Hello, good day. Welcome to the Applied Therapeutics SORD Deficiency Conference Call. Now I would like to turn the conference over to Dr. Chuck Silberstein, Chief Financial Officer. Please go ahead. Welcome, everyone, and thank you for joining us on today's call. With me on the call are Dr. Shoshana Shendelman, Applied Therapeutics Founder, CEO, and Chair of the Board, Dr. Riccardo Perfetti, our Chief Medical Officer, Adam Hansard, our Chief Commercial Officer, and Dr. Stephan Züchner, Chair of the Department of Genetics at University of Miami School of Medicine and one of the original researchers responsible for identifying the genetic and pathophysiological cause of SORD deficiency. 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 during today's conference call, we'll 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, and we do not intend to update. With that, I will turn the call over to Dr. Shoshana Shendelman. Thank you, Chuck. We're pleased to share our pilot study data in patients with SORD deficiency today. Since this was the first clinical trial ever performed in SORD deficiency, I'd like to start off with some background on the disease. Sorbitol dehydrogenase deficiency, or 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. patient population of approximately 3,300 and an EU population of approximately 4,000 individuals living with SORD deficiency. This is outlined on slide three of the deck. On slide four, you can see that patients with SORD deficiency are missing the enzyme sorbitol dehydrogenase, or SORD, 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 then sorbitol is further metabolized to fructose by sorbitol dehydrogenase and used for energy production. Patients with SORD deficiency can't metabolize sorbitol, and as a result, sorbitol accumulates in blood and tissues, including neurons, leading to significant neuronal toxicity. Patients with SORD deficiency have approximately 100x normal sorbitol levels in their blood. Sorbitol accumulation results in significant disability, loss of sensory function, and neuromuscular dysfunction. Inhibition of aldose reductase to prevent sorbitol formation is a rational biochemical approach to substrate reduction in patients with SORD deficiency, blocking sorbitol production at the source. Patients with SORD deficiency primarily have a symptomatic diagnosis of Charcot-Marie-Tooth Type 2 or CMT 2, or distal hereditary motor neuropathy, or DHMN. Thanks to groundbreaking research performed by Andrea Cortese and colleagues in a seminal Nature publication in 2020, we now understand that 7%-9% of these patients actually have SORD deficiency and now can receive a correct diagnosis. We're partnering with the patient advocacy organizations, CMTA and HNF, as well as physicians, to ensure that patients have access to accurate diagnostic testing. As many of you know, Applied Therapeutics has developed a series of highly potent and selective aldose reductase inhibitors. One of these compounds, AT-007, was specifically designed to be central nervous system penetrant and cross into the CSF and spinal cord where motor neurons originate, and to effectively penetrate peripheral nerves. Both tissues are relevant in SORD deficiency. AT-007 was already in late-stage development for galactosemia, another rare disease, when the pathogenic cause of SORD deficiency was discovered in 2020. Thus, we were able to move quickly, thanks to collaboration with the team behind the Nature and the entire community of neuromuscular specialists, into clinical development for SORD. On slide five, our first objective was to demonstrate proof of concept in models of SORD deficiency that AT-007 is capable of reducing sorbitol levels. To this end, we worked with Dr. Stephan Züchner and Dr. Grace Zhai and colleagues at the University of Miami to study AT-007 in fibroblasts from SORD deficient patients and in a Drosophila model of SORD deficiency. AT-007 treatment significantly lowered sorbitol levels in SORD patient fibroblasts. This work was presented earlier this year at the Peripheral Nerve Society Annual Meeting. Moving on to slide six, AT-007 treatment corrects the SORD phenotype in a SORD deficient Drosophila model. Note that SORD deficiency leads to accumulation of sorbitol in Drosophila, which results in significant neuronal loss, which can be visualized by the presence of vacuoles in these slides. AT-007 treatment in the Drosophila SORD model prevented neuronal degeneration, as visualized by the absence of vacuolar structures, which was also quantified by neuronal staining, as shown on the right-hand panel. Recall that AT-007 had already been studied in approximately 100 healthy volunteers, approximately 15 adults with galactosemia, and 47 children with galactosemia, and was safe and well-tolerated in all populations treated. This proof of concept that AT-007 can effectively reduce sorbitol levels in SORD patient fibroblasts and can ameliorate the disease phenotype in the Drosophila model led to the pilot study in SORD patients, which we're sharing with you today. With that introduction, I will now hand the call over to Dr. Riccardo Perfetti, Chief Medical Officer of Applied Therapeutics, to discuss the pilot study data in SORD deficient patients. Thank you, Shoshana. Turning to slide seven, in our pilot study, eight patients with SORD deficiency were treated. These patients range in age from 19- 55 years old and were representative in general of the SORD population. Gender was equally balanced. There were four female and four male patients in the study. They suffer from mobility and motility issues, and depending on their age and stage of disease, range from walking with leg braces to use of a walker. Patients reported upper limb weakness, loss of sensory function, neuropathic pain, and tremor, all expected in SORD deficiency patient population. Patients had a genetic diagnosis of SORD deficiency as well as high sorbitol levels in blood, with a mean baseline sorbitol level of approximately 38,000 ng per ml. For most patients, a number of baseline samples were taken, for example, a screening as well as at time zero on the day of treatment. sorbitol values in untreated circumstances were very close to one another, demonstrating that there was not much day-to-day viability in individual patient sorbitol blood level prior to treatment. Patients were treated open label with AT-007 liquid suspension at 20 mg per kg once daily. There was no placebo treatment arm in this pilot study. A patient demonstrated a mean reduction of 66% from baseline over the 30-day treatment period. The range of individual reduction from baseline was 54%-75%. This level of sorbitol reduction is very substantial and meaningful and demonstrate proof of concept that AT-007 lower sorbitol in SORD patients. Although there were no placebo group in this study, we know the sorbitol level do not change day to day in these patients in the absence of treatment with AT-007, and the reduction we are seeing is from treatment with aldose reductase inhibitor. AT-007 was safe and well-tolerated in all SORD patients treated. Based on this data, we plan to initiate a registrational study in SORD deficiency toward the end of this year. We look forward to sharing details of the study design at the time of study initiation. Broadly, the study will be designed to provide both biomarker data as well as long-term functional outcome data and will include site in both U.S. and Europe. As you can see on slide eight, a consortium of center of excellence exists as well as a global patient registry to help support trial enrollment as well as eventual commercial treatment of patients with SORD deficiency. We're very pleased to share this data with the community today, we believe that AT-007 represent an important advancement in the treatment of SORD deficiency. Now I will hand it back to Shoshana for concluding remarks. Thank you, Riccardo. I want to take this opportunity to thank the many groups who have come together to make this study possible. Researchers and physicians, including many members of the Inherited Neuropathy Consortium, mobilized quickly to advise on study design of both the pilot trial and the upcoming registrational trial, as well as share learnings from SORD patients that they see in clinical practice. The CMT Association and the Hereditary Neuropathy Foundation have organized patient round tables and listening sessions to inform on the patient perspective and have helped to raise awareness of the clinical program. Most importantly, we're thankful to the patients who participated in our SORD deficiency pilot study, who traveled from all over the country to help develop the first potential therapy for SORD deficiency and provide hope for the rest of the community. With a potential treatment in development, it's also important to ensure that all patients living with SORD deficiency receive an early and accurate diagnosis. To this end, we're partnering with the patient organizations and the physician community to improve access to diagnostic testing. In fact, today, we're officially kicking off our free SORD deficiency diagnostic screening program. Patients can be screened via a simple blood test in their doctor's office or through a home health visit to determine if they have SORD deficiency and to find out if they may qualify to participate in the upcoming registrational study. More information on the SORD deficiency screening program is available in our press release. In closing, we're excited about the future potential of AT-007 for treatment of SORD deficiency, and we believe that AT-007 has the potential to be the first treatment approved for SORD, treating the underlying cause of disease through a reduction of sorbitol. We believe today's data is an important milestone in advancing the first potential treatment for SORD deficiency, and we look forward to launching our registrational trial in the upcoming months. Now I'll hand the call back to Chuck to moderate the Q&A. Thanks, Shoshana. As a reminder, we are joined today by the Applied Therapeutics management team, as well as Dr. Stephan Züchner, Chair of Genetics at the University of Miami Medical School. I do want to mention that as many of you are aware, we are planning to submit our NDA in galactosemia by the end of this quarter. I want to reiterate that we remain on track with galactosemia guidance. The purpose of this call is to discuss the SORD deficiency program. We appreciate questions being directed as such. With that, operator, will you please open up the lines for Q&A? Thank you, Doctor. Participants, to ask a question, you will need to press star one on your telephone. That's star, then the number one on your telephone keypad. If you'd like to withdraw your question, press the pound key. Your first question comes from the line of Marc Frahm with Cowen. Your line is open. Thanks for taking my question, and congrats on the data this morning. 66% reduction in sorbitol certainly sounds very impressive. It does seem to imply that the patients are still at about 30x elevation versus healthy subjects. Can maybe you, the company or the physicians as well, just kind of walk through why they believe a 2/3 reduction is enough to drive a clinical benefit over time, maybe what type of difference that makes to cell death? Sure. Marc, maybe I'll start off and then let Dr. Züchner jump in. I think this is a really substantial reduction, right? 30x higher where they are now is still a lot better than 100x higher where they started off. I think it's a pretty simple story with SORD deficiency. We know that sorbitol is toxic. There's been decades of work demonstrating sorbitol toxicity, even though this is a relatively new understanding of the pathogenic cause of disease in these patients. Reduction in the toxic species here is meaningful in terms of preventing damage and eventually leading to clinical benefit. I think it's pretty simplistic. I don't think we need to sort of overanalyze what level of reduction. Sorbitol is toxic. Reducing any levels of sorbitol is meaningful. Dr. Stephan Züchner, do you want to jump in as well in terms of what this means to you with treating patients with SORD? Sure. Glad to do that. First of all, of course, it is a significant reduction over a 30-day time period when these patients basically accumulate sorbitol since their birth. Keep that in mind. Also, as Shoshana mentioned, this disease is part of what we call inborn errors of metabolism. These are diseases that affect specific enzymes that utilize specific substrates. There are other examples in medicine where we know quite well how to treat those, and it's always either substrate reduction, this is what Applied is doing here, or enzyme replacement. That works for other diseases very well. It's also supported by the newborn screening programs around the U.S. They wouldn't happen if there wasn't a treatment available. We think that this falls in the same kind of category and it's known that just significant reduction makes difference, is expected to make a clinical difference. Ultimately, this question will be answered in the phase II or III trial. Okay, great. Thanks. That's very helpful. Maybe Shoshana or Riccardo, just early thoughts on the design of the next trial. Will there need to be some dose exploration just because it's a new disease? Because you had your dose set from galactosemia, can you just stick with 20 mg going forward? Yeah. It's a great question, Marc. I think that we do know a lot about AT-007 already from our galactosemia studies, as well as all the healthy volunteer work that's been done. I don't think that there's huge amounts of additional information that we need prior to the registrational study, and that's why we're able to run this pilot study, demonstrate proof of concept, which we've done here, and then move directly into the registrational trial. There's nothing approved for SORD deficiency, and these patients are degenerating every day. The sooner we can move into the registrational trial and potentially make this drug available, get the drug approved, the better it is for the patient community. We are on track to launch the registrational trial later this quarter. We will provide additional information on the specific design when we launch the trial, but we do have a very good idea of what it will look like at this point in time. Not to delve too much into the details, but I think that you can expect a trial design that looks at biomarker reduction of sorbitol in the first part, and patients will continue to be assessed for clinical outcomes over the long term. We believe that that approach will allow us to apply for accelerated approval based on a biomarker, so based on sorbitol reduction, but also to generate data on long-term functional outcomes over time, which is important here. We do believe that the best way to answer that long-term functional outcomes question definitively is through a clinical trial setting, as Dr. Züchner said. I do think it's important to put into context rare diseases, why accelerated approval exists, and why that approach is really relevant here. In the registrational trial, we do expect to generate biomarker data for accelerated approval. I'm sure you're aware the bar for accelerated approval is reasonably likely to predict clinical benefit. I think we all agree this is a pretty simple metabolic story. These patients are missing the enzyme to metabolize sorbitol. They have very high sorbitol levels. We're lowering sorbitol levels, that meets the reasonably likely criteria pretty quickly. The long-term functional data is important to generating evidence over time. Similar to the approach that we've taken in the pediatric galactosemia study, it is possible to design one seamless trial where you get biomarker data in the beginning, and patients are assessed for clinical outcomes over time. I think that that's the approach that will be taken here as well. More information to come when we launch the study soon. Okay. Thank you. Congrats on the data. Thanks, Marc. Your next question is from Yigal Nochomovitz from Citigroup. Your line is open. Hi, Shoshana and team. Thank you very much for taking the questions. I'm just curious, in this 30-day pilot trial, did you see any anecdotal evidence of improvements in disability or sensory function or neuromuscular dysfunction? It's a good question, Yigal. I'm going to try to answer that in the most compliant way possible. This study was not set up to look at clinical outcomes. They weren't assessed at baseline and end of treatment. That will be done in the next trial. This was an open-label study, right? The patients all knew that they were receiving active drug. We did hear from several patients that they felt better on the drug. Now, take that for what it's worth. We're not saying there's an impact on feeling function. I think that's really the most that we can expect to get out of a pilot study that wasn't designed to look at functional outcomes. I do think that that level of unprompted feedback from patients is really helpful and does also help us to inform on some of the patient-reported outcomes that we'll be looking at in the registrational study. I think that's very promising. That's not what the study was designed to do. It definitely was encouraging to us as a team, to even think that we could be helping patients in such a short period of time. That's what the registrational study is designed to look at. I know a little bit more patience, guys. I know everyone wants that data now, but I think we've had a lot of encouraging patient-reported feedback right now, and we'll see where that goes with the registrational study. Have you had a discussion yet with the FDA on the potential design for a registrational study? Would you need to have a placebo-controlled study? Given that this is a new disease and biomarker is just newly understood, you wouldn't need to have a placebo-controlled trial? Yeah. We have met with FDA, and that's how we're able to start the registrational study so soon, and it will be placebo-controlled. Okay. My last question was on the onset of action of AT-007. I was just wondering, did the sorbitol levels rapidly drop within the first few days of dosing, or was it more gradual? Because if it's more gradual, you would anticipate that if you treat it for longer than 30 days, you would continue to see a reduction beyond the 66%. Yeah. I think that at this point, what we know from the study is that levels started to trend down within the first day of treatment, but were still pretty high at that point in time. I do think that you're thinking in the right direction, Yigal, that the kinetics here may be on a slower scale. To Stephan's point, sorbitol does accumulate over many years in these patients. We did start to see sorbitol levels trend down during the first 24 hours of treatment, which was the period of time that we held the patients in the clinic and did PK/PD monitoring. It was over the longer period of several weeks that we really started to see the very substantial reductions that we're seeing here. I think it's a good point. It is a much slower kinetic curve to reduce sorbitol levels than, for example, what we've seen in sorbitol levels in diabetic patients or galactitol with galactosemia. I think that should be taken into account here. I want to try to manage expectations carefully. 66% reduction is really substantial. I think it's great data. We're very excited about it. I don't want people to be sort of looking like, "Well, maybe there could be more reduction over a longer period of time." That is true. I think we kind of need to put the stake in the ground here and say this is substantial. You could always be looking for more information. This was a pilot study. What we were looking for was proof of concept. We have that here. I think the data's quite impressive. I do think that it's easy in rare diseases to ask questions over really long periods of time. There's always something more that you could learn. Given the urgency here and the fact that there's no available treatments, I think the best format for answering a lot of those questions is in the registrational study. Great. Thanks. Thanks, Yigal. Your next question is from Robyn Karnauskas from Truist. Your line is open. Hi, this is Alex on for Robyn. Congrats on the great data, 56% reduction. Nice. Could you talk a little bit more about how long you anticipate until you could see a clinical benefit from lowering sorbitol in these patients? Yeah. There's been no clinical studies in SORD deficiency patients to date. This is the first trial. We've worked very closely with experts in the field, taking a look back at many SORD patients or patients that we now know to have SORD deficiency. Many of them were tracked in CMT2 or HNF registries over the period of several years. Even though SORD deficiency is a relatively new understanding of the pathophysiological cause of disease, there is data on many of these patients going back several years. What that allowed us to do was to understand how quickly their function degenerates in the absence of treatment, so that we could really design a robust registrational trial that will look at sorbitol as the biomarker for accelerated approval, but is also designed to look at meaningful functional outcomes over an extended period of time. Similar to what we've done in galactosemia, we do expect to be able to assess outcomes at numerous time points for these patients moving forward over the course, probably of several years. Please stay tuned for more data on that when we announce the design of our registrational trial. I think that there's an opportunity for us to learn a lot based on what we already know. We've incorporated that into the design. We do anticipate that it may be years of treatment that are required here, but we're able to design a registrational trial that looks at a period of assessments every, for example, what we've done in galactosemia is every six months their assessments are performed. I think that we can take a similar approach here. What that allows us to do is not to have to draw a line and say, assessments are at this point in time, because it is a new disease, and we're still learning a lot about the period of time over which these patients have a functional decline. I would anticipate functional outcomes over a series of several years. But there's an opportunity to look at functional outcomes at much shorter time periods over the course of that study. That's a little bit of a preview to what the registrational design will look like, but we will announce full details of that very soon. Okay, thanks so much. As a follow-up, could you talk about the age of onset of the disease, and do you anticipate having to catch it early and treat early in order to see clinical benefit? Yeah. What type of variability do you sort of expect to see there? I'll start that off, and then I think we could just hand it over quickly to Dr. Züchner. They've looked at this across many SORD patients and looked at the age of onset. The mean age of onset in SORD deficiency is age 17. In a lot of the patient roundtables and listening sessions that we've done, that is really what comes through. In late adolescence, usually towards the end of high school, is when these patients start to notice that something isn't quite right in terms of mobility and motility. They're having difficulty walking. They're tripping. There's balance issues. This does seem to be an age of symptomatic onset towards the end of adolescence. It does progress into adulthood. Many don't actually receive a diagnosis until they're in their early 20s. It does progress over time. It does worsen over time. I do think that the earlier the better to catch these patients. Potentially offering a treatment early in the disease will be very relevant here. We do know that no matter what age or stage of disease they're at, they will continue to progress over time. It's just at a later stage of disease, as they get older and it's taken its course. Dr. Züchner, would you like to jump in with anything else about sort of the age of presentation and what that might look like in terms of treating over time? Yeah. You summarized it very well, Shoshana. We have published this data. The mean age of onset is around 17 years, ±8 years. Just again, drawing parallels to other disorders, we would think that an earlier treatment would be beneficial, possibly starting even before onset of symptoms. I'm not part of the company, so I'm not bound to regulatory. Thanks so much. But one can dream that something like this could become part of a newborn screening program in the future to identify these individuals really as early as possible and offer them treatment years before they actually develop symptoms. Obviously, accumulating high sorbitol levels seem not to be a good idea. Somebody is born with high sorbitol levels, that should be treated in the future, I think. Thanks. Riccardo, do you want to comment perhaps on sort of how we're thinking about treatments in the clinical trial and including a wide range of patient ages? The clinical trial will involve patients as young as age 16 and also adult up to age around 60. Due to the progressive nature of the disease, we believe that the opportunity benefit may last for many years. The fact that the young adult continued to worsen suggests that perhaps the opportunity for benefit will always be there. Depending, obviously, on the severity of the disease, the potential outcome would be different. All of those parameters are being considered in the design of this phase II, phase III study. Okay. I think we have a couple more minutes for questions here. Okay. Your next question is from Brian Skorney with Baird. Your line is open. Hey, good morning, everyone. Thanks for taking the question, and really impressive sorbitol measurements here. I guess I'm really pleasantly surprised with the magnitude of effect here being kind of greater than what you've seen in diabetics with AT-001 since there isn't an obvious pathway for getting rid of sorbitol in these patients as there is in diabetics. Did you look at urine sorbitol levels at all, or patients just peeing out the excess sorbitol once production has stopped? Is there another metabolic pathway to think about for getting rid of it? Yeah. Carter, that's a good biochemical question. Oh, sorry, Brian. It's a good biochemical question. I think there's two possibilities, right? One is what you just outlined. They could be actually excreting the sorbitol in their urine, and we did not measure urine sorbitol levels in the study. The other option is, we know that patients have, actually, all people have sort of scavenger enzymes that are capable of breaking down sugars and substances, even though it's not a specific metabolic enzyme to catalyze that reaction. I think both are possibly in play here. I think sorbitol can actually be removed from the body as one possibility and then actually degraded through scavenger enzymes as another possibility. I think, was there supposed to be a formal sorbitol measurement at day seven in addition to day 30? Can you talk about what that day seven sorbitol reduction looked like at all? Yeah. Brian, in this study, we're looking out to 30 days of treatment. We did do a biochemical analysis on day one. We basically kept patients in the clinic around the first day of dosing. They had PK and PD measurements throughout the 24-hour period. That's when we were able to see a bit of a dip down in sorbitol towards the end of that 24-hour period. To the point we were discussing earlier, it was not necessarily immediate. I think that the kinetics here are a little bit over the longer term, and what we have right now is 30-day data. I know that there's definitely an interest in more parameters, more data, which we hope to provide to everyone in the registrational study. This was a pilot study, so very limited information here, but I think it is very important in proof of concept, which was our goal here, but definitely not a complete biochemical picture. The last question, could you just remind us what division of the FDA would be handling this application? Yes. It's Neurology I for this program. Thank you. Thanks, Brian. Next, we have Carter Gould from Barclays. Your line is open. Great. Good morning. Congratulations, Shoshana and team, and thanks for the credit on Brian's great question. I guess first one for the KOL on the call. As we think about sort of patient segmentation here, are there any relevant segmentations to kind of keep in mind or specific mutations in patients that progress differently? For the company, just to be clear, are we going to see additional data from this open label study presented this year or early next? Is that still in the cards? Thank you. Yeah, we actually do have to let Dr. Züchner go. I think he actually needs to jump to a meeting as well. Maybe I'll let him jump in on potential patient segmentation. Stephan, I know that your work showed that there is one mutation that is definitely more frequent in the population, and there are some other potential variants there. Do you think about all SORD patients sort of being eligible for the same approach to treatment because, at the end of the day, biochemically, they're all missing the enzyme and have high sorbitol levels? That's kind of the way I'm thinking about it. If you don't mind, Stephan, if you're still on the line with us, maybe answer that question, then we'll let you jump to your meeting. I think we lost him already. Sorry, Carter. That's my answer. I think it's also Stephan's. I think that several mutations were characterized in that Nature publication. There is one mutation that's much more frequent than others, but at the end of the day, all patients with SORD deficiency are deficient in the enzyme. They have high sorbitol levels. I think the way we're approaching it from a company perspective is that all patients are eligible for the clinical trial as well as potential commercial treatment. I think that probably means we need to close the call because we've gone over time. Chuck? Yes, that's correct. Operator? Yes. There are no questions at this time. Please continue. Okay. Excellent. Thank you everyone for joining us today. Have a great rest of the day. This concludes today's conference call. Thank you for joining. You may now disconnect.