Welcome everyone to H.C. Wainwright's Fifth Annual Ophthalmology Conference. My name is Matthew Caulfield, and I'm a Senior Biotech Analyst here at H.C. Wainwright. We are grateful to welcome Dr. Todd Brady, President and CEO of Aldeyra Therapeutics. Thank you very much, Todd, for joining us this morning. My pleasure. Nice to see you as always. Thanks for having us. Absolutely. To start things off, Todd, maybe you could give us kind of a high-level view of Aldeyra's pipeline, the focus on RASP modulation across the different relevant indications. Yeah, I like to tell people we're an immunology company starting in the eye. This ophthalmology company, this conference is apropos to our very beginnings. You know, initially we started as a retina company and then moved to the front of the eye. Now, as we'll talk about, I think towards the end of this fireside chat, we're moving back towards the retina again. Ophthalmology is great. It's an interesting area in that vision is critically important to people. People really want to see, in fact, of the quality of life measures, vision is right up there at the top. Whether it's the front of the eye or the back of the eye, therapeutics that improve vision are important, and we're pleased to be part of the community. Mm-hmm. Very exciting to hear. A main focus for investors has been the lead topical eye drop candidate, reproxalap, for the treatment of the signs and symptoms of dry eye disease. We recently learned the PDUFA date is set for December 16th of this year. What has the NDA resubmission acceptance meant for the platform? I know that was kind of a process of getting that package accepted by the agency. Reproxalap is our lead RASP modulator. You mentioned RASP in your first question. RASP is really the platform upon which the company was founded. It's a really unique pharmacologic approach. You know, most drugs target proteins. RASP modulators target RASP, which are small molecules, reactive aldehyde species, that modulate a whole system of proteins. In effect, with a RASP modulator, you have a drug that modulates many, many different proteins, even systems of proteins at once. Reproxalap is the vanguard of that approach. Dry eye disease, front of the eye disease, is something that we're interested in with Reproxalap. We've submitted an NDA back in 2022, resubmitted the NDA about a year later, and then our last resubmission earlier this year, we hope will be the one that brings the drug across the goal line, from the FDA's perspective. The last issue, at least that the FDA raised, was that they wanted to see one more symptom trial. Mm-hmm. Dry eye disease is assessed in terms of symptoms and signs. Symptoms is how the patient feels. Signs are what investigators can observe. An example is redness, which is what we're using as our sign. We had a symptom trial that we resubmitted last year. The FDA identified a baseline imbalance. We reran the trial in parallel, really, with that submission. There was no baseline imbalance. That's why I say, third time should be a charm, in this case. No, that's excellent, to see that progress. Maybe taking a step back for a moment to consider the dry eye disease indication. There are several topical therapies that are available and many over-the-counter options. What do you think are the greatest limitations that still exist from a standard of care perspective in dry eye? The first thing I'd say is that dry eye will affect all of us at some point. As we are getting older, our eyes are drying out. Unfortunately, we're all using more screens. We're zooming. We're looking at our phones constantly. My children seem to have a phone 1 ft from their face for most of their waking hours. What that's going to generate societally is more dry eye disease. It's a problem that we're going to have to deal with in growing proportions. Unfortunately, on the scripted side of dry eye disease, there are only a few approaches. We could always use more. There are no approaches that seem to work quickly. By quickly, I mean within minutes. Our whole clinical trial paradigm has been to demonstrate, particularly in dry eye chambers, which are small torture chambers where people have hot air blown in their face without humidity, is to really show that the drug has activity within minutes. That's what matters to people. No one wants to wait weeks. No one wants to wait months. Therein lies the big hole in the dry eye market. A lot of patients use artificial tears, over-the-counter options. The challenge there is they just simply don't last very long. Moderate to severe patients are driven to optometrists or ophthalmologists for the next step of therapy. We've had drugs like RESTASIS. I think we have three kinds of RESTASIS now. Cyclosporine is the active ingredient. For many years, RESTASIS makes you cry. We have a nasal spray that makes you cry. I think we're good at making people cry. Unfortunately, that's not the whole solution here for dry eye. You need better tears. You need less redness. You need patience to feel better. Ultimately, that's been our approach. As I mentioned earlier, on our label, we will have, "Do you feel better?" And we will have, "Do your eyes look better?" in terms of symptoms and redness. I think that's a really differentiating characteristic in the market. There is no dry eye disease drug that has both redness and symptoms on the label that's for chronic use. You can use steroids for a couple of weeks. Sure. Redness gets better. For chronic use, we are the only drug in development that I'm aware of that highlights redness and symptoms. I agree. I think that's very differentiated. What more can you tell us about the reactive aldehyde species modulation itself and how that plays into sort of the dry eye mechanism of what's happening in the end? RASP is not true. It's a great question because, you know, dry eye disease is this, it's really an immunological disease and it's multifactorial. There are a lot of different issues going on. When you dry out tissue, you create inflammation. It doesn't matter where that tissue is, and your eye is no exception. RASP are really the bad actors of inflammation. They lead to increased redness. They lead to pain. They probably diminish tear production. All sorts of issues that you have when you dry out your cornea or your front of the eye. By binding RASP, by sequestering RASP, these RASP modulators really nip inflammation at the bud in so many words for dry eye patients. I think that's important because it's not just making more tears. It's not just making you, you cry. It's really a sort of a one-stop shop in a sense in terms of how you look and how you feel. Excellent. That's very helpful. One piece of reproxalap development has been the ongoing option agreement with AbbVie. I wanted to make sure we covered that. That's related to the possible development and commercialization of reproxalap in the U.S. market. Option execution could occur potentially before approval, or the agreement is set to expire 10 days following prospective approval. What are the most important considerations for this possible option execution? Right. As you mentioned, and it has been publicly disclosed for some time now, AbbVie has an option on reproxalap, not just for dry eye disease, but also for allergic conjunctivitis, which I think we'll touch on later in this call. We believe we've completed the pivotal trials necessary for an NDA submission in allergic conjunctivitis, which is a comorbid disease with dry eye, by the way. AbbVie would have an option on all of that. As you mentioned, that option expires 10 days after approval. They can exercise anytime. I would think it's safe to say that AbbVie knows what it's doing in the dry eye space. They were the ones behind RESTASIS, the first dry eye drug. Honestly, for years, they controlled the dry eye space because there were no other options. For years after that, there was only one other option. I feel like AbbVie, if you're going to have a partner in dry eye, AbbVie is the partner to have. I also think they're the only big pharma left in the front of the eye. Mm-hmm. In a sense, we're very privileged to be working with AbbVie. I can't predict what AbbVie will do in terms of exercise or not exercise. I can tell you that AbbVie and Aldeyra have been working very closely together, as is specified by the terms of the option agreement, both on a clinical regulatory front, but also on a commercial front. We announced an option extension at the end of last year, where we're both spending money on commercial activities together. As you'd expect, before you launch a drug, there are lots of things that need to be done. Sure. Those are the sorts of things that I think we can assume that either Aldeyra or AbbVie are doing. No, I think, I mean, at least from our side, we've long advocated for the, you know, generic risk for RESTASIS as well, being part of, you know, part of this equation of timing, of maybe this is a good strategic move, you know, to branch out to a new mechanism. Also from a data standpoint, we most recently had the positive phase 3 dry eye chamber trial that you mentioned, statistically superior primary endpoint ocular discomfort benefit on reproxalap from 80 minutes- 100 minutes after the chamber entry. Can you speak further to the nuance of measuring benefit in minutes? I mean, it's kind of hard to underemphasize how standard of care can really take upwards of months potentially for people to really get, you know, the full benefit. Right. If you download the FDA guidance for dry eye disease drug development, I think what you'll find is that there's two ways that the drugs can get approved, right? One is a field trial where patients go home, they take the drug, they fill out a diary, and all that kind of information is collated at the end. You know, the drug either works or it doesn't. The other way of doing it is in the chamber, which I described earlier. It's really just a small room. There's hot dry air blown into the faces of these patients. There's forced visual tasking. The idea behind the chamber is really to simulate a flare. I would say with any chronically disturbing disease, what we're concerned about are flares. We're concerned about bad days, not good days. The good days, whatever, but the bad days, and those are flares. Those are disease, those are disease flares or exacerbations where you don't feel good, your eyes are red, what have you. That's what the chamber simulates. In a sense, the chamber really is an attempt to measure a drug's activity during the worst phases of the disease and possibly the most important aspects of the disease. Again, we're not really concerned with good days. Mm-hmm. The chambers are about 100 minutes long, 90 minutes long. We're able to measure over time in the chamber how well the drug does, essentially within minutes. That's a paradigm shift. There are no drugs out there today with chamber data in their label. I think the reason for that could be that there are no drugs that work sufficiently fast to test in a chamber. If your drug doesn't work in minutes, you're not going to have activity in chambers. You might have it in field trials. In field trials, you can show activity in weeks and maybe over days. Patients don't care about days or weeks or months. They care about minutes. They want to feel better immediately. That's where we're going with the chamber. No, I think that's excellent. How critical is the signs and symptoms in treating dry eye? I mean, I guess conceivably you could have therapies that address one more than the other or one in exclusion of the other. How critical would be a hypothetical label that incorporates both? You can go to the labels, in dry eye disease. You can look at RESTASIS, for example. Sure. Look at CEQUA. There's another cyclosporine out there now. You can look at the labels and you can see what the labels say in the clinical section. Often what those labels will talk about, Tyrvaya is another example, the nasal spray. Mm-hmm. What the labels will talk about is Schirmer test. What is Schirmer test? Schirmer test is a strip of paper that you put in your eye, and you measure the wicking of tears. That's sort of an indication of how much tear volume you have in your eye. Mm-hmm. If you have more patients with 10 mm of that wicking in the drug group than you do in the vehicle group, then that's considered a Schirmer responder and you can get approved just for that score in itself. Now, I know no patients that wake up in the morning and think, "I wonder if I am a Schirmer responder. I wonder what my Schirmer test is. Is it greater than 10 mm or not? How's my tear volume?" No one wakes up thinking that. They wake up thinking my eye hurts. It's just, it's uncomfortable. It's gritty. My eye is red. There are all sorts of issues that people worry about, but Schirmer test really isn't one of them. Yet, that is the predominant clinical aspect on labels today. There are really no symptom data. I don't see any symptom data on the RESTASIS label. I don't see any symptom data on the CEQUA label. I don't see any symptom data on the other cyclosporine label. The idea really is here we have a drug, reproxalap, with the potential to have, how do you feel? That's discomfort. And how do you look, which is redness? Oh, that's great. In terms of the relevance of the dry eye chamber analysis, can you comment on this reflecting an unambiguous symptom standpoint compared to the variability of subcategories that could measure dryness, stinging, grittiness, which are obviously much more subjective? The FDA's comment on that, Matt, is that they don't distinguish between symptoms, right? What one patient calls a dryness may be what another patient calls discomfort. Right. Grittiness or burning or stinging or what have you. The FDA's perspective, at least as has been relayed to us, is that if you show statistical significance in a chamber for any symptom that's classically recognized in dry eye, then that merits a positive trial. That's what we've done with dryness in the case of the field trials, and that's what we've done with discomfort in the case of the chamber trial. We will also be the only drug, if approved, with two different symptoms on the label. There are drugs with symptoms on the label, but they're the same symptoms. Now we would have two different symptoms, two different kinds of trials, field trials and chamber trials. As I said, the only chronically administered drug for redness. Understood. Kind of returning to the former CRL from the FDA, the agency took issue with the potential baseline difference across treatment arms in the previous dry eye chamber trial. How was that specifically addressed for the resubmission to kind of give, you know, folks a little kind of reassurance or confidence that, you know, like you said, three could be the charm. The first CRL was one another symptom trial. Mm-hmm. We provided a symptom trial from a dry eye chamber, based on a long back and forth with the FDA. The message was, congrats, looks good except there's a baseline imbalance. Mm-hmm. As I mentioned in my preliminary comments, we repeated that chamber trial, which fortunately we're able to do quickly. Chambers are in minutes, so you don't need to spend months running trials. There was no baseline imbalance, and we got the same kind of statistical significance. I think in the first trial, we had a 0.004 p-value. In the second trial, a 0.002 p-value, if I remember correctly. Mm-hmm. The same sort of effect size of drug versus vehicle. Regardless of the baseline, which by the way is controlled for statistically anyway, the drug seems to have this acute activity, which I think ultimately will be market defining. No, absolutely. I mean, as we get a little bit closer to time, I wanted to make sure to highlight that the RASP platform and pipeline far exceed just the reproxalap development. Maybe we could talk a little bit about ADX-2191, which has the single trial for approval in ocular lymphoma as well as retinitis pigmentosa development. Yeah, happy to talk more about RASP. 2191 is an intravitreal methotrexate. We bought a company five or six years ago now called Helio, that had an intravitreal formulation of methotrexate. The idea there was to test it in diseases where methotrexate is used in a compounded version, a standard of care. One of those, as you mentioned, is ocular lymphoma or primary vitreoretinal lymphoma is what it's called. We submitted a literature-based NDA, with the backing of the FDA some time ago. The FDA came back and said, "We read the literature, but what we really want to see is a trial." There are no adequate well-controlled trials, which is understandable. I mean, there are probably 500 - 600 patients in the U.S. that get ocular lymphoma each year, yet there is no therapy. There is a median survival of less than five years. Mm-hmm. I don't think there's a bunch of groups out there itching to run placebo-controlled trials, which you can't do. We went back to the FDA. We got a special protocol agreement, which we announced some time ago, for a single trial to approval. What that means is if the trial that we've agreed upon with the FDA works, that could form the basis of an NDA submission in combination with the other literature or NDAs around methotrexate. Methotrexate's been approved since the 1950s, I believe. Yeah. In lymphoma, we'll submit the old NDA from the 1950s with methotrexate lymphoma, which by the way, Matt, is two pages long. We will submit that along with our many hundreds and hundreds of pages around the new trial, assuming the trial works. The idea is that this would be the first drug for ocular lymphoma. I think that's great. There's also pivotal trial development possibly starting later this year in retinitis pigmentosa for 2191. Maybe you could speak a bit to that opportunity. RP is a large disease, but it's not fatal, that I'm aware. I mean, instead of lymphoma, which ultimately takes your life, this disease takes your vision. Yeah. There is probably, I don't know, with the mutations that are relevant to methotrexate therapy, there's probably 80,000 patients or so. The idea there is that methotrexate, at least in a trial that we've run in an open-label trial, has shown activity in reducing, or at least I should say, improving visual sensitivity versus baseline. Retinitis pigmentosa is about your rods, your peripheral vision in your retina, what you can see at night. We're looking at each other, we're focusing, we're using our fovea, which is central retina. That's color vision, it's fine vision. Rods are not fine vision and they're not color. That's what you lose, though, first in retinitis pigmentosa. You have night blindness and you have patchy vision and ultimately, you lose your vision. Except for one very minor mutation, there are no drugs approved for retinitis pigmentosa. We're pleased with the data we've shown, at least in an open-label setting with ADX-2191 in a clinical trial. This data is on our corporate deck, just like all our dry eye data. The idea is to start a pivotal trial later this year, early next year, treat patients for about a year and show that, relative to sham injections, we can improve the course of the disease. I think that'd be great. Can you also discuss ADX-246 and the possible relevance in dry AMD or geographic atrophy? Right. Back to RASP. Yeah. ADX-246 is a, I would say, sort of a third cousin of reproxalap, if you will, related chemically, same idea, sequestration of RASP. In dry AMD, which is another disease, by the way, we will all get. It's sort of like males, we'll all get prostate cancer if you live long enough. We will all get dry eye disease, and we'll probably, if we live long enough, all get dry AMD, age-related macular degeneration. We, as an industry, are focused on the wet form of that disease. That means, you know, sort of there's a vascular influence there. Dry AMD is accumulation of drusen in your retina. Drusen are metabolites that aren't taken care of by your retina otherwise. They accumulate. You lose vision. What you lose first, like with retinitis pigmentosa, is your peripheral vision, night vision, difficulty seeing at night. Vitamin A is a form of RASP, retinaldehyde, which would be sequestered by 246. When vitamin A escapes the light cycle, we need some vitamin A to see, but when it escapes the light cycle, it leads to the formation of these sort of indigestible aggregates that form lipofuscin, that form drusen. The idea is that we can trap those metabolites before they form these accumulations or lead to these accumulations in the retina. I think the other thing that's interesting about retinaldehyde is if you're able to, at least in animal models, sequester those retinaldehyde metabolites, you can actually improve dark-adapted vision on a short-term basis. That'll be something obviously we're looking out for in clinical trials. If you ask patients what they hate the most in the beginning parts of the disease, they can't see at night. They trip over their dog when they go to the bathroom or, you know, they can't find their slippers in the morning or what have you. Low light vision is what goes first. That's something that we'd obviously love to treat or improve. I think the drugs we have today are about lesions in a form of dry AMD called geographic atrophy. Right. Patients don't wake up thinking, "I wonder how my lesions are." They wake up thinking, "I can't see as well." That is something we're going to hopefully directly address in our clinical trials. Great. Very helpful. Just lastly, as we get closer to time here, when we think about the overall Aldeyra platform and a novel topical dry eye therapy potentially on the verge of FDA approval this year, what can investors be missing about the platform or underappreciating? The two most common questions I get about our platform are about atopic dermatitis, not in eye disease, Matt, but also dry AMD. Those are two untapped markets. Atopic dermatitis is all about there's no oral, that orally administered drug that people use, particularly for the mild to moderate forms of disease. It's very similar to dry AMD, right? We as a community are focused on treating severe diseases, maybe because it's easier to see a drug effect. I don't know. We really don't have anything for mild to moderate dry AMD. We're good at focusing on geographic atrophy or what have you in the later stages of the disease. I think something about RASP that's interesting and really our whole pipeline is that we're able to focus more on the mild to moderate forms of the diseases. That's what most people have. That's what we all have and how we all start. We don't start with severe disease usually, unless we're born with some genetic disease. This is where I think the field of medicine needs to go. On top of that, you have a RASP modulation platform. This is a way of affecting many proteins at once. You know, when we have grandchildren, Matt, we're not going to be having one pill for one thing. We're going to have one pill for a lot of things. That is sort of the direction that RASP takes us. Oh, that's very exciting. I'd like to thank Todd Brady and Aldeyra Therapeutics. You know, a great conversation as always, and obviously a very exciting platform to see the future of RASP modulation. Thank you, everyone. Thank you. Thank you, Todd.