Morning, everyone, and welcome back to the Cantor Global Healthcare Conference. My name is Rick Bienkowski. I am one of the analysts here on the biotech team, and today we have the pleasure to be hosting Shoshana Shendelman of Applied Therapeutics. She is the CEO and founder of the company, and she will be giving a presentation. So please, Shoshana, take it away. Thank you. Thanks for having us. You can see our forward-looking statements. So at Applied Therapeutics, we're developing urgently needed drugs for patients with rare diseases. We have near-term potential for approval in two different rare disease indications, and we're preparing for those commercial launches. Our lead asset is clinically validated. It's a small molecule aldose reductase inhibitor called govorestat, which we're developing for two different rare disease indications, one which is a rare metabolic disease called Classic galactosemia, and the other, which is a rare neuromuscular disease called SORD deficiency. As a company, we're based here in New York. We're well-capitalized and I think right-sized for where we are as an organization, and in the process of making that transition from clinical development stage to a commercial stage company. In terms of our pipeline, our late-stage asset, govorestat, is under regulatory review right now for Classic galactosemia, in the U.S. as well as in Europe. We had some positive news this morning, so this presentation is well timed. We recently completed our late cycle review meeting with FDA, which was very positive. They had previously communicated maybe there would be an advisory committee meeting. They let us know at the late cycle meeting that they no longer felt that was needed. Our next interaction with them will be in about a month when we discuss post-marketing requirements and overall, you know, our message there is that things are going well. We're very encouraged by the dialogue with FDA, and we're excited about moving forward into this last stage of regulatory review. Our review in Europe is happening about in parallel. And so we're in the Day 120 clock stop period with EMA. That clock will restart soon with our submissions this fall, and we're looking at a CHMP opinion likely just at the end of this year or early 2025. In parallel, we have this other rare disease indication, SORD deficiency, sort of at that transition point into regulatory phase. So we completed an interim assessment of our Phase III study in SORD deficiency. We discussed the data with FDA. The SORD deficiency program is with the neurology division at FDA. They confirmed that the data we already have generated to date is sufficient for a potential NDA submission under accelerated approval, and we are planning to submit that NDA at the very beginning, early first quarter of 2025, so those regulatory reviews and hopefully commercial launches are really back-to-back with one another, and as you'll see when we walk through the indications, these are very synergistic, rare disease indications. It's a place where we can really be successful with our commercial infrastructure in launching in both indications. In the background, we developed another aldose reductase inhibitor, AT-001, for diabetic cardiomyopathy. We completed a Phase III study late last year, and we've decided to focus our efforts as a company on the rare disease portfolio, although we have created a lot of value in that program, and we are in an active process to, hopefully sell or license, the AT-001 program, so from here on out, our efforts really focus on rare disease, so govorestat is an aldose reductase inhibitor. Aldose reductase is an enzyme that's involved in alternative sugar metabolism. It's an enzyme that only becomes activated when you have too much sugar around, and this is not our primary mechanism for metabolizing sugars. In galactosemia, that sugar that we'll be talking about is the sugar galactose, and in SORD deficiency, it's glucose. But in either case, this enzyme represents the first step in a pathway that's generally toxic in metabolizing sugars. It converts a sugar to a reduced sugar alcohol, which serves a short-term purpose of sort of, you know, getting rid of some levels of sugars, but the longer-term damage that that causes by creating mitochondrial derangement, reactive oxygen species formation, and really overall negative effects for the cell, cause damage. Aldose reductase is an enzyme that's been known to be a bad actor for thirty years. A lot of companies have tried to develop aldose reductase inhibitors, but the old drugs were always plagued by being weak inhibitors and non-selective inhibitors. And so old attempts to inhibit this enzyme resulted in off-target inhibition of a structurally related enzyme called aldehyde reductase. And prior to our technology, there was basically no therapeutic dosing window. If you dosed high enough to block aldose reductase, you had off-target aldehyde reductase inhibition. Our technology was developed at Columbia University. They took a structural, approach and medicinal chemistry approach to really targeting this enzyme, aldose reductase, selectively. So our drugs, which include govorestat, are a thousand times more potent than any of the old drugs that were attempted, and they're completely selective for aldose reductase without any aldehyde reductase off-target inhibition. And that's allowed us to really effectively target this enzyme to block these, disease pathways with a clean safety profile. So again, two rare disease indications happening in parallel. Classic galactosemia is a rare, progressive metabolic disease where patients are missing one of the enzymes required for galactose metabolism. And because they can't metabolize galactose the normal way, aldose reductase starts converting galactose to a toxic metabolite called galactitol. govorestat, our drug, blocks the production of that toxic metabolite. govorestat is an oral small molecule, so it's an oral liquid drug suspension that's dosed once daily. We've shown in galactosemia patients that we effectively reduce galactitol levels in a rapid and sustained fashion, and that galactitol reduction leads to improvement in clinical outcomes over time. There is a little over three thousand patients in the U.S. with galactosemia. There's mandatory newborn screening and state-based registries for this disease. galactosemia is one of the diseases that every infant born in this country has a blood spot test for. We know exactly how many patients there are in this country with galactosemia, and we also know that it's a growing disease state. There's thirty-three hundred patients alive today with galactosemia, and there's about eighty new births per year. So we expect this disease, indication to grow over time. The reason there is mandatory newborn screening is because infants need to be put on a galactose-restricted diet at birth. Without the galactose-restricted diet, these infants will unfortunately die because of galactose exposure in breast milk and dairy-based formulas. So infants that are alive today are primarily children because they only survived birth after newborn screening was introduced. Newborn screening became mandatory in this country in 2005. So again, this is a primarily pediatric population. There are some young adults living today with galactosemia if the states they were born in happened to have had newborn screening, but this is an indication where we do expect it to grow over time. And now that there is newborn screening and introduction of a galactose-restricted diet, these children survive, and they will become adults eventually. SORD deficiency is also a rare disease, a little bit larger, though. So this is a rare neuromuscular disease. It's somewhere around twice the size of galactosemia, but again, we're talking about five thousand patients in the U.S., with SORD deficiency. It's a subtype of Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease, as many of you may be aware, is a rare neuromuscular disease. There are no treatments available today for any form of CMT, and so govorestat, as a potential treatment for SORD deficiency, would be the first treatment not only for SORD deficiency, but also for any form of CMT, which is a really important milestone for both us and for the FDA. Talking a little bit about galactosemia, you know, again, this is a disease that affects children. They do have to be on the galactose-restricted diet in order to survive, and that blocks their external intake of galactose through foods. However, galactose is a sugar that your body makes endogenously, and you can't stop that from happening through the diet. And so there's two aspects to this disease. There's early identification through newborn screening and implementation of a galactose-restricted diet, which they will have to stick to for the rest of their lives, but they also need a drug treatment because the body is producing galactose endogenously, no matter how strict they are with the diet, and that galactose that their body produces gets converted to this toxic metabolite, galactitol. What that results in over time is a progressive neurological disease. So these children actually develop behavioral problems, issues with cognition, adaptive skills, motor skills, tremor. They develop seizures as they get older, and speech difficulties. There are no drugs available today for treatment of galactosemia or SORD deficiency, so govorestat has the opportunity to be the first drug approved for both of these indications. So we've talked through this verbally, but it's helpful sometimes to see it on the screen. govorestat blocks aldose reductase, which converts galactose to galactitol. And so by blocking that enzyme, we're reducing the levels of galactitol that are produced in these patients and decreasing the damage that's happening to their body over time. Quick summary of our efficacy. We've shown that govorestat results in a rapid and sustained reduction in galactitol levels. In our adult study, which was our first study in patients with Classic galactosemia, we looked at levels of galactitol in the blood through plasma samples, and we also looked at levels of galactitol in the brain through MRI quantitation, and we showed that govorestat reduces galactitol levels in the blood and the brain, just as we had shown previously in animal models. This galactitol reduction happens on the first day of treatment, and it stays reduced throughout the duration of treatment with the drug. We then moved into pediatric subjects, children aged two to 17, and showed also rapid and sustained reduction of galactitol in the blood, and we also showed that on clinical outcomes, we were able to stabilize or improve the symptoms of disease, things like behavioral symptoms, cognition, and tremor. govorestat has an extremely clean safety profile, so there's a very favorable benefit risk. Here you can see the generalized treatment effect on many domains in galactosemia, so again, this is a multifactorial disease. It affects behavior, cognition, daily living skills, adaptive skills, and tremor, and what you see consistently across all of these symptoms is that govorestat treatment stabilized the children where they were and did not show any further decline, whereas the placebo group actually got worse over the 18 months of the trial. Again, very clean safety profile in the clinical studies. We've treated nearly 200 patients in healthy volunteer studies as well as a number of children in our clinical studies, but also in our expanded access programs, so I think the key message here is that we have a favorable safety profile. We have many patients that have been on the drug for over three years consistently, and so that gives us a very good idea of the long-term safety profile, and that safety exposure is growing, you know, as we move forward and more and more patients end up in our expanded access program, and we complete more trials. We are at that critical transition. You know, as I mentioned, we're in the last phase of regulatory review right now, and we're preparing for a potential commercial launch. Our PDUFA date with the FDA is November twenty-eighth, which is Thanksgiving Day. So, you know, we have a couple of months. We have been preparing for quite a while now. We have a strong, commercial team in place and medical field team, and I think that the key takeaway is that we're being thoughtful about our commercial preparation, and it's right-sized to our organization. Our team members are very experienced. They've done this before in very similar rare diseases. In the background, we're driving disease awareness and education with physicians, with nurses, with all stakeholders involved. We have very strong physician and payer engagement, and what's important here is that our commercial organization, everything from our leadership, straight through to our planned sales force, is applicable to both Classic galactosemia, which is our first indication, and SORD, which will hopefully come very shortly thereafter. There is a very strong awareness and demand for govorestat from the galactosemia community, from both caregivers, patients, and physicians. We've been working very closely with the Galactosemia Foundation from an advocacy perspective to make sure that we're meeting their needs moving forward. Just some basic sort of interest level from a market research perspective. You know, as you can see on this slide, the majority of physicians do plan to use govorestat in the early days of approval and would use govorestat in the first year of availability. I think that this really underscores the urgent need for treatment. These patients have a progressive disease. It's getting worse with every day, and there's no other treatment available, and so there is an urgency that's felt by the parents of these children, as well as by the physicians, and our hope is that that's reflected in the commercial launch as well. Shifting gears a little bit to the other rare disease indication, SORD deficiency. This is a neuromuscular disease which affects the lower limbs primarily, and like most neuromuscular diseases, it moves from sort of your most proximal part of your limbs, from your feet through to your ankles, through to your calves, and up through your legs. These patients lose their ability to walk over time, which is devastating. It's caused by genetic mutations in the enzyme that normally follows aldose reductase, which is called sorbitol dehydrogenase. I'll show you a mechanism slide in a minute, but basically, aldose reductase converts glucose to sorbitol, and sorbitol is usually very quickly metabolized by an enzyme called sorbitol dehydrogenase to fructose. However, these patients are missing sorbitol dehydrogenase, and as a result, aldose reductase converts glucose to sorbitol, and it has nowhere to go. They build up very high sorbitol levels in their blood and tissues, and this has a devastating effect on their neurons, especially their motor neurons. And they develop a neurodegeneration of the motor neurons, which causes a neuromuscular disease. These patients have only been identified as having SORD deficiency since twenty twenty. It's one of these success stories for the scientific community. Prior to twenty twenty, they were symptomatically diagnosed as having Charcot-Marie-Tooth disease based on their lower limb symptoms, but of unknown genetic cause, which is unfortunately the case for many patients with CMT. And as part of a whole genome screening initiative for CMT patients, in 2020, it was identified that about 10% of these CMT patients actually have a mutation and loss of function in their SORD enzyme, and that's what's causing their molecular pathogenesis of disease. This was the cover of a Nature publication in 2020. And the community, especially the neuromuscular physicians, really got to work very quickly on genetically testing all of their patients. So if they had CMT of unknown genetic cause, they were sent for a genetic test, and they now are diagnosed as having SORD deficiency, a specific subtype of CMT. Originally, it looked like there were about 3,500 patients in the U.S. with SORD deficiency. That number is growing because more and more mutations are being identified by researchers, and we now know that there's confidently about five thousand patients. We expect that may grow over time, again, as the science advances and more mutations are identified. The pathophysiology of disease, again, is that aldose reductase converts glucose to sorbitol, and then that sorbitol can't be metabolized in these patients, and sorbitol is toxic. So by blocking aldose reductase function with govorestat, we're stopping the conversion of glucose to sorbitol. And, you know, as I mentioned in the opening part of this presentation, aldose reductase is part of an alternative sugar metabolism pathway. It's called the polyol pathway, and this is an alternative sugar metabolism pathway because we don't need it. And so when you block aldose reductase, the sugars are metabolized in other ways, and that's the case in SORD deficiency as well. So we're able to block aldose reductase activity and stop sorbitol production, and the glucose is then metabolized through other pathways. So we've conducted a few clinical trials in patients with SORD deficiency, always demonstrating a rapid and sustained reduction in sorbitol levels in their blood. The most relevant is probably our phase three study, which forms the basis of our planned NDA submission. So this was a phase three study set up to look at sorbitol reduction and correlation of sorbitol levels with clinical outcomes over time. And so we had a three-month biomarker analysis that was highly statistically significant and positive, again, showing the rapid and sustained reduction of sorbitol in these patients. And then at a 12-month interim assessment, we looked at the correlation of that sorbitol reduction with actual clinical outcomes change over time. So change in 10-meter walk, run speed, 6-minute walk test, dorsiflexion, hard clinical outcome tests. And that was our objective at 12 months. That was our primary endpoint at 12 months. It was correlation of the biomarker with clinical outcomes. That was the package that we took to the FDA over the summer, to discuss whether this data was sufficient for a potential NDA submission. They agreed and aligned that, it is, and that that submission should be under accelerated approval, with a confirmatory study planned that will look at a hard clinical outcome, like 10-meter walk/run test, over a much longer period of time. You can see here the rapid and dramatic sorbitol reduction in the govorestat-treated patients as compared to placebo. Safety, again, was very similar to what we've seen in the galactosemia population and healthy volunteers. Very clean safety profile, nothing unexpected. We're really fortunate in the SORD deficiency space to have two strong patient advocacy organizations, the CMTA and the HNF, and again, we have the opportunity with govorestat to be the first treatment approved not only for SORD deficiency, but for any form of CMT, and that's really meaningful to patients with all forms of CMT, and it creates an alignment that's important between the patient community, us, obviously, and the FDA. So to close, we have two late-stage programs, galactosemia, which we're in the sort of last leg of regulatory review with both the FDA and the EMA, and we're hopeful for a near-term approval and launch. We're preparing diligently, but thoughtfully, for those commercial launches to make sure that we're set up for success, but that we remain well capitalized, which is important to us, and I think we're in a very good place from a capitalization perspective. And in SORD deficiency, we are preparing our NDA submission. We're meeting with the neurology division two more times in the next couple of months, once to finalize the confirmatory study that we'll perform, and again, at an administrative pre-NDA meeting, and then that NDA submission will go in. Again, we've sort of staked that for the very early part of 2025, early first quarter. And with the potential to have two indications launched, and that synergy within our commercial infrastructure and sales force, I think we're very well set up for the future to be successful as a rare disease company and also to do something really meaningful for patients with these diseases. Again, there's just a huge unmet medical need in both galactosemia and SORD deficiency, and so we have an opportunity to bring something to those patients in need, which I think is what gets us all out of bed in the morning. So thank you very much for your time.