Welcome to Applied Therapeutics SORD Deficiency Interim Data Conference Call. I would now like to turn the conference over to Dr. Shoshana Shendelman, Applied Therapeutics Founder and CEO. Please go ahead. Welcome, everyone, and thank you for joining us on today's call. With me on the call are Dr. Riccardo Perfetti, our Chief Medical Officer, Adam Hansard, our Chief Commercial Officer, and Dr. Michael Shy, Director of the Division of Neuromuscular Medicine at Carver College of Medicine, University of Iowa, and one of the original researchers responsible for identifying the genetic and pathophysiological cause of SORD deficiency. Dr. Shy is also the principal investigator on the INSPIRE phase 3 trial. Before we begin, let me remind you that today's conference call will be making forward-looking statements that represent the company's intentions, expectations, or beliefs concerning future events. These forward-looking statements are qualified by important factors set forth in today's press release and the company's filings with the SEC, which could cause actual results to differ materially from those in such forward-looking statements. Information discussed on today's call is accurate as of today. We do not intend to update. We'll start off the call with our prepared remarks. We'll follow up with an open question and answer period. To provide background information for investors, I'll start by discussing what we know today about SORD deficiency and the tremendous progress that has been made since its initial discovery in 2020. Sorbitol dehydrogenase deficiency, SORD deficiency, is a rare, progressive, debilitating hereditary neuropathy that affects peripheral nerves and motor neurons. SORD deficiency affects approximately one in every 100,000 people, which represents a U.S. population of over 3,000 patients and an E.U. population of over 4,000 individuals living with SORD deficiency. SORD deficiency, which is also sometimes called SORD neuropathy or CMT SORD, was first identified in 2020 as a genetic cause of disease in patients who had been symptomatically diagnosed with distal hereditary motor neuropathy or Charcot-Marie-Tooth disease. Patients with SORD deficiency are missing the enzyme sorbitol dehydrogenase, which is responsible for the metabolism of sorbitol. Sorbitol is a sugar alcohol which is produced as part of the polyol pathway of alternative glucose metabolism. The polyol pathway consists of two enzymes, aldose reductase followed by sorbitol dehydrogenase. Glucose is metabolized to sorbitol by aldose reductase, and sorbitol is then further metabolized to fructose by sorbitol dehydrogenase and used for energy production. Polyol pathway is an alternative metabolic pathway, and this is not how the majority of the body's glucose is metabolized. In fact, only 1% - 3% of the body's glucose is metabolized by this pathway in healthy people. However, since patients with SORD deficiency can't metabolize sorbitol at all, even when produced at these low levels, sorbitol accumulates in blood and tissues, including neurons, leading to significant cellular toxicity. Sorbitol accumulation results in significant disability, loss of sensory function, and neuromuscular dysfunction. Inhibition of aldose reductase to prevent sorbitol formation is a valid biochemical approach to substrate reduction in patients with SORD deficiency, blocking sorbitol production at the source. We have worked diligently with the scientists responsible for the original Nature publication and characterization of SORD over the past two years, and we can now conclusively demonstrate on a molecular level how sorbitol elevations lead to neuronal toxicity and why motor neurons in particular are sensitive to SORD deficiency. Sorbitol accumulation causes derangement of mitochondrial membrane potential, leading to formation of reactive oxygen species and decreased ATP production. Since motor neurons both rely heavily on ATP production and are extremely sensitive to reactive oxygen species, these effects are especially detrimental to motor neurons. Motor neurons then lose their synaptic potential, causing decreased muscle denervation, and the result is axonal neuropathy and loss of lower limb muscle mass that we see in both humans and to the Drosophila model, a decreased ability to walk. We have also demonstrated that treatment of patient fibroblasts as well as treatment of SORD knockout fruit flies with AT-007 corrects every step along this molecular pathway and prevents neuronal damage as well as the clinical phenotype in Drosophila. It improves their ability to walk and climb. Additionally, a rat SORD knockout model has been developed by Dr. Stephan Zuchner, which similar to humans, demonstrates high sorbitol levels and results in axonal neuropathy. Our manuscript with the SORD researchers, which is an especially detailed and elegant scientific piece of work, has been accepted for publication and will be available shortly. We have also developed important information on the correlation of blood sorbitol level with clinical outcomes. Generally, healthy volunteers have a blood sorbitol level between 200 and 600 nanograms per milliliter with a mean of about 450 nanograms per milliliter. Diabetic patients have elevated sorbitol levels about 2 x normal, with a mean closer to about 1,000 nanograms per milliliter. Although diabetic patients have an intact SORD enzyme, their higher glucose means that more glucose goes through the polyol pathway and is converted to sorbitol. While diabetic patients do demonstrate an effective elevated sorbitol, it manifests as a slow progressing peripheral neuropathy called diabetic peripheral neuropathy instead of the fast-moving axonal neuropathy that we see in SORD patients. Sorbitol levels for SORD patients can range from approximately 16,000 nanograms per milliliter, which is the lowest we've seen to date in any patient, to above 47,000 nanograms per milliliter. Sorbitol level in SORD patients correlates closely with their severity of disease. Lastly, we performed genetic and sorbitol analyses on the unaffected family members of patients with SORD deficiency. Interestingly, these heterozygous patients who carry one normal allele and one mutated allele can have normal sorbitol levels similar to healthy volunteers, but many do have elevated sorbitol levels between 1,000 and 5,000 nanograms per milliliter. These heterozygous family members do not develop axonal neuropathy, upon closer inspection, many display a milder peripheral neuropathy similar to diabetic peripheral neuropathy. Therefore, broadly based on this data, we can say that up to 600 nanograms per milliliter is "normal." Approximately 1,000 nanograms per milliliter -5,000 nanograms per milliliter is mild peripheral neuropathy and not axonal neuropathy, and 16,000 nanograms per milliliter -47,000 nanograms per milliliter results in SORD neuropathy. We have also demonstrated that sorbitol level at baseline in the patients in the INSPIRE trial is statistically correlated with age and clinical outcome metrics. In other words, the higher a patient's blood sorbitol level, the faster they will decline with age and the worse their scores will be on 10-meter walk/run, four-stair climb, and sit-to-stand tests. Patients with lower sorbitol levels decline more slowly with age and have better scores on clinical outcome tests. This has allowed us to develop linear statistical models predicting the clinical effect of sorbitol reduction in SORD patients. We believe that based on this data, that sorbitol reduction in SORD patients is reasonably likely to predict clinical benefit. We also believe that the sorbitol reduction that we have seen in the INSPIRE phase 3 trial will result in clinical benefit as measured by the lower limb metrics such as 10-meter walk/run, four-stair climb, and sit-to-stand test. I'll turn the call over to Dr. Riccardo Perfetti to walk through the results of the INSPIRE three-month sorbitol analysis. Thank you, Shoshana. Sorbitol reduction at three months of treatment is a pre-specified interim biomarker analysis in the INSPIRE phase 3 trial, whereby we have measured sorbitol reduction in whole blood sample in the active group treated with AT-007, 20 milligram per kilogram per day via once daily liquid suspension versus placebo-treated patients. The primary sorbitol analysis is the maximum sorbitol reduction at three months of treatment, defined by the lowest sorbitol value at the time point sampled at zero, two, four, eight, and 12 hours post-treatment. The reduction in the active group was a mean of approximately 52% from baseline, whereas the placebo group, which we view as the natural ups and downs over the course of days or months, was approximately 10% from baseline. When measured as an absolute sorbitol reduction rather than as a% reduction from baseline, the active group demonstrated a mean reduction of approximately 16,000 nanogram milliliter, while the placebo group demonstrated a reduction of approximately 2,800 nanogram milliliter. For many patients, treatment with AT-007 brought their sorbitol level down to the range of their unaffected family members below the 5,000 nanogram milliliter, a reduction which we expect to clinically translate into halting of disease progression. For others, the reduction in sorbitol brought them from the high end of the SORD patient range, which is correlated with a very aggressive disease progression, into milder range, which correlates with a much slower progression of disease. Based on the linear models of sorbitol correlation with clinical outcome in the cross-sectional analysis that Shoshana described, we expect this level of sorbitol reduction to impact the primary clinical outcome measuring these patients, the 10-meter walk and run speed, which will be analyzed at 12 months of treatment. An exploratory analysis of the neurofilament light chain at baseline and at three months was also pre-specified. The data is not yet available today based on the longer analysis time required by the outside lab. The full three-month data as well as the NFL analysis of change from baseline to 90 days will be presented at an upcoming medical conference this spring. From a safety perspective, AT-007 continues to be safe and well-tolerated to date. In the INSPIRE trial, an unblinded Data Monitoring Committee evaluates unblinded safety data every three months. The company is working with the FDA to determine the appropriate regulatory path forward as well as data required for an NDA submission with the shared goal of bringing a safe and effective treatment to patients with SORD deficiency as expeditiously as possible. In the meantime, the INSPIRE study will continue in blinded format to the 12-month interim clinical outcome assessment. If the primary clinical outcome measure, the 10-meter walk run, reaches statistical significance at 12 months, the study will be completed and unblinded. If not, the study will continue in blinded format to 24 months, where clinical outcome will be assessed again in a final statistical analysis. I will now turn the call over to Dr. Shy to discuss the clinician's perspective on what this data means to him. Dr. Shy? Thank you, Riccardo. It's a pleasure to be here. First, I would like to say how impressed I am with the progress that we have made as a medical and scientific community in such a short period of time. We've gone from identification of the disease and the gene that causes it to a potential, phase 3 readout in just a three-year period of time. As a neurologist and neuromuscular specialist, the importance of the sorbitol reduction in this disease is crystal clear. The disease is caused by high sorbitol levels, AT-007 treatment significantly reduces these sorbitol levels. The magnitude of sorbitol reduction demonstrated in this study can be extrapolated to a clinical effect, whether based on more complex modeling or based just on an intuitive understanding that we bring patients with SORD closer to normal sorbitol levels. Patients who started off with very high sorbitol levels and aggressive disease get to a sorbitol level indicative of more mild disease and should see a decline, a slowing of decline. Patients who start off on the lower end of the SORD spectrum see their sorbitol levels go down to close to normal and may see a halting of disease decline. This is a very straightforward biology of disease and a clear potential impact of treatment, in my opinion. Alongside the favorable safety profile that we've seen to date, I hope that AT-007 will be an important treatment for patients with SORD deficiency. The sooner we can determine this, the better it is for patients. Thank you. Thank you, Dr. Shy. We'll now open up the line for questions. Operator, please go ahead. We will now begin the question and answer session. To ask a question, you may press star then one on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing a key. To withdraw from the question queue, please press star then two. The first question today comes from Yigal I'm sorry, Nochomovitz of Citigroup. Please go ahead. Hi, thanks. Hi, Shoshana and team. Just had a few questions. Can you comment on the time course of the sorbitol reductions for 007 versus placebo? What does that look like over the first 90 days? Yeah, thanks, Yigal. In this analysis, we're looking at the 90-day treatment period. As you know, we do have a pilot study that we completed a little over a year ago, where we did look at some shorter time periods. You know, we believe that sorbitol reduction really starts within the first few days of treatment. In the pilot study, we saw it go down over a 30-day treatment period. You know, here we see a really robust reduction at 90 days. You know, we think that this is a rapid and sustained reduction. Of course, we are continuing to look at this over time in the ongoing study. There are additional measurements of sorbitol at 12 months and 24 months. We'll be keeping our eye on that. We do know that we have a pretty rapid and sustained reduction in sorbitol. Oh, okay. This was the first measurement at nine. There were no earlier measurements. This was the first one. Is that right in this study? Yes. This is the pre-specified analysis at this time point. And I know- then- We also do have NFL samples that were taken at the three-month time period as well, which, as Riccardo said, are still under analysis, but we'll update with that as soon as we can. Okay. Can you just give us the background on. You're gonna measure the clinical outcomes at the 12 months, but you're not, you haven't measured them at the 90 days. Correct. Describe the thinking around that in terms of why you want to wait for 12 months as opposed to checking now for the clinical outcome? I mean, you're seeing obviously a very substantial reduction in sorbitol already. I'd also be curious, like what% are below the 5,000 nanogram per ml that you were referencing? Yeah. Just if you could comment on that. Yes. Maybe taking the clinical outcomes piece first. The primary clinical endpoint of this trial is 10-meter walk/run speed. Before, you know, before pre-specifying these analyses, we of course looked at patients and, you know, sort of how they progress over time. We also did a cross-sectional analysis once we had the first 25 patients into the trial just to confirm our thinking and our modeling. 10-meter walk/run speed does decline over time or with age in this patient population. Based on that modeling, we should see an effect at 12 months. three months is a very early time point, you know, especially with the disease biology here. We're, we're planning to prevent decline that is caused by sorbitol damage. The short answer is three months is a bit early to look. Also, you know, it has to do a little bit with the statistics of the trial. Obviously we discussed the endpoints and the statistical analysis extensively with the FDA before starting the trial. There's not a statistical penalty for this interim sorbitol analysis. Because the primary clinical outcome, you know, is a clinical metric of 10-meter walk/run, there will be a statistical penalty for each time we look at that. We wanted to ensure that we were really only looking at that clinical metric at a time point where we are assured to see a response, and three months was just a little bit early. Okay, got it. Are you able to comment, I was just curious, and I guess you could call it, you know, quote-unquote, responder analysis in terms of the% or number of patients that got below this 5,000 nanogram threshold that you think is sort of the demarcates getting into the safer territory. Yeah. I think it's important to steer folks away from thinking about, you know, that kind of quote, clinical responder analysis. Because I think that the concept here, and this is what Dr. Shy was referring to, you know, is that we know that there is a statistically significant correlation between sorbitol and disease progression or aggressiveness on all of these metrics. It's not as though there's a threshold where that, you know, starts or stops. Lowering sorbitol by any means is likely to impact those clinical outcomes. The lower we bring the patients, the better off they are, no matter where they are on the sorbitol spectrum. I would just note, and you can see this in the updated slides to our corporate deck, that, all the patients that were treated with AT-007 showed a substantial and meaningful reduction in sorbitol, such that we got the entire population of treated patients to below the lowest baseline at the starting point of the trial. Everyone moved down really substantially. It's true, some of them move into a range that, you know, were pretty certain results in no disease progression, but everyone should show a clinical impact of the sorbitol reduction that we're seeing in the trial. Thank you so much for those questions, Yigal. They were really good. Thank you. Can I just squeeze one more in? I just had one. It was a little unclear because you're saying you're still blinded, but then you're showing data obviously, you know, for 007 versus placebo. How are you actually defining what blinding is? Because I think some people might be a little confused by that. Sure. There's obviously an unblinded statistician who does this analysis. What the rest of the team sees is aggregated data. None of us have seen anybody's subject IDs. We have no idea who is on active or who is on placebo. We just get the anonymized numbers and the treatment group data. This has been very clearly laid out in the statistical analysis plan. It's not considered an unblinding of the trial in any way, and it was specifically discussed with the FDA that we would not pay a statistical penalty for looking at this data. We're very comfortable with the way that this has been handled, and nobody on the Applied clinical team has been unblinded. Okay. No, that's very clear. Awesome. Thank you very much. Thanks, Yigal. The next question is from Brian Skorney of Baird. Please go ahead. Hey, good morning, everyone. Thanks for taking my questions. I guess, you know, maybe help us understand what your conversations with the FDA had been leading up to this and sort of what your view of the pathway forward here. With this data in hand, can you request a pre-NDA meeting with the FDA? Was there any sort of specific threshold in terms of placebo-adjusted sorbitol reduction they wanted to see to grant you a pre-NDA meeting? Then, you know, I mean, what's sort of the timeframe that we can think about for an FDA discussion now? Yeah, it's a great question, Brian. We, we have been working with the FDA, you know, consistently since we started this phase 3 study. We are continuing a really active dialogue with them around, You know, data needed and how to determine if sorbitol reduction can be a biomarker for accelerated approval. It's an active dialogue. We've made a lot of progress. There's, you know, still some questions going back and forth. You know, we've had several conversations with them. We are pretty hopeful for an accelerated approval pathway here. We do believe that the biology of the disease is very straightforward. We've shown, you know, a lot of data on statistical correlation of sorbitol level with disease severity. We've done everything you could possibly imagine in the, in the animal models, and that's being published soon. I think we're getting very close. It's, it's a little bit early right now to say, you know, that we could submit an NDA with this data. I think we're not quite there yet with FDA, but it's going in the right direction. It's an active dialogue, and, you know, I think we all share the goal of using Accelerated Approval where possible for these rare diseases. It has been a very productive and collaborative scientific dialogue with the agency. This program is under the Division of Neurology I at FDA. I think it's a bit early to... You know, we're not planning to say we're taking this data, you know, and submitting our NDA now. We are continuing that conversation, and I think that there's a lot of options on the table for a potential earlier approval. I guess the question was less about submitting for an NDA, but more about submitting a type B meeting request. Is that the next step? Are you gonna do that? Do you get to select whether it's a pre-NDA meeting or an end of phase 2 meeting? I think that's not necessarily the path that we would take. We've had a few, Type C meeting on this topic with FDA. That's where the dialogue is back and forth. I do think because we're in that active dialogue, I don't think that requesting a pre-NDA meeting in the midst of that would be productive right now. I think we do just need to, you know, complete these couple of, you know, requests for information, follow this process that we already have underway. Then the next step would be a pre-NDA meeting. Got it. Then, it was just a little unclear for me, Yigal's question. Are you guys doing serial measurements of sorbitol over the entire timeframe? Ultimately, when we see unblinded data here, is it sort of like daily measurements, weekly measurements? Will we sort of have a time course over the 24 months when the full data set is unblinded? It's definitely not daily or weekly measurements, but I think, yeah. We, you know, we have this 3-month pre-specified analysis. We also are looking at sorbitol at the 12-month analysis. You know, there's an additional correlation analysis of sorbitol with clinical outcomes at that point. I would say that, you know, I'm sure you know, Brian, how these statistical analyses work. You know, you have to pre-specify what the primary analysis is at that time point. The primary analysis at the interim three-month time point was the sorbitol reduction. The primary analysis at the 12-month time point is 10-meter walk run speed. You know, there is a sorbitol analysis at that time point. Also if the study is not statistically significant at 12 months, at 24 months as well. Okay, great. Thanks. Thanks, Brian. The next question is from Colin Bristow of UBS. Please go ahead. Hey, good morning, and congrats on the data. I think we've covered most of it, but Just with regards to baseline characteristics and the trends that you saw, could you just give a little more color on the depth of reduction, et cetera, that, you know, with patients at the various baseline levels of sorbitol? Thank you. Sure. I'm not sure we totally understand the question, but we'll try. If we're not on topic, then please let us know, Colin. You know, this is a much larger study than the pilot study. We gave the range that we see, which I think is a pretty robust range of sorbitol, which is important here because we know that sorbitol level statistically correlates with disease progression. I think we cover, you know, what we expect the population to look like in real life. You know, some patients on the lower end of sorbitol at the start of the study, some patients on the higher end. And, you know, it gives us a good population to work with. You know, I know we haven't talked about this, but in terms of the genetic mutations in SORD that we see, we've captured a very broad range. You know, at baseline, this is really the population that we would want to target, both in terms of sorbitol reduction, but also thinking about the long term, and being able to impact their clinical outcomes, their 10-meter walk/run speed. You know, I think what we spoke about a little bit earlier is that when you look at the baseline range of where these patients start, and then the range of where they get to on AT-007 treatment, every single patient moves to a place that's below even the lowest starting sorbitol level or lowest baseline sorbitol level of a patient in the trial. I think we're really moving the whole population in the direction on active treatment where we want them to go. You know, based on what we know on the correlation of sorbitol and clinical outcomes, this should translate into a really robust clinical effect. Was that your question or was your question a little different? No, I think that covered it. Just in terms of the, how the baseline level correlated with change over the period of measurement was essentially it. Apologies if I overcomplicated that. Thanks, Colin. There are no additional questions at this time. This concludes our question and answer session. I would like to turn the conference back to Dr. Shendelman for closing remarks. Thank you very much, everyone, for joining us today, and we look forward to future updates on this program and on our pipeline. Have a great rest of the day. The conference has now concluded. Thank You for attending today's presentation. You may now disconnect.