to partner ex U.S. rights following Phase III data to provide additional runway as we start preparing for our own U.S. launch of eDSP. We've also had a very robust engagement with investors and potential strategic partners, hopefully setting up for a range of different options post Phase III data. I hope you found this helpful and I'll be happy to answer any questions you may have during the Q&A session.

Well, thank you, everyone, for joining us today. I hope you found the [Audio Gap] Okay. I think that was a great overview of all the activities we're working on. I'd like to open the floor to questions now. This is Dirk, by the way. Jon, you're on mute.

Can you guys hear me now?

Yes.

Sorry about that. Jon Wolleben from Citizens. Thanks for hosting the day. Very helpful information. I just want to focus in on the upcoming readout, Dirk, and I was hoping you could...

I cannot hear you.

Can you guys hear me now?

Yes. Yes.

For the upcoming readout, what are your powering assumptions? And then when we look back at RmICARS, you gave us those 2 charts showing the more sensitivity for RmICARS versus the other endpoints. But wondering if you could -- I'm confused by the placebo-adjusted benefit and then the worsening of symptoms. So can you tell us if the change is driven by stabilization and worsening of placebo or a drug effect? And then when you talk about worsening of symptoms on a scale like this, is this like patients have any worsening? Or is there some categorical consideration to say that their symptoms have worsened?

Okay. Let me start with the question of powering and then I'll move on to RmICARS versus ICARS and the magnitude of change versus placebo over time. So I mentioned this in my part of the presentation, but the statistical assumptions for powering the NEAT study came from a test and the test had that problem with 26% missing data. So the confidence intervals around the point estimate of response were wider than we will see in ours. Nevertheless, those are the assumptions we use to come up with the sample size originally of 86 patients. As you'll recall, we ended up enrolling 83 of the planned 86. It was powered at 90%. And I think we're at or above 90% because we only have 6% missing data versus 26% that was used for the data set that generated the statistical assumptions. So does that address the question around the powering.

What's the effect size you're powering for though?

I think it was -- Brendan, you might have it in front of you, but I think it was at [ 2.14 ] points versus placebo.

Correct, 2.4 points against placebo and then confidence intervals of 3 for active and 3.7 for placebo.

Yes. Okay. So now with respect to your question about, is this disease-modifying or delays progression? So the placebo group gets worse over time and the ICARS score goes up over time, and the treated group stabilizes. So it's really a delay in progression of disease and 2.4 points of an RmICARS is pretty significant over a 6-month period relative to placebo. It's about a 24% difference. So the full ICARS itself is divided into different domains. You have gait and posture, kinetics, speech and oculomotor and each of those 4 domains has a number of points. And over the years when the FDA started narrowing down what they wanted to look at, they focused more and more on the gait and posture domain. So when you get to -- from the ICARS to the RmICARS, you end up going from 100 points to 29 points. And most of those, the vast majority of it is in the gait and posture domain. So really what we're looking at when we look at a 2-point difference versus placebo, it's mostly with respect to the ability to walk. And a 2-point difference, for example, could be -- could mean for RmICARS the difference between walking autonomously and walking with help. So it's a big -- it's a very clinically significant difference over that short period of time.

This is Elemer Piros from Lucid Capital Markets. So I would like to go back to the RNA sequencing study for a moment. Is there a difference between low-dose and high-dose eDSP in terms of the magnitude of the changes in gene expression that's...

There was a very strong dose response that was one of the exciting things that we saw in that data set, but I'll let Caralee expand upon that.

Yes, Dirk is absolutely correct. There was a dose response, especially in the genes that we highlighted today to you. We really wanted to focus on the high dose for this presentation since that's where we saw efficacy in ATTeST and where we're focusing NEAT.

And have you been able to pick up a signature and the difference between responders -- medical responders and nonresponders?

Great question, and we're actively working on that now. So stay tuned.

Okay. And I just have two more. I don't know, Dirk, if you talked about the size of the pediatric trial that the EMA requested. And was there a discussion about the wearable device? Or what sort of potential efficacy indicators you might be able to pick up? Was it their suggestion? Or was their requirement purely focused on the safety aspects?

Their requirements are purely focused on PK and safety, and I did not mention the number of patients, which is 12 evaluable patients dosed over 6 months, 6 doses over approximately 6 months. It's only safety and PK. And the wearable device was my idea, and I had to battle some of my team members to actually implement it because it's expensive and it's not generally considered standard. But I think these devices, to me, they're really interesting because they will -- they have the potential to be far superior to these physical exam tools that we use right now. So we don't know exactly -- it's exploratory work. It hasn't been discussed with either agency in Europe or the U.S. But we'll collect a lot of data, and we're working with academic investigators who have experience in these neurological rare diseases to look at a variety of different endpoints. I don't expect that we'll be able to use it for any type of efficacy claims, but I do think it will be extremely valuable for guiding future work. That's especially important in these young kids, too, because you can't even use these neurological assessment tools. You can't walk them through the physical exam components in order to do the score.

Yes. I just have one more, maybe for Charles. When you look at the IQVIA data and look at the geographic distribution of the patients and compare it to the footprint what Horizon has. Roughly what percentage of the 5,000 patients would be close enough to these infusion centers to go on a monthly basis?

So our analysis is that we could capture at least 80% in a very close geographic range so you certainly could have some outlier patients that are in a more remote area. But the nice thing about Option Care is that they have a very significant footprint, and they're continuing to expand. So we think that there's a lot of flexibility even relative if we were to have some pockets of populations that were not geographically connected now that we could actually resolve that.

And it looks like we have a couple of questions from Hartaj in the chat box here. One is I'm going to direct to Pam. Well, the pediatric trial, I think he's referring to the PIP requirement from the EMA, supplemental NDA, get a pediatric priority review. And I don't think that's the right way to look at it because it's a requirement at the EMA to study the safety and PK in that population. It's not designed to get an indication. But Pam, do you want to -- is that correct? Do you want to expand upon that?

Yes, I can. So of course, you cannot request a priority review until you actually submit the marketing application or in this particular example, the supplemental marketing application or NDA. However, if the main application receives a priority review, there's no reason to suggest that the smaller weight children supplement would not also receive a priority review. Importantly, for the study that we're referring to in the EU, the data being generated are indeed safety and PK primarily, as Dirk has described with an exploratory use of the wearables. But those data are then intended to be included in a currently existing PK and simulation model, which would allow confirmatory dosing in those smaller patients, which we anticipate could in fact allow the supplement to be supported in terms of efficacy for the small children.

Okay. Second question is assuming a positive Phase III in an approval of the product in A-T, how long will it take to screen, treat and record revenues from an A-T patient? This lag can often affect first and second year revenues. Brendan?

Yes, I can handle that one. So it's going to depend on the patient. Some are already known and either in a registry with ATCP in the U.S. or known through IQVA or one of the genetic testing databases. So with them, it's going to be much quicker. They'll have to go through the patient hub, usually work through a prior authorization with the physician and then we'll be able to record revenue shortly thereafter, hopefully within a month or two as we'll be shipping just in time to each Option Care site. For those that haven't been confirmed as A-T yet, they will need a genetic test likely for the prior authorization. So that will take additional time to actually get patients diagnosed, work through the patient hub, get them on therapy and record revenue. So it's going to be dependent on patient.

Jason here representing Leland Gershell in Oppenheimer today. Great presentation and progress so far. I have two questions. First is going to be what disease-specific biomarkers or treatment responsive biomarkers are you going to be looking at as you build on the RNA sequencing pathway analysis? And do you have any insight on how that might map to the NEAT trial outcomes?

The short answer is not exactly, not yet, but I'll let Caralee walk through some of the details there.

Yes. We're taking a broad look at the treatment responsive biomarkers on all possibilities from the ATTeST study. We're also going to be doing this in NEAT. And we'll focus especially on anything that comes out confirmed through the DNA sequencing that we're doing as well on the same samples.

Great. And one more question. So unlike A-T, there are a couple of steroids approved for DMD, some of which are generically available. I guess how do you see eDSP's opportunity given the landscape and how you're thinking about positioning that product?

Yes. I'll say a couple of things, and then I'll let Brendan expand on some of the commercial details about it. But -- yes, if you go to the last couple of years, I've gone to the DMD academic conference, a big academic conference. It's a really interesting conference because it's very much patient centered and there are a lot of patients and their families that attend the conference. And one thing that's very obvious when you go to this conference is that a lot of the discussion is focused on the problems associated with the therapies and corticosteroids are the primary therapies for almost all of the children despite ASOs and gene therapies, almost everyone is on steroids, and it is -- other than the underlying disease, it's the biggest problem in their lives. It causes a lot of adverse events. They get a lot of weight gain, they get Cushingoid, behavioral issues, osteoporosis, they develop diabetes. So it's a major, major problem. And deflazacort and vamorolone have slightly different safety profiles and some marginal benefits. But even when you speak to the KOLs in this field, they'll tell you, they're still steroids. They're still very, very toxic. So I think if we can demonstrate that we have comparable efficacy, doesn't need to be better efficacy, just comparable efficacy and we can eliminate the adverse effects. And this was, by the way, EryDel years ago did a study in ulcerative colitis, where they took steroid-dependent patients and they randomized them to converting over to encapsulated versus staying on their current steroid and then they weaned both groups. And upon weaning, 80% of the patients that remain on standard of care had a recurrence and only 20% in the encapsulated group had a recurrence and all the steroid toxicities resolved. So that's what we want to see in DMD. We want to see that the efficacy is the same or even better maybe, but the steroid toxicities resolved. If that happens, it's not -- it's less convenient than taking a pill, you have to go to the clinic every month. But if we can demonstrate that we're likely going to have a different price point. So we anticipate. And this is where I'll hand it over to Brendan, but will anticipate you'll have to step through a couple of therapies before you're authorized to take ours, but I'll let you carry on from there, Brendan.

Yes, Dirk is completely right. So there's likely going to be step edits for prednisone/deflazacort and even vamorolone before getting to [ EDSD ] given the premium price point. And as he mentioned, nearly 100% of these patients have toxicity. So we don't expect there to be issues with prior auths given that the first and second line steroids are considered toxic. So even with a small percentage of DMD patients, you're still getting to very significant sales with about 15,000 DMD patients in the U.S.

Great presentations. So I just had a couple of questions with regard to the timing of the NDA filing. What needs to be done before you can file the NDA? And how quickly can you supplement the NDA?

When you say supplement, are you talking about...

Pediatric.

Yes, yes. Okay. Well, the first thing that has to happen is we have to have positive data. So that's the thing we're all eagerly looking forward to in the middle of Q1 next year. And we're already planning and working on elements of the NDA as we speak. But I'll let Pam outline for you kind of the major milestones along the way in the NDA process. And with respect to the -- she can add comments about the mechanism by which we would supplement with the younger data, the PIP data, but we don't yet have an exact idea of how quickly we'll be able to enroll that study. I'm not sure if it will go quickly or if it will be a little bit challenging. We do have a bunch of pre-identified patients and we only need 12, so it's possible it could go pretty quickly. And most of the patients should be eligible because the screening criteria are not extremely strict. But Pamela, I'll let you kind of walk through the major milestones along the way with respect to the NDA filing.

Sure. Thanks, Dirk. So as we've mentioned, we are looking forward to seeing top line data in Q1 2026. And assuming that those data are positive, we have a very good plan in place to efficiently develop and submit our NDA in the last half of the year. We intend to continue, and frankly, we are already engaged in routine discussions with the FDA as we move forward here to make sure that what we include in our application is going to meet their standards. And as I mentioned during the earlier presentation, in addition to the actual protocol, which has been reviewed and agreed by the FDA, they have also reviewed and agreed to the statistical analysis plan. So prior to database lock, we intend to provide the final versions of those documents. And then after top line data are available, we'll move forward with our -- earnestly with our NDA submission process. We have work streams in place already for each of the functional areas. We have plans in place for inspection readiness. We have plans in place for pre-submission meetings with the FDA prior to submission of the NDA to make sure that we're all on the same page with respect to the content and format of what will be included. And then we look forward to submitting last -- towards the end of the year. While we mentioned it cannot guarantee a priority review, we have every reason to believe that the application in the unmet medical need, assuming positive data that we would be eligible for a priority review. When it comes to the second part of your question and the pediatric study that's ongoing in the EU, as Dirk has mentioned, we don't have timing for completion of that study yet. If it's not completed in time to include in the initial NDA, then that would be submitted as a supplement as you've indicated earlier, and that would be submitted as soon after the initial NDA approval as possible.

Okay. Great. And in terms of the label expectation, is it that it will be 6 years and older initially. And once you have a supplemental, it will be from 2 years and older?

So while we can't -- until the final label negotiations are completed, we can't state that emphatically, but my speculation would be that they would not necessarily need to be a limitation of 6- to 9-year olds, especially since while the primary efficacy analysis is on the 6- to 9-year olds, this study is actually enrolling patients above -- 10 above. And that was actually at the recommendation of the FDA, so that we were not excluding the older patients, even though the efficacy signals for the older patients may be more difficult to detect.

And that group of older patients isn't included in the primary analysis population, so it doesn't have an adverse effect on our chances of success for the primary outcome measure. Looks like we're coming up at the end of our time. Thank you very much for joining us today. There was a lot of effort to put this together. So it's great to see people actually show up and listen to it, and thank you for your great questions. And we look forward to updating you as we generate more news throughout the rest of the year and into next year when we'll have data from the Phase III NEAT trial. Take care, everybody.