Good afternoon, everyone. Welcome to the next presentation. I'm Brian Skorney, one of Baird's senior biotech analysts. Next fireside chat I'm hosting is with the CEO of Applied Therapeutics, Shoshana Shendelman. This is a really exciting story. I've been covering it for a while now. Have a drug that's under FDA review right now. That same drug may be up for FDA review for another indication in the very near future. So maybe for those of us not familiar with the company, Shoshana, you can just give us a little bit of an overview of what Applied's doing these days. Yep, absolutely. I have a tutorial on the slide, too. So this is our pipeline. Applied Therapeutics is developing drugs for rare diseases, specifically rare diseases that have no treatments available. So our drug, govorestat, which Brian mentioned, is under FDA and EMA review right now, for a rare disease called galactosemia. It is advancing towards hopeful potential approval. Our PDUFA date is November 28th. And we have a second rare disease indication right behind it, called SORD deficiency, which is a neuromuscular rare disease. And we have plans to submit our NDA in SORD deficiency under accelerated approval, in the first quarter of next year. Both indications, again, have no treatments available, and so this is an opportunity to be the first drug approved for both indications. They're rare diseases, so classic galactosemia has about 3,300 patients in the U.S. It's a growing population, and SORD deficiency has between 3,500 and 5,000 patients in the U.S. So they're rare diseases, but with a well-identified, addressable population and in urgent need of treatment. Great. So maybe starting with galactosemia, maybe if we could dig in a little bit and tell us a little about what the, you know, sort of life is like for these patients. How's the disease diagnosed? How heterogeneous are sort of the symptoms? And how severe of a disease can this be? Yeah. So galactosemia is a disease that's fatal without dietary restrictions. So classic galactosemia is a disease that has mandatory newborn screening in the U.S., and in most European countries. And this is fantastic because all patients are identified. We don't have to go out looking for patients, making sure that they have the right diagnosis. All infants have a blood spot test within the first two days of life, and they're identified immediately as having galactosemia. And this is important because without implementation of a galactose-restricted diet, those infants will unfortunately die. And so they're identified, and they're put on a galactose-restricted diet, which they have to adhere to for the rest of their lives. While on this diet, they survive, but they still have a lot of long-term complications of disease, primarily neurological complications, because galactose is a sugar that's found in foods, but it's also produced endogenously by the body. These patients are missing one of the two enzymes responsible for metabolism of galactose. If you exclude foods that contain galactose, you save their lives, but their bodies are still making galactose endogenously, and no amount of dietary restriction can stop that from happening, and that's why they need a drug to prevent the long-term progressive symptoms of disease. Interestingly, it's not actually galactose that is causing these long-term symptoms. It's a toxic metabolite of galactose that's formed by the enzyme aldose reductase. Our drug blocks that enzyme. And so even though these patients will be producing galactose by their bodies, they're not converting that galactose to this toxic metabolite any longer. The long-term symptoms of the disease fall into mostly central nervous system, neurological complications. They have behavioral symptoms, cognitive deficiency, psychiatric symptoms, and they also develop issues with tremor and fine motor skills. And so govorestat stops the progression of disease and has been able to improve symptoms in children treated. That's the basis of our pediatric study that we've submitted for review. Great. So I don't want to. It's kind of a long development in regulatory history, so it's probably too short of time here to go through all of it. Yeah. But maybe just on the high notes, talk a little bit about sort of the effect that the drug has on the biomarker galactitol, how that sort of potentially translates into efficacy and what you've actually shown in terms of the action in galactosemia kids study, analysis? Yeah. That's the basis for submission. Yes. So govorestat blocks conversion of galactose to this toxic metabolite, galactitol. And in both our pediatric and adult studies, there's a rapid and sustained reduction in galactitol level, which is highly statistically significant versus placebo. It's between 40% and 50%, depending on the trial. And what that galactitol reduction resulted in was an improvement of symptoms in children with galactosemia. So improvement on the behavioral symptoms, improvement in cognition, improvement in tremor. Our initial study had a composite primary endpoint. You know, we've shifted away from talking about the composite primary endpoint and really discussing each of the symptoms individually because our application that's under review right now focuses on the consistency of effect across multiple symptoms of the disease and the totality of the data. In adults, we have not yet looked at the clinical symptoms. We have very strong biomarker data. And we know that in this progressive disease, they don't just stop progressing because they turn eighteen. And so, you know, we've requested approval in adults as well, based on the biomarker reduction, and our hope is to do a clinical outcome study in adults, later on in development. Great. Can you talk a little bit about, you know, what you saw in the primary endpoint as analyzed prospectively, how that primary endpoint had sort of changed based on FDA dialogue? And, you know, with the FDA request didn't change the endpoint, what that sort of analysis would show. And I think you recently updated some of the cognitive data as well? Yeah. Can you walk through that? So galactosemia is, you know, similar to other rare diseases of this size and with no treatments available. This was the first clinical trial ever in galactosemia, and there's also no longitudinal natural history data. So you know, it makes doing a long-term study a little bit difficult. Our approach was to look at all of the symptoms of the disease and to look at change over time with govorestat treatment as compared to placebo across the totality of the symptoms. So you know, behavior, cognition, tremor, fine motor skills, all of those endpoints. And you know, what we experienced through our development program was a little bit of, you know, changing of the endpoints on the FDA side, as you mentioned. But I don't think that's what's relevant. I think that it's important for us to just look at what happened on all of those symptoms, and with all of the symptoms that progressed in the placebo group, we saw a strong effect of govorestat. The one symptom that didn't show an effect of the drug was speech, and that's because the speech endpoint improved in the placebo group, so the way that we framed this, you know, in our regulatory discussions as well, is that in a progressive disease, in order to show a drug treatment effect, you need the placebo group to decline. Mm-hmm. And on all of the endpoints that were progressive in the placebo group, we showed a strong treatment effect, and that was essentially all of the endpoints except speech. Great. So now you have an NDA, it's been accepted, you have priority review. There's a tentative advisory committee scheduled for October 9th. I guess, how should we be thinking about that date? You know, at what point do you think that gets in the Federal Register and is set in stone? And what are you hearing from the FDA in terms of the timeline for confirming that? And you know, what's sort of your plan? What do you think are gonna be the major questions the FDA has for the company? Yes. So you're correct. We received a letter from the FDA that they intended to tentatively hold an advisory committee meeting on October 9th, with lots of the usual disclaimers about that. It's not been confirmed in the Federal Register. It could change or move or be canceled at any time. And so, you know, we've been preparing for that. I think advisory committee meetings are really important and, you know, how you present the data, the experts that you bring, all of that really factors into how the totality of the data will be perceived. So we've been preparing basically the whole summer for the advisory committee meeting. I think we're in great shape, just noting that it's tentative and remains to be confirmed. And we have our late cycle meeting with the FDA very soon. And so, you know, our understanding is that we'll receive an update there. Okay, great. And then, so this is the Genetic Metabolic Diseases Advisory Committee. I guess for people who don't know, this is a brand-new advisory committee. Yes. I think it was just they just started taking applications for it at the very end of last year. But there was a recent GeMDAC held for Zevra's drug. I guess any takeaways from that advisory committee in terms of the composition of the people that are on the advisory committee, the way the discussion went down at that ad com? Yes, um- And what is that applicable at all to your, your situation? Yes, you're correct. This was the first advisory committee meeting ever held by the Rare Disease Division at FDA, so you know, I think we see a lot of rare disease drugs approved by FDA in general, but obviously those can come through different divisions, and a lot of rare disease approvals, as I know you're aware, Brian, but maybe not everyone is aware, have been coming through other divisions, like the Neurology Division, and we typically see advisory committees happen there, and you know, we're kind of used to that. The Rare Disease Division had not held an advisory committee ever prior to August 2nd, and so forming the advisory committee and having that first advisory committee meeting, which was for another company in August, was an important step. Obviously, you know, the programs are not identical. There will be some differences, but I think what was important to us to learn was that this division is understanding the need for flexibility with rare diseases and that they're sort of changing the way that they approach approvals for rare diseases. I think that forming an advisory committee and having the first advisory committee meeting was an important step in that direction, and you know, again, knowing that the programs are very different, the diseases are really different, I think what applies to us, you know, is that increased flexibility that the division is exhibiting and really understanding that with rare diseases, maybe not everything is perfect, but it's a risk-benefit decision, and that when there's an urgency to treat, as we believe is the case with galactosemia, it's a progressive disease. It affects children. There are no drugs approved, you know, and we have a favorable safety and efficacy profile. Our hope is that same flexibility that they've shown with that last advisory committee meeting really applies to our program as well, and we see an approval in galactosemia in the near term. Great. So, the focus is really on FDA approval, but you're also under review at EMA. I guess what's the status in terms of the EMA being reviewed over there? We're in a good place with the MAA review. We did apply for conditional approval in Europe, so that's a little bit similar to accelerated approval in the U.S. So it's a slightly different review that's going on in Europe, but with the biomarker reductions in galactitol being front and center, again, we have very strong, you know, rapid and sustained reductions there, and with the clinical efficacy data from our pediatric study being supportive of what those galactitol reductions mean. We submitted in Europe and the U.S. almost exactly the same time. It was November in Europe and December in the U.S. And so they're progressing in parallel. We had our Day 120 rapporteurs meeting in the spring. That went well. We're getting ready to submit our Day 120 comments soon, and so I think we're well-positioned in the review in Europe as well. Great. I noticed over the last month or so, there's been a number of job postings from Applied for various regional sales positions. I guess to start, you know, what do you think of as sort of the commercial build that's going to be necessary here to launch galactosemia? And do sort of those job openings underpin a level of confidence in your potential approval? Yes. So, you know, we do feel that the review is going well. We're where we should be. But we're also being thoughtful and trying to right-size our organization to where we are at that point in time. And I think that's important as well. And so our goal is to be prepared for the launch and to take all the necessary steps that we should be doing now, without unnecessarily burning through capital, and ensuring that we have a strong cash runway, which we do. And so the way that we framed this is, you know, we waited until we felt sort of an additional de-risking. The mid-cycle review meeting, you know, was completed at the end of the spring. We've currently hired in all our heads of functions for commercial, and while you might see that we're, you know, maybe posting for sales force, we have not hired a sales force yet. And, you know, I think, like a lot of companies, we'll wait till a little bit closer to the approval date to get that moving. But I think we have the right level of commercial preparation happening as we move through the approval process and towards the launch so that we can really have a strong launch, while at the same time, you know, ensuring that we're appropriately building the organization. Okay, great. So, we talked earlier that there's another parallel indication that you're pursuing with the FDA, planning to file for a review early next year. SORD deficiency. I think this is like a really fascinating story. Yes ... of how this came about. Yeah. Tell us about SORD deficiency and what the disease is? And how govorestat, you know, plays a function here that's equally as compelling as it does in galactosemia? Yes. I share your enthusiasm, by the way. I think SORD deficiency is a really exciting indication. You know, and it's interesting from a scientific perspective, how it came about. So, you know, just a little bit of background mechanism, as you know, discussed with galactosemia, aldose reductase is the enzyme that converts galactose to this toxic metabolite, galactitol. And aldose reductase also converts glucose to a metabolite called sorbitol. And then what would normally happen in the sugar metabolism process is that an enzyme called sorbitol dehydrogenase metabolizes sorbitol. This is not the primary way that we metabolize glucose in our bodies, so in a normal person, only about 1% of your glucose is metabolized by aldose reductase and then by sorbitol dehydrogenase. Patients with sorbitol dehydrogenase deficiency are missing the SORD enzyme, and so aldose reductase converts glucose to sorbitol, and then it has nowhere to go. And so these patients build up very high levels of sorbitol in their blood and tissues. And just like we said that galactitol is toxic in galactosemia, sorbitol is similarly toxic, and especially toxic to neurons. And so patients with SORD deficiency develop a neuromuscular disease. Their motor neurons degenerate, they lose their ability to walk over time, and then eventually, they lose their upper limb skills as well. The way it was discovered is really interesting, because these patients were previously diagnosed as having Charcot-Marie-Tooth disease of unknown genetic cause. And so they were diagnosed as having a neuromuscular disease, but we don't know the molecular cause of it. It was through a whole genome sequencing initiative in 2020 that, you know, researchers figured out that they actually are missing the SORD enzyme. You know, the second we saw this, we said: "You know, we have a drug for that," and we can actually lower sorbitol levels by blocking the aldose reductase enzyme and hopefully slow or improve their disease. This is a disease where we were already developing govorestat for galactosemia, and we were able to just jump right into SORD deficiency and move very quickly through the clinical development period. We started with a small pilot study. We showed that we could lower sorbitol levels in those patients, which was very effective. Similar to galactosemia, rapid and sustained reduction that starts within, you know, the first day of treatment and is maintained over the long term. And then we did a phase III study, where we looked at, okay, does reduction in sorbitol levels correlate with a clinical benefit, either on lower limb function, we were looking at 10 m walk, run, speed, or the patient-reported outcome measure, which is called the CMT-HI. We did an interim assessment at 12 months, where we showed a statistically significant effect on the patient-reported outcome measure and a strong trend on 10 m walk/run, and of course, a highly statistically significant effect on sorbitol reduction. And so we thought we had a strong case, but we, you know, needed to discuss that with the FDA. I think a recent development that's been really important to us was meeting with the neurology division, which is the division evaluating SORD, and aligning on a path forward for approval based on the data we already have in hand. So we took them all of that 12 month data and said: "Is this sufficient for a potential NDA submission?" And then discussed everything that came after that. You know, if yes, which the answer was yes, you know, what type of submission should it be? And so we aligned that this should be a submission for accelerated approval based on sorbitol reduction and the correlation of sorbitol reduction with changes in 10 m walk/run speed and the patient-reported outcome data. Our plan is to submit that in the early first quarter of 2025. Really, we'll be having these two indications through the regulatory process pretty much back-to-back. Great. So I guess, what are the gating factors to submission? I think you had a end of phase III meeting. Mm-hmm. You have a pre-NDA meeting scheduled. What are sort of the checkboxes that need to be filled out in that pre-NDA meeting to ultimately submit? Yes. So we had, as you said, an end of phase III meeting, where we discussed the broad strokes of what an NDA submission looks like, and also the sort of broad strokes of a confirmatory study. With this being an application under accelerated approval, we aligned with the FDA on the need for a confirmatory study. You know, we discussed what that confirmatory study should look like. We are having two more meetings with them in the next few months. One is a Type C meeting to discuss the specifics of that confirmatory study. You know, we've submitted a full protocol. We'll make sure that that's exactly what they want before implementing that study. And the second part is a pre-NDA meeting, where we'll discuss a little bit more of the administrative aspects of that NDA submission, to ensure that it goes smoothly through the approval process. So I think the important thing is that we're in lockstep with FDA. The neurology division has been very clear about what they want us to do and how they want us to do it, and we've been moving that forward over the last few months. We'll have these two additional meetings with them, and then we'll submit our NDA. Okay. And then when you think of in the best-case scenario, we're sitting here a year from now, we have one drug approved or one program approved, maybe on the verge of a second one approved. How do you think about commercial then? Is there overlap between a marketing team that's selling galactosemia in kids- Yes. -and SORD deficiency in adults? Or is one plus one gonna equal two? Yeah. How do you think about that? Yes, it's a great opportunity for us as a company because it really is a commercial infrastructure that we can build effectively for both indications. It's different prescribers or different physicians that see these two different rare diseases. So galactosemia patients are primarily seen by metabolic geneticists, and SORD deficiency patients are primarily seen by neuromuscular specialists. So different prescriber, but they're almost always at the same center of excellence. And so it's possible for us to use the same medical field force same sales force. Obviously, all of our commercial infrastructure on, you know, marketing, market access, that is applicable to both indications. But to be able to use the same field force to cover both indications, I think will be really effective for us in the long term. Okay. And then obviously, it's a pretty small number of patients that you'd have to treat, but just in terms of like API production and ready to launch, can you ship vials into the channel immediately upon an NDA approval? And is there any limitation in terms of supply? Yes. Well, sorry. Yes, we're ready. No, there's no limitations in terms of supply. So, you know, this is a small molecule, and it's a relatively simple oral drug suspension. And so, you know, I think that the fact that it's an oral suspension and, you know, ease of use and adherence and persistence on therapy and the willingness for, you know, for parents to ask for this drug and for physicians to prescribe it, it is really fantastic with an oral treatment. The fact that it's a small molecule has made it relatively easy to produce with a very long shelf life, and, you know, our cost of goods is low on the CMC front. So we're in a really good place from a supply chain perspective. We will be ready to go pretty much right at the outset of approval. You know, we have quite a few patients on expanded access in galactosemia and, you know, now moving through on SORD as well. And so our ability to meet the needs of the expanded access patients, as well as the commercial prescriptions post the launch, is in really good shape. And we, you know, are, of course, now working through our supply chain projections for the- Mm-hmm ... few years that comes after that, but I think we're in great shape with regard to being ready to put drug product out there at the launch and really, support a robust supply chain. ... I'm sure it's like way too early to speak very specifically about pricing, but when you think about pricing for the two indications and how the cadence of potential approvals here, you know, there's a bit of a nuance in terms of weight-based dosing and pricing structure. How do you kind of think about those potential scenarios where you have galactosemia and SORD versus SORD, then galactosemia, and how to work around pricing? So, you know, we plan to price, like, in line with other rare diseases of a similar size, so there shouldn't be any surprises there, but I think what's interesting about our particular drug, and we see this a lot of times with small molecules, is that, in smaller children or people that weigh less, you actually have to give them a larger dose of the drug in order for them to absorb it and have the same exposure in their system, and so it's weight-based dosing, but children need a higher dose than adults, and so what this means is that at the end of the day, it's all pretty much the same. The kids for galactosemia are going to end up with a similar dose to the adults for SORD deficiency, and I think we'll see, you know, because that dosing is really similar, the pricing will be similar as well. Great. We're just in the last couple of minutes here, so we'll see if there's any questions from the audience. Anyone? No. Well, with that, I guess I'll just ask, is there anything else that I haven't asked that investors should be thoughtful of as they consider APLT? I think that we're in really good shape with both programs. We're looking forward to the catalysts that we have ahead. I think it's a really important time for us as we hit the final stretch into approval of both of our programs, and I think we're in a good place with regard to commercialization and being prepared for that big transition ahead of us from a development stage to a commercial stage company. So I'm excited about what's ahead. I think we have a few really big things coming ahead, and we're excited. All right. Well, thank you so much, Shoshana.