All right, great. Well, thanks, everyone, and welcome to the final session of the day. I'm Brian Abrahams, Senior Biotech Analyst at RBC Capital Markets. We're really pleased to have Applied Therapeutics represented by their CEO, Shoshana Shendelman. Shoshana, thank you very much. Thanks for having me. Maybe just to kick things off, bigger picture question, maybe you could take a moment to describe govorestat and maybe how it differs from some of the other aldose reductase inhibitors that have been looked at in the past, both with regards to PKPD properties and then also how the overall profile might impact the efficacy and safety profile, especially with respect to liver tox, which has been an issue for some of the previous, historical drugs in that class? Yes, it's a great question. So I think taking a step back, govorestat, as you said, is an aldose reductase inhibitor. Aldose reductase is an enzyme that's involved in sugar metabolism. And historically, aldose reductase inhibitors were developed for treatment of diabetic complications, of course with glucose being one of the molecules that, that goes through this pathway, when there's an overage of glucose. So aldose reductase is an enzyme that becomes activated when there's too much of a particular sugar around. The old class of aldose reductase inhibitors, which were, developed in the 1990s and early 2000s, were not very potent inhibitors, but the bigger issue is that they were non-selective. And so while they were targeting aldose reductase, which is a bad actor, they also off-target inhibited a structurally related enzyme called aldehyde reductase. Whereas you want to block aldose reductase to prevent these disease outcomes, aldehyde reductase is how we detoxify aldehydes in the liver. And so those old drugs basically didn't have a therapeutic window. And so some companies chose to dose high enough to hit on efficacy endpoints, primarily in diabetic complication studies, but then had very intolerable safety issues. So when we talk about liver tox with those old drugs, we're talking about liver failure and death, so really serious liver tox issues. Some companies decided to dose low enough to avoid some of the off-target tox but then missed on efficacy because of the potency issue. But I think it's also important to mention that none of those drugs were ever central nervous system penetrant. And so our technology is a mechanism of selectively and potently inhibiting aldose reductase with no off-target aldehyde reductase. And of course, we did develop an asset, AT-001, for diabetic complications, and we could talk about that another day, but it, it did succeed in achieving what we wanted to. It's very selective. It had a clean safety profile. It blocks the enzyme. But we specifically developed govorestat to be central nervous system penetrant because we knew that there were CNS rare diseases that involved sugar metabolism like galactosemia and SORD deficiency. And for those instances, we needed not only a potent and selective compound but something that could get into the central nervous system. And so I think that's another big differentiator of govorestat versus the old class. Got it. And maybe we can talk a little bit about some of the ongoing work in galactosemia and SORD deficiency. And maybe starting on galactosemia, can you talk about the latest status of the FDA review? Yes. So things are going very well with the FDA. Just to recall the timeline here, we submitted our NDA in December, and the NDA was accepted in February with Priority Review, which gave us an initial PDUFA date of August 28th, which is a very close timeline if you think about all the things that have to happen during that review period. We engaged with the FDA. They did delay the PDUFA by three months, we believe, because they needed additional time during the review. And the PDUFA date is currently November 28th. In that time frame, though, we have worked very successfully with them. We've been having some interesting conversations. You know, you don't just submit an NDA and then wait for the PDUFA date to come, as you well know. There's a lot of meetings that happen. There's a lot of interactions with FDA in the interim. And that's all going very well and on track, and we feel very encouraged. Can you elaborate a little bit more? I guess, was there any sort of one particular area that the FDA seems to be sort of honing in on that you think may have been responsible for the delay or where there were sort of a couple of one or two major questions that they wanted answers to or wanted a little bit more time to analyze the data around? Or should we think about the delay as really, "Look, this is just it's a complex data set. It's a new disease to them. They just need more time"? Like, I guess, how confident are you that there aren't a few different one or two major sticking points with the agency at this point? We actually don't think that there are any major sticking points with the agency. We just believe that a six-month review for a first-in-disease state asset so this is the first drug ever developed and under review by the FDA for galactosemia. So we don't think that there are any sticking points. We did meet very collaboratively with the FDA prior to submitting our NDA, and we asked them very openly if the data we had generated was acceptable for a potential submission and approval. We wouldn't have submitted otherwise if their answer was no. And I think that, you know, the NDA acceptance and the positive interactions that we've had, you know, have also provided a lot of additional comfort there. So we feel very good about their review. We don't think that there are any big issues. We think it's all a risk-benefit analysis with diseases like galactosemia. With govorestat having a very positive safety profile, we think the risks are very low. Then we look to the benefit. I think the benefit that we've demonstrated in our clinical studies is very clear and substantial, and clinically meaningful to parents and to patients. So we're very confident in the process, and we're very hopeful that this will be the first drug approved for galactosemia later this year. Good. How has your communication been with the agency since the announcement of the delay? It's been very positive and sort of normal course. Good. It sounds like the FDA is likely to convene an ADCOM to discuss the drug, as one might expect for a first-in-class first-in-indication. I guess what would your expectations be with regards to potential timing of when the FDA might assemble this committee? I know there isn't a standing committee necessarily with this division. What does that mean? And what would you expect the key discussion points would be once this is put before an ADCOM? We are anticipating an ADCOM, although we don't have a date for it yet. So that's something, you know, we're watching for as well, from the FDA. And we believe that and, and I think this has been publicly stated by, by Bob Califf, that they are moving towards having advisory committee meetings for diseases where it's the first-in-class, first-in-disease state, which is clearly the case for galactosemia, and that they would like to see those discussions really focused on risk-benefit. So our anticipation is that if there is an ADCOM, it will really be a risk-benefit analysis, which is very similar to the conversations that we've been having with FDA. I know there's been some differences in how CDER has approached rare diseases versus how I guess at least what CDER has said has been vocal about, in terms of the potential standard for approval. And it seems that CDER has been a bit more stringent in terms of the robustness of the data and the potential importance of hitting a primary endpoint but has also emphasized the importance of patient and caregiver outcomes in influencing how the FDA looks at the benefit-risk profile overall. So I guess can you talk to maybe how your experiences have aligned with some of those philosophies that they've outlined or conversely, if there have been any sort of surprises or deviations? No, I think that's a very good summary of their view and where they've been moving. I know that traditionally, they have been more stringent, but I think we've seen that change over the past year. And I think there is more of a focus on the clinical meaningfulness of benefit in clinical studies. And I think we have really demonstrated that the impact of govorestat is not only differentiated in terms of the impact on the endpoints but that that magnitude of change is clinically meaningful to caregivers, which is a big point for them during the review. And we've shown this through caregiver exit interviews as well as Caregiver Global Impression of Severity and Caregiver Global Impression of Change. I think it's very important to be able to tie numerical endpoints and things like standardized tests to the everyday meaning of those endpoints on the caregivers. So I agree with your summary. I think we're moving in that direction a lot more. I think there are a couple of drugs, ours is one of them, that will hopefully vet that out under the review. Any additional non-clinical or other work that needs to be done, ahead of the PDUFA to satisfy all the requirements for the FDA? And can you talk about if so, can you talk about any progress on those fronts? I think just like any program that's under review, there are certain points that you need to hit from a manufacturing perspective, from, you know, an informational perspective along the review timeline. We've met all of those points, so I think we're in great shape. There's nothing, you know, really outstanding that we need to. No gating factors. The review will be the gating factors. That was it? Yeah. Okay. Good. As you think about how to position the drug in the galactosemia treatment paradigm or the galactosemia paradigm, I should say, what parts of the profile demonstrated benefit do you think would resonate most with the patients and the physicians? And how would you characterize the, I guess, the sense of urgency to treat? Is there sort of a portion of patients that you would expect physicians would treat first and then maybe other patients who might follow later? Or how do you think about the overall, I guess, uptake dynamics and positioning? So I think it's important to remember that galactosemia is a progressive disease that worsens over time. So this disease is getting worse in all patients regardless of their age. But of course, in younger patients and we recruited patients age two and older in our pediatric study. In the younger patients, they're not so far off from their peers. Their disease hasn't progressed as much. But the disease is progressive overall, and that really affects every patient. So from our perspective in terms of the benefit to patients and how urgently physicians and caregivers should seek treatment with govorestat, it should be as early as possible, as soon as the drug is approved and, and made available. And the question is really, what does that offer people? So in all patients, it should offer a slowing or halting of disease progression. In the pediatric study, we saw some patients actually improve versus where they were at baseline. But to your question of uptake in the commercial setting and who we believe will potentially be the first users of the drug, we know that the parents of children with galactosemia feel a huge sense of urgency to get their children on govorestat as quickly as possible. And so our anticipation is that it will mostly be pediatric patients that drive uptake at launch. Although the drug does still provide a benefit for adult patients, we know that they're essentially lining up at this point in time on the pediatric side. And so the adult penetration may be a little bit slower on uptake. Got it. I would also highlight just as a reminder that because newborn screening was implemented or became mandatory in 2005, the large majority of this population is actually pediatric to date. It's a much smaller percent of the population that are young adults. Got it. And then I guess if things go smoothly, you're really only about six months away from potentially launching this drug. So can you walk us through some of the initial pre-launch activities that you're undergoing? And then what do you envision more broadly in terms of the type of sales force commercial infrastructure or strategy you might need for a successful launch? So you may have seen we recently hired a chief commercial officer who has launched a similar drug in a similar situation very recently at Reata. And I think there are a lot of parallels here. We have a strong commercial team in place. They've done a lot of preparation already behind the scenes, and that's obviously getting ramped up and scaled up in the months ahead. I think we're in very good shape as we approach the launch, in terms of market access, sales force, medical field force, all of the steps that you would expect to be happening six months before the launch, we have moving. Can you quantify, I guess, what you might expect with regards to how this will impact SG&A investment, sort of the number of like, are you kind of hiring the sales force at this point yet? Will that or are there gating factors such as the ADCOM or the PDUFA that would I guess that would be rate limiting there? I guess how are you thinking about being fully prepared but also being judicious about gating the spend? So, to your point, we're being thoughtful about it. I think it's important to be thoughtful about our expenditures on all fronts. I think we're like many companies. In this phase, we're seeing our clinical trial costs scale back a little bit as the trials are completing. And so some of that capital will be allocated to commercial spend. We are able to gate things so that, in our particular case, we'll be hiring the sales force closer to the launch, so not now, but doing as much prep work as we need to do for those functions in the time we have ahead. So we have gated things accordingly, and we are being cautious about our spend to ensure that we have an appropriate cash runway. Right now, we're in a very good cash position. We have cash through early 2026, and that does not factor in the PRV that we would hopefully get and monetize upon approval for galactosemia. So I think we're in a great position from a cash runway perspective. We'd also like it to stay that way. Right. Makes sense. Makes sense. Maybe shifting gears toward, to SORD deficiency, can you talk about some of the benefits that you saw with govorestat in the SORD deficiency interim analysis that you recently reported and just, I guess, the relative importance of, of function versus patient-reported outcomes and then the correlative biomarker? Yes. How do we put that all together? So, as hopefully most people are aware, but I'll give a little bit of an overview here. SORD deficiency is a neuromuscular disease where patients are missing the enzyme that follows aldose reductase. And so, as a result, aldose reductase converts glucose to sorbitol, and then they're missing the enzyme that follows to convert sorbitol to fructose. So they build up very high levels of sorbitol in their system. And as a result, they have a neuronal deterioration, which is primarily focused on motor neurons. And so they lose their ability to walk over time. This happens from the distal point, right? So like most axonal neuropathies, you see it first affecting the foot and ankle and then sort of moving up the body. There's also a systemic sort of effect of the elevated sorbitol levels, which we see manifest in things like fatigue, and a generalized sense of feeling unwell from these patients. So getting to your point of which endpoints are important here, we structured this trial to provide a biomarker endpoint for accelerated approval and also clinical outcomes data. And so we have demonstrated a clear effect on the biomarker, which was sorbitol reduction versus placebo, and also correlation of that sorbitol level with change in clinical outcomes over time. And then we had as secondary endpoints the 10 m walk/run test as a functional endpoint and the CMT Health Index or CMT-HI as a patient-reported outcome measure. We showed a strong trend on the secondary endpoint of 10 m walk-run, but we actually hit statistical significance on the patient-reported outcome measure. We believe the reason for that is this generalized feeling of feeling unwell and fatigue and all of the other pieces that go along with the functional endpoints. It's an important piece of the disease. We know that there's been a movement at FDA towards focus on patient-reported outcomes. So we think that that's a pretty strong position to be in, to have statistically significant data on the patient-reported outcome measure as well. Okay. And so I guess along those lines, what do you think you'll need to show with the 24-week data in order to support initial approval or, I guess, support surrogate confirmation of approval if you get accelerated approval ahead of that? And are you thinking about any changes to the design or endpoint based on what you've seen so far and based on some of the things you've said about what's most important to the FDA? Yes. So just maybe starting with what's required for submission of an NDA under accelerated approval. We believe we have what we need for submission of an NDA under accelerated approval, and we are in the process of meeting with FDA to discuss that. This program is with the Neurology One Division, and we will be providing an update in the next few months. Is that a formal meeting, or is that sort of a written correspondence? It's a formal meeting. Part of that discussion will be the potential submission of the data generated to date under accelerated approval. The other part of that discussion will be, to your question, the confirmatory data or confirmatory study and what form that takes. There are some things to discuss there. I think you had some really good points. We know that when we were designing this phase III, the FDA was open to either 10 m walk-run or CMT-HI as a clinical outcome for a confirmatory study. You know, we have our 12-month data, which showed good data on both, but it's a little better on the CMT-HI. So we'll be discussing that with them. So what you should expect in the next few months is some clear guidance on our timeline for submission of this data, most likely under accelerated approval for SORD, and what the confirmatory design or study data will look like, whether it's alterations to the current study that's ongoing or an additional study. Got it. Okay. A lot to digest there, but that makes that makes a lot of sense, though. And, and just in terms of maybe the timelines for, for a potential meeting and what you think will be sort of the key aspects of, of discussion there? So we have a meeting scheduled. We will provide an update after that meeting. We will. Post after right after or post the minutes? I know some companies do it different ways. Details. It's a big catalyst, so we're curious to understand. We tend to wait for minutes. I do think that's the more cautious approach. Okay. And then I guess what's your level of confidence? I mean, it sounds like you're leaning towards an accelerated approval filing. But maybe what's your confidence around the degree to which the surrogate would be sufficiently validated and some of the correlations that what I guess whether the correlations that you're showing between sorbitol reduction and efficacy within the confines of your study, whether that would be enough validation of the surrogate, in the eyes of CDER? So we've had extensive conversations with FDA leading up to this point. So obviously, we're not going in there on our first discussion of accelerated approval. And the agency has been very collaborative, in detailing for us what they've wanted to see in order to facilitate an accelerated approval. And we've basically done those things. And so we're very appreciative for that. She's not going in blind. We're not going in blind. They've given us a roadmap. We use that as the basis for all of our data generation and our trial design. So we believe we've done everything they've asked for. I think this meeting will be a very important validation of that. But I think we knew what we needed to do, and we did it. Good. And then maybe talk a little bit more about the market opportunity. I mean, it sounds based on some of our work like there's a lot of KOL interest. And it's a, I guess, a more, I guess, less heterogeneous disease in terms of its manifestations versus galactosemia because it starts as a distal neuropathy, and it's fairly predictable in its course. So I guess what are you guys hearing on the ground in terms of your market research, the types of patients and the overall potentially eligible population that could potentially be interested in starting govorestat and how quickly that could ramp up initially? Yes. So you're, you're correct. There's a huge amount of KOL interest here. They've really partnered with us from the start. I think part of that is the, kind of ownership that KOLs have had over the disease state. As you are aware, the identification of SORD deficiency and the genetic cause of disease was a collaborative effort amongst many KOLs, and the patient organizations. And so they, they do feel, a partnership with us, which we're very appreciative for, that, you know, they were responsible for identifying the cause of disease, and we have a drug for it. And we've been in lockstep with them in terms of identifying patients, designing the studies, our regulatory conversations. And so I think that's a fantastic partnership that we have with the KOL community. And you're right. They, they feel that they, understand these patients. They're identified. And so we feel very confident that we've studied the population in the clinical trials that they'll be prescribing the drug for. Good. Maybe just in the last minute, we recently saw the publication for AT-001. Can you talk about, I guess, the strategic opportunities there, where you stand with regards to partnering, getting a partner? Is that something that's still high priority, and what's been some of the reaction out there in the community to the publication? Yes. It is still high priority. So maybe just a little bit of background for anyone who's not aware. Our other asset, AT-001, which is a selective and potent aldose reductase inhibitor but is not central nervous system penetrant, and it's a different structure handled on different IP. So it's kind of perfectly poised for a partnering or acquisition of the product. It had a very successful phase III study readout, but there is going to be another requirement for a second phase III for approval in diabetic cardiomyopathy. And so there has been a lot of interest from large pharmaceutical companies across the diabetes and cardiovascular spaces. Here again, we have a huge amount of KOL support as well. And so I think we're in a good place with discussions. As you may be aware, large pharma discussions sometimes take a little longer than people would like. But we do feel that there's a clear path forward to, to value in that program for Applied shareholders. So we feel that that's more appropriate for a large pharmaceutical company to take forward from here so that we can focus on the rare disease assets, which we feel we're better poised to do as a smaller company. But again, there's been a lot of innovation there and value creation. And so our goal right now is to bring that value to shareholders. Good. Well, with that, we have to wrap up. Shoshana, thanks so much. That was great. Thank you, Brian. Really helpful.