Hello, and welcome to Applied Therapeutics INSPIRE Trial 12-month interim data conference call. Today, all participants will be in a listen-only mode. Should you need assistance during today's call, please signal for a conference specialist by pressing the star key or one followed by the star key. After today's presentation, there will be an opportunity to ask questions. If you would like to ask a question, you may press star then 1 on your touchtone phone. To withdraw your question, please press star then two. Please note, this event is being recorded. I would now like to turn the conference over to Les Funtleyder, CFO of Applied Therapeutics. Please go ahead, sir. Thank you. Good morning, everyone, and thank you for joining us today. With me on the call are Dr. Shoshana Shendelman, Applied Therapeutics Founder and CEO, and Dr. Riccardo Perfetti, our Chief Medical Officer, and Dr. Michael Shy, Director of the Division of Neuromuscular Medicine at Carver College of Medicine, University of Iowa Medical Center, and the Principal Investigator on the INSPIRE phase III trial. Shoshana and Riccardo will highlight the data announced this morning, and we will then open up the call for questions. Before we begin, let me remind you that today's conference call, we will be making forward-looking statements that represent the company's intentions, expectations, and beliefs concerning future events. These forward-looking statements are qualified by important factors set forth in today's press release and in 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, and we do not intend to update it. With that, I will turn the call over to Dr. Shoshana Shendelman. Thank you, Les. We're pleased to share our 12-month interim data from the phase III INSPIRE trial today. SORD deficiency is a debilitating hereditary axonal neuropathy caused by mutations in the sorbitol dehydrogenase gene, leading to an inability to metabolize the sugar sorbitol and resulting in accumulation of high levels of toxic sorbitol, which then causes motor neuron degeneration and loss of mobility and motility. Govorestat, or AT-007, is a central nervous system penetrant aldose reductase inhibitor, which blocks the conversion of glucose to sorbitol and has previously been shown to reduce sorbitol levels in patients with SORD deficiency. SORD deficiency affects approximately 1 in every 100,000 people, which represents a U.S. patient population of approximately 3,300 and an EU population of approximately 4,000 individuals living with SORD deficiency. The INSPIRE trial is a phase III double-blind, placebo-controlled registrational study evaluating the effect of once daily oral govorestat or AT-007 in 56 patients aged 16- 55 with SORD deficiency in the U.S. and Europe. The INSPIRE study is a 24-month study, and the primary endpoint at 24 months is designated as the 10-meter walk/run test, a component of the CMT-FOM or CMT Functional Outcome Measures, Lower Limb Domain. A pre-specified interim analysis at 12 months to evaluate early indicators of govorestat treatment effect in order to inform future regulatory discussions and support a potential new drug application or NDA submission due to the urgent need for treatment and absence of any other options for patients with SORD deficiency. The 12-month interim analysis was comprised of a clinical efficacy primary endpoint based on correlation of sorbitol with the composite clinical outcome measure from the CMT-FOM and a biomarker or PD primary endpoint based on sorbitol reduction. Both primary endpoints for the interim 12-month analysis were met. Regarding sorbitol reduction, govorestat treatment demonstrated a statistically significant and sustained reduction in sorbitol level in patients over 12 months of treatment, compared to placebo with a p-value of less than 0.001. Regarding the correlation of sorbitol level with the CMT-FOM composite, statistical significance was achieved with a p-value of 0.05. The pre-specified CMT-FOM composite included the 10-meter walk/run, four-stair climb, sit- to- stand test, six-minute walk, and dorsiflexion. The analysis was pre-specified in this way to demonstrate that sorbitol changes are mechanistically driving a treatment effect and to further substantiate that sorbitol is a surrogate endpoint reasonably likely to predict clinical benefit. Perhaps most importantly, govorestat treatment resulted in a highly statistically significant effect, with a p-value of 0.01 on the CMT Health Index or CMT-HI. Aspects of the CMT-HI that demonstrated a treatment effect included lower limb function, mobility, fatigue, pain, sensory function, and upper limb function. These effects are also in line with feedback we had received previously from patients who participated in the SORD open label pilot study and noted that they generally felt better and their overall levels of functional ability, fatigue, and pain were improved. In summary, we believe the results of this 12-month interim analysis confirm the role of sorbitol as a key driver of disease severity and progression over time in SORD deficiency. We believe that govorestat has demonstrated consistent effects on sorbitol, as well as correlation of sorbitol with clinical outcome measures and clinical benefit on how patients feel and function based on CMT-HI effects. Full 12-month data will be presented at an upcoming medical conference, including biomarker data on neurofilament light chain and muscle MRI. The INSPIRE study remains ongoing, and clinical outcomes of the INSPIRE trial are expected to be assessed again at 24 months, where the 10-meter walk/run test serves as the primary clinical efficacy endpoint. I'll now turn the call over to Dr. Riccardo Perfetti, our Chief Medical Officer. Thank you, Shoshana. Let me start with patient demographic information. The study was randomized 2-to-1, active- to- placebo. Overall, the mean age in the study was 34. BMI was 24. Patients were primarily white Caucasians. There were more males included in the study, 66% as compared to 34% female. Mean sorbitol level at baseline was approximately 30,000 ng/mL. These baseline characteristics were all well-balanced between the active and the placebo. With regard to safety and tolerability, govorestat was safe and well tolerated. There were five discontinuations in the study throughout the 12 months, four in the active group and one in the placebo group. Adverse events were generally mild to moderate and were balanced between active and placebo groups. There was one serious adverse event reported, which was not related to the study, the study drug. It was a motorcycle accident, and there were no deaths. We believe that based on the govorestat risk-benefit profile and the absence of any other treatment option for patients with SORD deficiency, it's important to make this treatment available to patients as quickly as possible. We plan to discuss a potential NDA submission for approval based on the data to date. Before we open the call for Q&A, I will ask Dr. Mike Shy, Director of the Division of Neuromuscular Medicine at Carver College of Medicine, University of Iowa Medical Center and Principal Investigator on the INSPIRE phase III trial, to say a few words regarding this important data. Dr. Shy? Thank you, Riccardo. I'm so pleased to see such compelling results from just 12 months of treatment with govorestat. SORD deficiency is a debilitating disease with no existing treatment options available. It's a monogenic disease in which inability to metabolize sorbitol and the resulting high sorbitol levels cause the problems. Patients get worse over time, and to date, we have nothing to offer them to stop or slow disease progression. Data provided in this interim analysis confirms the disease-modifying effects of lowering sorbitol. The improvement on the parameters of lower limb function is very meaningful as patients with SORD deficiency are affected by relevant limitations of their mobility. I'm also especially excited to see the strong effects of govorestat on the patient-reported outcome measure, the CMT Health Index or CMT-HI. As I've seen personally, how substantially the disease affects a patient's quality of life or disease burden firsthand. A treatment effect that offers improvement in how patients feel and function is very meaningful, and I really hope this treatment will become available to patients, soon. So thank you, Riccardo. Okay. Thank you very much, Mike. I want to take this opportunity to thank the many groups who have come together to make this study possible. First, the investigators in the INSPIRE trial, the researchers and physicians, including many members of the Inherited Neuropathy Consortium, who mobilized quickly to advise on the study design and to recruit patients to the clinical sites. The patient organizations, including the CMT Association and Hereditary Neuropathy Foundation and the CMT Research Foundation, have organized patient roundtables and listening sessions to inform on the patient perspective and have helped us to raise awareness of the clinical program. But most importantly, we're thankful to the patients who are participating in the INSPIRE study to help develop the first potential therapy for SORD deficiency and provide hope for the rest of the community. In closing, we're excited about the potential of govorestat for treatment of SORD deficiency, and we will work with the FDA to bring this important treatment to patients as quickly as possible. Now I'll hand the call back to Les to moderate the Q&A. Thank you, Shoshana. Before we get started on Q&A, I just want to remind everybody, though many of you are aware, that we have submitted an NDA for govorestat for the treatment of galactosemia, and we anticipate receiving feedback from the FDA, Rare Disease Division by the end of the month. We'll update investors on that at the time. However, given that this is a SORD call, we would appreciate if you restricted your questions to the SORD topic. And with that, operator, can we please open up the line? Thank you. We will now begin the question and answer session. As a reminder, to ask a question, you may press star then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If your question has been asked and you would like to withdraw it, please press star then two. At this time, we will pause momentarily to assemble our roster. Today's first question comes from Brian Skorney with Baird. Please proceed. Hey, good morning. Thanks for taking my question, and congrats on the data. I guess I was wondering if you could provide any detail on the CMT- FOM comparison of treatment and placebo, not the sorbitol carryover analysis, but just sort of the raw comparison. And do you have any data on the individual domains in the composite, like the 10-meter walk/run? Can you say if there are trends favoring treatment here? Yes, that's a great question, Brian. So, we did see trends on the individual components of the 10-meter walk/run, as well as the individual components of the CMT-HI, although that's a little bit of a moot point because we actually hit strong statistical significance on the CMT-HI. But, you're correct. Obviously, the level of impact was different on each of the different tests. I think not surprisingly, we saw the strongest effects on 10-meter walk/run, six-minute walk, and dorsiflexion. Little bit lower effects on four-stair climb and sit- to- stand. So I think what's really driving the treatment effects and probably what's correlating with the patients feeling that their mobility is improving is actually being measured by those key metrics on the CMT-FOM, the 10-meter walk/run, six-minute walk, and dorsiflexion, which, you know, Dr. Shy could talk a little bit more about, but that's something that's really consistently been measured in SORD patients and it's a metric that, you know, clinicians use. It's a little less translatable into patients' everyday life, but, you know, dorsiflexion is really driving patients' ability to walk, and, you know, and to move their lower limbs. Great. Maybe if I could- Do you want me to comment? Do you- Oh, go ahead. Sorry. I'm sorry. This is Dr. Shy. I didn't know if you wanted me to comment, Shoshana, or just, Sure. Yeah. I would just say that, first of all, I agree with what you said, and just so that we're clear about what dorsiflexion is meaning, we're talking about foot drop. So patients are not able to elevate their, the front part of their foot towards their nose, is how we say it. So they will drag their feet and have foot drop, and as a result, they have, can have a prancing gait, and this really is very debilitating for them to get around. So I think it's an important measure. Thanks, Dr. Shy. Thanks. Then maybe just as a follow-up, can you talk at all about the sorbitol reduction at three months versus 12 months and if there are any, you know, trends and differences? Did sorbitol continue to show declines in patients? Was there any... Did it start to trend back upwards? Just any sort of characterization of that curve. Yeah. Thanks, Brian, for the question. So it's really consistent. At 12 months, it's very similar to what we saw at three months. Ricardo and I find that to be very, you know, reassuring and also in line with what we've seen in galactosemia with galactitol reduction. So, you know, the reductions in sorbitol really do seem to happen primarily in the first few weeks of treatment. You know, they're mostly stable by the first month of treatment, and then we see that consistent, sustained reduction, so it stays low. It doesn't get any lower than that, you know, over a longer treatment period, but I think what we're looking for here and what it shows is that it's sustained over time, which is great. I think what's really important about today's data is that we finally, for the first time, have something to translate that sorbitol reduction into in terms of clinical outcomes and clinical meaningfulness. So, you know, prior to this data, we were able to say, "Well, there's cross-sectional correlations. Patients with higher sorbitol, you know, are more severe than patients with lower sorbitol." But here we can actually say that the sorbitol reduction that we're achieving with treatment with govorestat is impacting clinical outcomes, and it is impacting how patients feel and function, based on the CMT Health Index. Great. Thank you. The next question- Okay, next- Comes from... Sorry. The next question comes from Colin Bristow with UBS. Please proceed. Hey, Colin. You hear me okay? Yes, now we can. Okay, super. Sorry about that. Can you comment on the interpatient variability that you saw, you know, in the CMT- FOM domains? Yeah, just thinking out loud, you know, was there a cohort of hyperresponders? And then how many patients were analyzed at the interim, and can you give any color on the reasons for discontinuations in the 007 arm? Thank you. Yes. Okay, let's start with how many patients were analyzed at 12 months. So, it was 49 patients. I'll give you a little bit of a breakdown there. So we started with 56 patients in the study. Riccardo mentioned earlier that there were five discontinuations prior to 12 months, so that leaves us with 51. And then there were two patients who actually could not perform the assessments at 12 months because of things having nothing to do with SORD deficiency. Like Riccardo had mentioned, one of them was in a motorcycle accident, and so, you know, therefore, couldn't perform the metrics. So this was 49 patients that performed and were analyzed for the 12 months assessments, and it's a 2- to- 1 randomization of active- to- placebo. And sorry, Colin, can you repeat your other question? Yeah, sorry if it's a bad line. I just wanted to get some color on interpatient variability, and just understanding were you seeing sort of a cohort of hyperresponders? And if any color you can give around the variability across the domains would be helpful. Yeah. So I, I think overall the effects are very consistent, and we're going to delve more into the details, you know, subgroup analyses of effects in patients who were mild, moderate, or severe at time of entry to the trial. I think what, what we're seeing thus far is, is consistent effects and probably not surprisingly, you know, we, we see depending on their stage of disease and their, their starting sorbitol level whether we're halting progression and the patients are not getting worse on treatment with govorestat or some patients actually improved on treatment with govorestat. So, you know, we'll, we'll delve into the details of which, which patients are responding on, on which level. But I think based on what we've seen thus far, it's very consistent effects across the patient population, with all patients showing halting or slowing of disease progression, some showing an improvement in these outcomes. That's helpful. Thank you very much. Again, if you do have a question, please press Star, then one on your touchtone phone. The next question comes from Yigal Nochomovitz with Citi. Please proceed. Hi, Shoshana and team. Thank you for taking the question. You mentioned earlier that you saw some trends with respect to the individual components on the CMT-FOM. I'm just wondering if you could get into a little bit more detail there, specifically, not with regard to placebo, but actually with regard to sorbitol level on each of the subunits of that composite. So for example, did you see stronger correlations with sorbitol with the 10-meter walk and the six-minute walk versus the sit-stand? I just wanna get a better sense as to how that broke down, you know, beyond just the composite p = 0.05. Thanks. Yes. So I think that the correlations that we see with sorbitol do line up with the magnitude of change or treatment effect that we're seeing on those individual domains. So the strongest were 10-meter walk/run, six-minute walk test, and dorsiflexion. A little bit less so in four-stair climb and sit- to- stand test. Okay, got it. And then going back to, to Brian's question regarding trend, the versus placebo, you mentioned you, you're seeing some trends, on the, on the primary endpoint, 10-meter walk. And we talked a lot about that design of that, that 10-meter walk-run, setup and how it's done in the hospital and, and everything that needs to go into to make sure that that's done in an effective way. Is there anything that you're seeing in, in what you've observed so far that would suggest you, you know, you need to provide additional training or, or refine the instructions to the patients with regard to how to conduct that test? Or how the clinic, the clinicians that are collecting the data need to behave or modify anything to move closer to deepening that trend so that you can hit on the primary of the 10-meter walk-run test? Thanks. Yeah. That's a great question, Yigal. And as you know, we, we've discussed previously, we took, you know, really extensive steps. We were, you know, really critically focused on that endpoint and how it's performed and training. And we actually videotaped all of the performance of the 10-meter walk-run test and had master trainers, one of whom was trained by Dr. Shy, another one from University of Rochester, reviewing those videos in real time and making sure that the tests were performed properly and that we felt good about the quality of the data. And so I think that what we're seeing at 12 months is that those extra quality control steps that we put into place were very important and have really helped to keep us on track. So, I think we feel good about the endpoint. I think, you know, one of the things I had wondered about more so than than some of these metrics, like 10-meter walk-run, what was actually the patient-reported outcome measure. So, you know, CMT-HI, we know is a very important measure for physicians on severity of these patients, and we know it's also important to the FDA on measuring how patients, you know, feel and their, their overall well-being. Prior to this data, I had actually been a little bit skeptical about showing effects on the CMT-HI, because it's a patient-reported outcome measure and, you know, sometimes those are subjective and, you know, it's, it's sometimes difficult to translate the actual, functional metrics into patient well-being. So I think that was probably most surprising to us in a really positive way, that what we're measuring on 10-meter walk-run and six-minute walk and dorsiflexion are actually translating to patients feeling that their mobility has improved, and that they have a better quality of life overall. They're less tired, they feel less pain. And so, you know, I think that we're in great shape on the functional metrics. I think we're happily surprised about the patient-reported outcome and seeing the translation of those functional metrics into overall patient well-being. But your question is really well taken. I think we did institute really aggressive quality measures on these functional metrics in the trial, and I think we just have to really remain diligent with those from now until the end of the study. Thank you very much. Shoshana, Shoshana, this is Mike. Can I also comment on that? Please. Yeah. So Tim Estilow and others are really aggressive in terms of making sure everybody does these as carefully as possible. And I can tell you that the site PIs like me are very aggressive, making sure that things like that 10-meter walk-run that they're done to the patient's best ability, because we're well aware that we can't have any noise or sloppiness in that, and that's something we really emphasize. Thanks, Mike. Thank you. At this time, we are showing no further questioners in the queue, and this does conclude our question and answer session. I would now like to turn the conference back over to the management team for any closing remarks. Great. Thank you so much. We just want to thank everyone for joining our call today. Again, one last thank you to the patients who are participating in the trial and the investigators in the study, and all of the groups that have come together to make this work possible. Thanks, everyone, and have a great day. Bye-bye. The conference is now concluded. Thank you for attending today's presentation, and you may now disconnect.