I'm Todd Brady. I'm the president and CEO of Aldeyra. It's so great to see so many of you here for the 2024 Aldeyra Therapeutics Research and Development Day. I must admit I rather like these days. It really gives investors and analysts a chance to glimpse into the future, two to five years from now maybe. We don't typically talk about these things because we're so focused on data releases and near-term events and what's happening next quarter, but R&D days, in my view, are a great chance to think about really the foundational basis of the company and where we, as management team members, intend to take the company. And so we're excited to be here. And for all of you listening online, thanks for your support. We're a publicly traded company. As you all know, we'll be making forward-looking statements. We take no obligation to update those statements in the future, and things change. Our disclaimers are important to consider. For today, I'll start out talking about RASP, which is how Aldeyra was founded in 2004. Our lead RASP modulator, as you know, is reproxalap, in development for dry eye disease, partnered with AbbVie. I'll talk a little bit about reproxalap, mostly reviewing information that we released last month regarding the plan for reproxalap. I'll invite my colleague, Adam Brockman, up here to talk about our next-generation RASP modulators. We have a large class of new molecules that will be advancing into clinical testing shortly. We're thrilled to talk about those and the new indications associated with those molecules. Today, we have two vitreoretinal surgeons, so if you have a retinal issue during this conference, you're in good hands. Dr. Tomasz Stryjewski is a long-term consultant with Aldeyra. He is here to answer questions about retina. Our keynote speaker is Dr. Ramiro Maldonado from Duke, who is the principal investigator of our phase II retinitis pigmentosa trial with ADX-2191, and he'll be talking about that later. Then I'll conclude today after lunch with a pipeline review, and I'll discuss milestones as well. There'll be plenty of time for questions and breaks. We have several important members of the Aldeyra team here today. First of all, many of you know Laura Nichols, who runs our internal operations. She also holds a finance role, and she is our internal head of investor relations, a good person to know. Our external head of investor relations is David Burke, sitting next to Laura. Dave and I worked off and on for over 10 years now. We both hail from North Carolina. I'm not sure if that's good or bad, but David is here at your service. We have our Chief Development Officer, Stephen Machatha. Stephen oversees everything related to development, so from CMC to preclinical to IP to clinical and many other things as well. And if you have a chance, feel free to say hello to Stephen as well. RASP are an amazing target. I think most drugs today target a single protein. So most drugs, maybe 95% of them, are receptor agonists, or they're receptor antagonists, or they're enzyme inhibitors, or they're an antibody against a protein, or they're gene therapy for a protein. There are very few non-protein-directed drugs available today. RASP are promiscuous. They're all around us. We're particularly concerned about the RASP that we generate endogenously. They're pro-inflammatory. We just saw a paper come out the other day, which is cited on this slide, that RASP are intricately linked to aging and diseases associated with aging. Yet no company has ever targeted RASP systematically in the way that Aldeyra has. What's so interesting about RASP is that they bind many proteins. Any protein with a free thiol group or a free amine group is targeted by RASP, and certain proteins have more of those moieties and thus are more RASP-sensitive. So RASP binds the proteins. They alter the structure of those proteins and ultimately alter the function of those proteins all at once. So by targeting RASP, we're able to influence protein systems. We characterize ourselves as a systems biology company, whereby binding RASP, we're able to affect many proteins at once. I think a challenge with today's pharmacology, if you are simply affecting a single protein, turning it on or off, there are toxicology implications for that. Our proteins aren't meant to be turned on or turned off exclusively. Our bodies work by modulating proteins in an analog way, more like a volume switch or a volume knob as opposed to an on/off switch. And that's what we're trying to illustrate here on this slide, whereby modulating RASP, we sort of think of our platform as a master volume knob as opposed to an on/off switch. That allows us to affect a large variety of proteins at once and avoid some of the toxicity that may be associated with turning something on or off. I like to tell people, "Imagine that if you lived your life on or off, you had only two speeds in your car, zero or as fast as it would go, or two volumes in your headphone, zero or as loud as it would go, or two lights in your house, complete darkness or complete brightness. We simply don't function as organisms in that way. And it's just interesting to me that pharmacologically, we treat our bodies that way. We're on or off with most drugs or turning proteins on or turning proteins off, whereas with RASP modulation, we have the ability to influence a variety of proteins without turning them on or off." I want to switch now to talk a little bit about our lead RASP modulator, reproxalap, for dry eye disease. A lot of this information was previously disclosed. We've announced as of last month that we'll be running three clinical trials. The FDA, based on our last NDA application for dry eye disease, wanted another symptom trial. In conjunction with our partner, AbbVie, we have decided to run three of those trials. I think what's interesting is two of them will be in a dry eye chamber. That is interesting because dry eye chambers allow the assessment of drugs over minutes. Most dry eye trials typically are over weeks. They take months to run. Patients take their drugs home. They take them for many, many days, and they rate their symptoms. A dry eye chamber, which is part of the FDA dry eye guidance, allows for patients to go into a small enclosed room with forced dry air and rate their symptoms so that we're able to assess the activity of drug relatively quickly. The chambers in these upcoming trials will be 100 minutes long. Based on previous chamber trials, in fact, the data here are from four previous chamber trials. We believe the next trial is likely to work. These data are from clinical trials run at fixed dry eye chambers. That is chambers in buildings. There are some mobile chambers, but we're focusing on fixed chambers in buildings. 110 patients were tested in those chambers. There is one chamber in the United States. There is one chamber in Canada. There may be other chambers in the world, but we're not aware of where they are. The two upcoming chamber trials, one will be in the United States and one will be in Canada. These data summarize data from the results from both of those trials, and as you can tell, highly statistically significant reduction in ocular discomfort relative to control. In fact, all of these time points are statistically significant except for the time point right after the second dose. You can see that during the chamber, a second dose of test articles administered, either vehicle or drug, and the volume effect, that is, the liquid in the eye, tends to mitigate ocular discomfort acutely. But over time, you can see those curves separate, elucidating the true effect of drug. The label we surmise will have symptoms, which would include a field trial, so chronic, durable benefit, and chamber data. The chamber data is acute benefit. The field trial that we've run previously used ocular dryness. The chamber data will use or the chamber trials will use ocular discomfort. So not only do we have two models of symptoms, a chronic and an acute model, but also two different symptoms on the label. All of this is quite unique in the dry eye landscape, as many of you know. And then for the sign, the FDA requires a sign that is ocular redness. Ocular redness was demonstrated also in dry eye chambers, so acute activity and reducing redness. I've often said, and I continue to believe, that redness is the only sign that patients care about. I don't think too many dry eye patients wake up in the morning thinking, "What is my Schirmer score? What is my fluorescein staining score?" But redness is important to us all, and with any luck, we'll have both redness and symptoms on our label. Let me just pause briefly, take questions on reproxalap. I know some of you have some reproxalap questions, and then we'll shift to Dr. Brockman to talk about our other RASP modulators. Right. The question is, we're running two chamber trials, one in the U.S., one in Canada. Is there any difference between the two chambers? I will say I think they are remarkably similar. Obviously, they have different protocols. They have different standards. But the actual data from those chambers is remarkably similar across the United States and Canada. And I think that speaks to the activity of the drug relative to vehicle. So we don't see dramatic differences, even though they are different physical units with different SOPs and so forth. Right. So the AbbVie agreement with Aldeyra is an option agreement. That option was extended in December, which means that from the outset of the agreement, they have 18 months to exercise, which is roughly a year from now, to exercise the agreement. I can tell you that AbbVie has been a wonderful partner. We work together very closely. The result that I just presented regarding the three trials, the two chamber trials, the field trial, obviously was derived in conjunction with AbbVie. AbbVie is a dry eye leader. Restasis, which was their drug, now generic, was the first dry eye drug. Obviously, they know what they're doing. Hey, Yale, I think you had a question. The question is about, of the three trials, are they all going to start at the same time? And then I guess a follow-up question would be, are they all going to read out at the same time? There's going to be a stagger. The trials will all be staggered. In general, when there is one remaining requirement to submit an NDA, the first trial that meets that requirement is then submitted to the NDA. The other trials will read out after the NDA review. In our case, because this is a resubmission, the NDA review is six months, and the other trials would read out after the first trial that works is submitted. You don't want to submit a trial during the NDA review because that is extra data. The FDA has to review that data. There could be a PDUFA extension as a result of that. So that's why we stagger the trials. Catherine, I think you had a question. Sure. The question is, is there a seasonality component, and have we started enrolling, and when is the last patient last visit? The seasonality is really important during field trials. So if you're testing patients over 12 weeks, or in our case, six weeks, the last thing you want is for a patient to start in allergy season, say, and end in the summer, or start in the fall and end in the winter. I think patients crossing seasons is a bad idea because the activity of the drug can be impacted by pollen or pollution or some other aspect of the season, like humidity, for example. The chamber trials avoid that because the vehicle chamber and the test article chamber are so close together. Remember, these patients are coming into the chamber with a relatively low level of symptoms. So these might be considered mild to moderate patients. But the beauty of the chamber is their symptoms escalate in the chamber, and the impact of pollen or humidity acutely is less important because of the short duration of the chamber itself. In terms of enrollment and timing, we've said that we plan to resubmit this NDA the second half of the year. So you could expect that, by and large, we would have clinical data in Q3 or early Q4 to enable that submission this year. Tom. For the conduct of the trial, patients show up. Then what fraction get into the trial? They'll have some exclusion criteria. Then you have a first round where you compare vehicle against vehicle. Don't get worse. Don't get into the trial. What's the cut there? Just kind of curious how big your population is, though, average person would think. The question is, how do you enroll patients? What are the exclusion criteria? What percent of patients fail? I think about 85% of our patients qualify ultimately. As you pointed out, Tom, patients must escalate in the chamber on vehicle. This is a very classic approach in pivotal clinical trials. It's called the placebo run-in in many cases. If patients get better in placebo, in our case, vehicle, there's no point in having them in the trial. So the theory goes. That theory may be incorrect, but we have, by and large, proven that it makes sense to do it based on the four completed trials that I showed you just a few minutes ago. Patients have to increase, I think, in ocular discomfort by at least 15 points at two different time points. I think they have to have a score of 15. So this is a 0-100 scale, a score of 15 to enter. They can't be higher than 85 before they enter the chamber. So all this is relatively well thought out and scripted, as you say, Tom. And the reason for that is we have so much data from prior trials. We have the luxury of testing all sorts of different inclusion and exclusion criteria. And I think we picked the ones, as you can see from the data I just presented, that work. Hey, Yale. The question is, if one trial works and the NDA is submitted, let's say the drug is approved. What's the rationale for reading out the additional trials? I think there's maybe a marketing angle along those lines. Obviously, the decision to read out the trials at all will be a joint decision between Aldeyra and AbbVie. Is there any benefit to having an additional field trial or an additional chamber trial? Probably not, in my view, but it's always nice to have backup plans. In our case, backup plans to those backup plans. Okay. Why don't we move on? It is my pleasure to introduce to you Adam Brockman, who runs our translational science efforts at Aldeyra. What that means is pre-IND, toxicology, in some cases, clinical trials. He's going to talk about the ethanol toxicity clinical trial, which was his brainchild, among many others. So I'm thrilled to introduce Adam, and he'll talk about, I would say, next-generation RASP modulators as follow-ons to reproxalap. So, Adam. Thanks, Todd. Thanks, everyone, for your interest. It's really a privilege to get the opportunity to talk about the funnel and discovery efforts and the early R&D efforts at Aldeyra that our team has conducted. Of course, this includes the work of Stephen Machatha and Charlie Montgomery and our collaborators at places like University of Nebraska and elsewhere. But our funnel really starts with in vitro RASP binding. We determine that our various molecules and ideas give us molecules that strongly and quickly bind to RASP, quickly followed by the murine sepsis cytokine assay. So this is a really tough model where you're inducing a cytokine storm with LPS. And so right off the bat and these mice are dosed orally. So we determine right off the bat that we have a druggable molecule that's orally bioavailable. We ensure that these molecules can be scaled up at a reasonable cost, that the synthesis isn't a huge hurdle, and that no heroics are really required in terms of formulation and that sort of thing. Following that mouse cytokine assay, we go into in vitro druggability characterization. And so that's really ensuring that the druggability that we determine in the mouse will also translate into man in terms of optimizing the pharmacokinetics, the clearance of the drug, ensuring that the hepatocyte microsome-driven clearance in man is going to match what we saw in the mouse. Then we go into exploratory toxicology to ensure that these molecules are going to be safe. So by the time we get to our candidates, pre-candidates, and then candidates, we have safe, druggable molecules that can be scaled up at a reasonable cost and that strongly bind RASP and are able to show efficacy in that tough mouse sepsis model that I described earlier. Let me just highlight the molecules that we're going to be talking about. ADX-629, which we've discussed at our last R&D day and that we've shared various press releases on, is our signal-binding molecule. I guess in this presentation, which you don't always get in research presentations, we get to show that we have clinical translatability in most cases to the models in the mouse that I'm going to show you. And we can really highlight how we've taken advantage of that model and the knowledge of that translatability to come up with next-generation molecules that are even better. Two of those molecules that I'm going to talk about are ADX-246, probably our most active, our sort of hottest RASP trap, and maybe our most hydrophilic. And then ADX-248, which is sort of intermediate, but also maybe a little bit more permeable. And so we'll talk about what some of those differences in activity profile might look like. So what indications are we going to talk about? Well, RASP, in all cases, is a bad actor. Aldehyde molecules are toxic in general by their nature. And so we can look across different indications and inflammation, and we can look at how RASP interact in that particular cascade of inflammatory events. And we can look at indications that we think are particularly attractive for our molecules. I'm going to start with atopic dermatitis. Obviously, that's an upregulation of pro-inflammatory cytokines. And the model that we're using in that case is oxazolone, atopic dermatitis model in the mouse. Following shortly thereafter, alcoholic hepatitis. Alcohol and acetaldehyde, in particular, have an obvious tie-in with hepatotoxicity. And so ethanol toxicity in the mouse is our model there as well. We've also taken a look at non-opiate analgesia. So RASP can activate TRPA1 and TRPV1 receptors. And so to study that, we're looking at the carrageenan inflammatory pain model. Finally, I'll talk a bit about lipogenesis modulation and the DIO mouse model, the diet-induced obesity mouse model, and the activity of RASP in terms of potentiating lipid synthesis. This is a model that we're particularly excited about in terms of obesity and the activity of RASP in obesity. So starting with atopic dermatitis, as we recently press-released, we have some exciting phase II data with our RASP-binding ADX-629 molecule. We have both investigator-assessed and patient-reported outcomes that were highly significant in this model. On the investigator-assessed side, we had Eczema Area and Severity Index, of course, and the Investigator Global Assessment. On the patient-reported side, we had the patient-reported itching score and Patient-Oriented Eczema Measures. Again, highly significant results in the clinic that sort of validate this atopic dermatitis indication feeding back into the mouse model. So what is this mouse model? This is oxazolone sensitization. This is a well-characterized preclinical model for atopic dermatitis. Oxazolone forms a hapten, which generates a T-cell response, a TH2-mediated T-cell response, which is exactly what is the causative effect in eczema and atopic dermatitis. So on day zero, we shave the backs of the mouse, and we sensitize with a 5% oxazolone solution that upregulates these T cells and causes the induction of the immune response in the mouse. On day four, we start treating orally with our molecule. On day seven, we challenge the animal by painting a little bit of this oxazolone with 3% solution of oxazolone on the ear of the animal. Then on day eight, we do histopathology, and that drives the outcome for this model. So what do these results look like? We looked at our signal molecule, ADX-629, which we had already shown was active in the clinic, and characterized that side by side with the two molecules I mentioned earlier, ADX-248 and ADX-246. All of them dosed orally in this model. Excuse me. So start with spleen to body weight ratio. You can clearly see a significant effect for ADX-629 and 246 in that particular outcome. Then we have the thickness of the epidermal layer. All three molecules highly significant in that outcome with ADX-248 in particular showing a very strong response. Epidermal erosion. Again, all three molecules showed some activity, but again, ADX-248 had a very strong response. And proliferation, epidermal hyperplasia. Again, ADX-248 had a very strong, significant response. But I think for all three of these molecules, this highlights a high degree of interchangeability for these molecules, ADX-629 already being shown to be active in the clinic. And this shows that our pharmacophore is broadly applicable across the full range of inflammation, again, leading to the sort of interchangeability of these RASP molecules and giving us a lot of flexibility in terms of which molecule we choose to advance for a given indication. So I'll move on to alcoholic hepatitis. Again, this model has been validated in the clinic with our signal-binding molecule, ADX-629. And of course, in alcoholic hepatitis, the causative agent is really acetaldehyde, a very basic RASP molecule. And we had three significant outcomes in that study. In terms of balance, we saw that we had some advantage against placebo with ADX-629. Flushing, we saw that ADX-629 radically diminished flushing that we saw the next day. And acetaldehyde levels, we were able to, of course, decrease acetaldehyde exposure with ADX-629. I'll tell you a little bit about the design of this study. So we really challenged these subjects with a very high bolus of ethanol. So we dosed the drug at 1:00 P.M. We dosed the drug at 6:00 P.M. Between about 8:00 P.M. and 10:00 P.M., we were feeding the subjects a very high dose of ethanol based on their body weight and based on the Widmark equation and so forth, with a target BAC for each subject of about 0.14, which is pretty intoxicated. The following day, we gave them a very early morning dose of drug and then, of course, further evaluated their flushing and various outcomes. So for balance, in terms of gross intoxication before there's a ton of acetaldehyde on board, you can see that we didn't really have an effect until the following day with ADX-629. And then with flushing, though, that effect really occurs the following day. And so we had a very marked response of ADX-629 versus placebo starting about 7:00 A.M., etc. So how does this translate to the mouse model? So with the mouse, we're giving an ethanol-plus-controlled diet for 10 days. So they have a steady, chronic exposure to ethanol. Then by day 10, we give them an ethanol bolus, so a very high dose of 31.5% ethanol. And then we conduct histopathology nine hours after that ethanol bolus. And they were treated on day 10 with drug. So to start with, does ADX-246 in this case, which is our model molecule that we decided to use in this particular study, are we able to decrease the aldehydes that are affecting this toxicity? So starting with, of course, acetaldehyde, the one we're all familiar with, we have a very significant decrease in acetaldehyde with both high and low dose ADX-246. The second measure I want to talk to you about or introduce in a little bit more depth is the antibody against malondialdehyde acetaldehyde adduct. So malondialdehyde and acetaldehyde are two different RASP that come together to form this hapten on the surface of proteins. The antibody response against that hapten has been shown by our colleagues at the University of Nebraska to really drive not only hepatotoxicity and liver disease as induced by ethanol, but also rheumatology and a variety of other outcomes. And we found that our RASP inhibitors were able to significantly decrease circulating antibody to this adduct. So what does the histopathology look like? On the far left, you have the control animals. And so you see a nice example of what an H&E stained liver slice looks like up top. That's what a healthy liver looks like. And then underneath that, you have Sirius Red staining. As you introduce ethanol in the middle two slides, you have those white circles. Like I said, I'm not sure I have a pointer here, but you have the white circles that you see pop up. That's lipid droplets. That's lipid deposition as seen with H&E staining. And then with the Sirius Red staining, you can see the fibrosis occurring very markedly on that liver slice. If you co-administer ADX-246 along with ethanol, you can readily see that the tissue pathology goes back to normal. The white circles, the lipid deposition is reversed, and there's far less fibrosis. We can quantify, of course, those images. And this is what the column plots look like after you quantify those images. So in terms of collagen, we have very significant and marked decrease in fibrosis. In terms of total lipid deposition, again, we significantly decrease that with both high-dose and low-dose ethanol or excuse me, ADX-246. And with triglycerides, we also have a significant decrease in triglyceride increase. So normally, when you dose ethanol into a human or an animal, you get a dramatic increase in triglycerides, and we're able to mitigate that. And that sort of feeds into some of our interest in lipogenesis that I'll go into it a bit later. We also improve liver function tests in these preclinical models. So both AST and ALT in liver and serum, we have significant decreases when we administer ADX-246 at either a high or low dose in terms of improving liver function tests. And then with TNF-alpha, which is one of the cytokines that we look at in our cytokine storm model with the LPS sepsis model that I described earlier in the funnel, we also measured that in this ethanol mouse study. We were able to significantly decrease TNF-alpha, which is normally increased by ethanol in both high- and low-dose ADX-246 treatments. So with that, I'll move on to non-opiate analgesia. This is a relatively new indication for us. We don't have clinical data underpinning this. But the carrageenan and paw pain model is very well established. So you take this molecule, carrageenan, inject it into the paw pad of a rat. And then there are three outcomes. There is the Von Frey test, the Hargreaves test, the ankle caliper. Von Frey is a mechanical pain tolerance outcome. So you take a wire, and you can measure the force that is required before an animal withdraws its paw. The Hargreaves is thermal pain tolerance. So you can take a heat source and show how much time it takes for an animal to withdraw its paw as it is exposed to a heat source. And then there's just swelling. You can take a caliper and measure the diameter of the ankle. How the model works, you treat the animal 30 minutes before introducing this carrageenan in an injection. You administer the carrageenan. And then over the course of four hours, you assess these outcomes. And the results are in area under the curve or AUC. So in all three of those models, we're comparing against diclofenac or Voltaren that some of you may be familiar with, which is a very potent NSAID. And in all cases, at least in terms of mechanical pain tolerance and thermal pain tolerance, ADX-246 actually outperformed Voltaren or diclofenac in these models. In the case of swelling, it was equivalent to Voltaren. All right. Lipogenesis modulation is another new indication that we're quite excited about. And as I mentioned, we were able to decrease lipogenesis in the ethanol models. We also serendipitously observed that we were decreasing triglycerides and improving lipid profiles in healthy volunteers in a variety of our different trials. So these aren't patients that have acute atherogenesis or atherosclerosis or anything like that. These are either normal, healthy volunteers in terms of our phase I trial, or they're psoriasis patients or something like that, right? So in our phase I trial, we increased HDL. We improved our LDL/HDL ratio, and we decreased free fatty acids. In our phase II psoriasis trial, we decreased cholesterol. We increased HDL. We lowered LDL. And we also markedly decreased triglycerides, which really started to pique our interest because, as some of you may be familiar, fibrates and a few other molecules are able to decrease triglycerides. But it's really been a relatively difficult thing to lower successfully. In our phase I/II ethanol toxicity trial, we also noticed that we were able to decrease LDL. I also want to point out that this is after a high-fat meal, particularly in the phase I clinical trial as well as the ethanol toxicity trial. We gave these subjects a high-fat meal with a high dose of sucrose. So these aren't fasted subjects. These are patients that have just been challenged with this high-fat meal, and yet we were still able to improve this lipid profile. So this was completely serendipitous. But it does make sense when we think deeply about what do RASP do? How do RASP interact with lipogenesis? And why would a RASP inhibitor decrease lipid levels? Any aldehyde, whether it be something like acetaldehyde or malondialdehyde, as many of you are aware, are changed into acetates by aldehyde dehydrogenases. These acetates go straight to coenzyme A and go into lipogenesis cycle. So the fatty acid synthase and triglyceride acyltransferase readily change the products of these aldehydes into triacylglycerol. So what does the high-fat diet-induced obesity model look like in the mouse? So we acclimate the animals for six days. This was done in collaboration with a collaborator. Fat mass assessment is characterized at B minus 2. Daily body weight is assessed. And then we treated either control vehicle control ADX-629, a GLP-1 agonist, or ADX-629 in combination GLP-1 agonist. Then on day 22, we do a fat mass assessment. And we were really surprised by the results. We have this mild decrease in body weight to the tune of about 5% with ADX-629 alone. With the GLP-1 agonist, as you would expect, that number can be between 5%-10% or more. And then when we combined the GLP-1 agonist plus ADX-629, we actually had an additive synergistic effect. And that also translated to fat mass loss. So we had a very significant effect in terms of, of course, the GLP-1 agonist by itself as a single agent. But that was increased significantly with a combination of 629 and GLP-1. So that's it. Any questions? Thank you, Adam. What we thought we would do is have a RASP free-for-all here. I feel a little bit like we're sitting in front of getting interrogated by the police with these bright lights and sort of a stark table. But here we are. Now is your chance to ask questions about RASP as a target, about our activity in RASP, maybe a little bit about our plans. So we hope to expand our pipeline. We see Tom is already raising his hand. So Tom, go ahead. I would say that the GLP-1 synergy isn't odd, right? We're seeing the same thing with NLRP agonists. So if you block information, you drive those drugs. Not out there. It kind of makes sense. Two questions. Your NSAID comparison study, are they additive also? You didn't have the combination one. Yeah. We haven't looked at that yet. You follow TNF-alpha. You talked about it in one model. Is it a good marker everywhere? At some level, they're all inflammatory? I think that does vary. So the question is, does TNF-alpha a good marker across all of our models, or is it that model in particular? I think there are some differences between models depending on the mechanism of pathology in that particular model with whatever the induction is for that model, whether or not TNF-alpha will be a prominent one. That said, I think TNF-alpha is a common signal molecule for inflammation in general. I have a question on TNF-alpha. I'm just wondering about sort of the real-world case of coenzymes. Is there any indication? So we actually have. So I think the question let me make sure I have the question correct. What does the real-world indication look like for the ethanol toxicity model in terms of administering this drug? So we actually have a phase II, a signal finding study ongoing as we speak in alcoholic hepatitis. These patients are very, very sick. They present with acute hepatitis. They have a certain MELD score in terms of how well their liver is functioning. It's actually a completely unmet need. There's really no treatment at this time whatsoever. We do use steroids to some extent, but steroids are relatively ineffective. Unfortunately, the outcome is mortality. So the actual outcome, and that's the study, is mortality in many of these patients. So that's, I think, the short answer. These patients are coming in with acute hepatitis. They're really no longer drinking. Too sick to continue drinking and can decrease the inflammation, block that immune response. I think the antibody effect is one of the things that are driving our interest in that model, that these antibodies are part of what continues to impact the hepatotoxicity in that disease. If we can stop that immune response, then maybe we can save these patients. Catherine, I would say I am always amazed at how, as a medical community, we're so fixated on NASH or now MASH. But we ignore ASH. And I think most people with these metabolic diseases consume alcohol. Many of us consume too much alcohol. And yet, there is no approved drug to treat liver disease that is due to alcohol consumption. And Adam described our current trial with ADX-629, and I'll talk about that at the end of today's presentation, where there's a 90-day treatment cycle for really severe patients with alcoholic hepatitis and the outcome is mortality. But one of the things, based on the pending data from this trial, we're interested in discussing with the FDA is, is there an earlier stage trial we can? Why are we waiting for patients to die? Why instead can't we treat patients with an earlier stage of hepatic inflammation due to alcohol consumption? I do want to emphasize something that Adam said. We're not developing drugs to help people drink more. We ran that trial in order to demonstrate that, A, we can modulate levels of acetaldehyde. And, B, modulation of acetaldehyde influences the signs or the classic signs of alcohol toxicity, in this case, balance and redness or flushing. So I think the evolution of our alcoholic hepatitis program is really going to depend on the data from the ongoing trial, but also our discussions with the FDA in focusing on milder patients that aren't yet ready to die but are suffering from alcoholic hepatitis. Hi, Frank. I assume you would discuss different MELD score levels for severity of the patients. But how do you handle enrollment of a trial exam if they are more mild? And how does the patient present? Do they even present to the hospital when they have mild or is it just moderate to severe? Because I just know between the patient presenting to the hospital with almost 30% mortality rate so fast, how do you it's hard enough to enroll moderate to severe. How do you think enrolling mildly? The question is, who do you enroll if we are targeting mild to moderate patients with alcoholic hepatitis? How do we find those patients? I would argue that finding those patients is similar to finding NASH patients. Those patients don't often report to the hospital. These are patients that are followed by their internists. They probably have a hepatology consult somewhere because their liver function tests are elevated, abnormal. They have a reported history of drinking more than they should, which for males is 2 drinks a day and 1 drink a day and in females. So I'll note there is no safe dose of alcohol. I would assume, Frank, that that's the kind of trial we'll run. We would look to our colleagues who are trialing NASH and ASH in that regard. More to come as we work through that and evaluate the data for the ADX-629 trial. Do people understand if it's binge drinking versus chronic hepatitis? Do people know where it comes from? The question is, does alcoholic hepatitis derive from binge drinking or chronic drinking? I think it's probably a combination of both. I would assume that most chronic drinkers also have binges. Obviously, binging is very damaging. But I would assume over time that damage from acetaldehyde is a chronic accumulation toxicity. As I mentioned, the aging paper that we discussed at the very beginning, that's probably the same phenomenon happening with alcoholic hepatitis. Yale. Is it part of the story and what do you think of it? Part of our obesity strategy relating to your question is, what is the plan for obesity? Part of our obesity strategy is to speak with the partners. And obviously, there are many large companies interested in obesity these days. And so that is the process, I would say, at this point, Yale. However, obesity trials and/or dyslipidemia trials, hypertriglyceridemics, folks with hypercholesterolemia, aren't terribly difficult to run. We're a well-capitalized company. And our expectation is, independent of any sort of partnering effort, we're prepared to initiate clinical trials on our own in that space. We haven't made that commitment yet. But stay tuned in the near future as we think about how we might advance something in metabolic disease. So the slides you just showed that, when you speak, the activity was less potential. How could it attract additional investment or other way to participate? The question is the activity of ADX-629 alone versus the activity of ADX-629 plus GLP-1 agonists and compared to GLP-1 agonists alone. I was involved as an investor in what I would say the first wave of obesity drug development. Those drugs that were ultimately approved reduced weight, I would argue, in the 5%-10% range, which is sort of what we're seeing with ADX-629, at least in animals. What has been an amazing advance is GLP-1 agonists, which essentially inhibit appetite, and patients eat less. As a result of eating less, however, patients lose both fat and lean mass, which is a problem. We have not by accident entitled our approach, lipogenesis modulation. Our idea is to target fat directly. As Adam showed, there is a good biochemical basis to believe that RASP potentiate fat, RASP make fat, or at least induce the synthesis of fat. So if we can modulate RASP, we might have a fat-targeted approach that makes sense in conjunction with GLP-1 agonists. I can tell you that most large companies, obviously, that have the GLP-1 programs are looking for ways to reduce GLP-1 dosing, to reduce the frequency of dosing, and enhance fat mass loss relative to lean mass loss. So I think activities such as the ones we're pursuing at Aldeyra could be of great strategic importance. On the slide, you see a notable impact. I'm curious about in humans our issues with flushing and aging skin. Is that something that you would want to look at? That's such a great question, Catherine. Your question is about ALDH polymorphisms that are particularly prominent in Asian populations such that individuals aren't readily able to metabolize acetaldehyde. What's interesting is that ethanol itself, in doses that we're exposed to after drinking, isn't that toxic. It's the acetaldehyde that's toxic. That's what makes you flush. That's what makes you nauseous. That's what gives you cancer. And there are certain populations, due to these polymorphisms that you referenced, that just simply aren't as capable of metabolizing acetaldehyde. The result of that, acutely at least, is flushing. We did not test those populations in our trial. In fact, we specifically excluded those populations from our trial because we didn't want to confound drug activity with differences in polymorphisms. But your idea is a really good one. That is, maybe one day, there's a clinical trial to be run just in ALDH polymorphisms in those populations, which I think may benefit from that approach. However, as I said earlier, our idea isn't to our goal isn't to help people drink more or flush less. It is to prevent the long-term chronic complications of alcoholic hepatitis, which are ultimately much more severe, of course. Thank you. Thanks so much, Heather. It seems like 248 showed bad efficacy. Maybe just remind us, how do people write molecules? What's your development plan? If you want to repeat it. Yeah. So the question was, ADX-248 looked like it had the strongest activity in atopic dermatitis. So how are we picking the best molecule? And so I would say I would like to emphasize that even though ADX-629 looked like it had less of an effect relative to ADX-248, ADX-629 performed rather strongly in the clinic. So I think, to some extent, that model demonstrates that our pharmacophore is quite active across all three of those molecules in that we have a high degree of interchangeability. That said, your question is really quite a good one. How are we picking the best molecule to move forward? And I think it's a mix of different things, ranging not just from one particular model but across a suite of models. How well does the molecule perform? Do we think it's the best molecule for an oral systemic administration? The cost of goods sold, just the entire sort of suite of questions that go into druggability of the molecule and the best molecule to move forward. So I think the short answer to your question is that there's no one model that we're going to focus on to pick our molecule for that indication. Across the whole suite of different models, and it becomes toxicology, pharmacology, etc. So Adam, there really is no difference between, statistically, molecules that we've seen. And you mentioned the pharmacophore relative to the backbone. We're thinking about structure-activity relationship or SAR. Maybe you could talk about the similarity across pharmacophores relative to backbones and how we think about those two things in our selection. So we understand our structure-activity relationship very well for this pharmacophore. So as I mentioned, ADX-246 is sort of our most juiced up, hottest molecule in terms of rapid binding and an extent of binding to RASP in vitro. ADX-248 is intermediate. And ADX-629 is a lower side. In addition to that, though, the backbone have different levels of hydrophobic index, different degrees of permeability, and slightly different characteristics as far as tissue distribution. So for atopic dermatitis, we want to make sure that we have the molecule that's going to have the best tissue distribution, best bioavailability, and the right mix of rapid binding to RASP versus sort of half-life and pharmacokinetic profile. And we do have the luxury of interchangeability, as you said, Adam, across molecules. You don't often see that. But because of our identification of certain pharmacophores, our characterization in vitro and in vivo, I do think we're able to switch back and forth as needed. Just to emphasize something that Adam said, as a clinical trialist, I'm particularly interested not only in activity but also PK. Adam mentioned ADX-246. We've said for some years now that 246 is our most active RASP molecule. And it's also one that's been optimized for PK. So the backbone is such that it could allow a once-a-day administration. We'll know more when our phase I completes, which is about to begin imminently for 246. Those are the kinds of things we're thinking about when we think about indication and field selection. Hey, Yigal. Yigal's question is, when we're speaking of pain, are we talking about acute pain? Are we talking about chronic inflammatory pain? Are we talking about neuropathic pain, which are sort of the chocolate, vanilla, and strawberry of pains? That is a great question. In fact, we were just on the phone last week or so with one of the leading KOLs in pain. That's the same question that he asked. Just a bit of history, and I'll allow Adam to comment further. A long time ago, and this is on our website, we tested reproxalap in inflammatory pain, in fact, the same model, carrageenan injection. The reason we did that was not so much for pain. It was for inflammation, to modulate inflammation. Well, it turned out that in dry eye disease, pain is important, right? Ocular discomfort is another way of saying ocular pain. And so we're interested in characterizing why reproxalap reduces ocular discomfort. By what mechanisms? And we've talked about the TRP receptors as a very RASP-sensitive series of receptors. That if you can pull RASP off those TRP receptors, we see all kinds of, in theory, positive effects. Well, Adam's idea was then to test 246 in the same model. Maybe you could hypothesize a little bit, Adam, about where we might go next, understanding that we haven't exactly decided. Yeah. Yeah. We haven't exactly decided that yet. We're obviously an inflammation company. And so I think our first reflex or instinct might be to think about inflammation-based pain. That said, there are a suite of different models that we can consider to drill down on where we're seeing the best effect in acute versus inflammation, chronic versus neuropathic pain. We do have some molecules that have better blood-brain barrier penetration, CNS penetration, for example, than others. So we could sort of drill down on, A, which category we work best in and which molecules work best for indications within that category. One thing that I'm particularly excited about, Yigal, is chronic inflammatory pain. The classic indication for that in humans is osteoarthritis. As those of us that are getting older all know, our joints ache. It's a chronic condition. Today, we have NSAIDs. NSAIDs can be toxic, kidney dysfunction, ulceration, GI tract. There just is a huge need for non-opioid chronic pain medications. And so one of the beauties of NSAIDs is, not only do they treat pain, but they also treat inflammation. And the argument we would make, at least at this point with the RASP platform, is we have both of those activities too. RASP are associated with pain, and they're clearly associated with inflammation. So there is our one-two punch. But again, stay tuned as to what we might think about down the road in terms of. Anything else? Yigal. Should we assume, on the pain side, that RASP—well, I think that what we've shown with reproxalap, at least topically applied to the eye, that if we're able to bind RASP, which is presumably what reproxalap is doing, we can very acutely modulate symptoms, including discomfort. So in dry eye, the symptoms have been dryness, burning, stinging, grittiness, and discomfort. And we've even measured pain in the past. And all of those seem to go the same direction. Presumably, that's because reproxalap is binding RASP, is pulling RASP off of the TRP receptors, and patients feel better acutely. I just want to say, there is an equilibrium between free RASP that is RASP just floating around and bound RASP. So what RASP modulators do is they bind free RASP. But because there's this equilibrium there, if you lower the free compartment, more bound RASP has to come off into the free. And so thereby, you're modulating protein structure function acutely. I'm not sure that acute pain is the best of markets. I think a better market might be chronic pain. I think we're generally pretty good at treating pain acutely, even with opioids or narcotics. Obviously, that approach couldn't be used for chronic pain. Therefore, I think the market we would focus on, for the reasons that I mentioned in response to Yigal's question, is more chronic inflammatory pain such as osteo.