Aldeyra Therapeutics, Inc. (ALDX) Earnings Call Transcript & Summary

Welcome, everybody. 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'd rather like these days, really gives investors and analysts a chance to glance into the future, 2 to 5 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 2 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. And our keynote speaker is Dr. Ramiro Maldonado from Duke, who is a principal investigator of our Phase II retinitis pigmentosa trial of ADX-2191 and he'll be talking about that later. And 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 operation. She also held 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 nonprotein directed drugs available today. RASP are promiscuous. They are 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 more RASP-sensitive. So RASP bind 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. And 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 live your life on or off, you had only 2 speeds in your car, 0 or as fast as it would go or 2 speed -- 2 volumes in your headphone, 0 or as loud as it would go or 2 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. We're turning proteins on. We're 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 3 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 3 of those trials. I think what's interesting is 2 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 they 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. And based on previous chamber trials, in fact, the data here are from 4 previous chamber trials. We believe the next trial is likely to work. So these data are from clinical trials run at fixed dry eye chamber. That is chambers in buildings. There are some mobile chambers, but we're focusing on fixed chambers and buildings, 110 patients were tested in those chambers. There is 1 chamber in the United States. There is 1 chamber in Canada. There may be other chambers in the world, but we're not aware of where they are. So the 2 upcoming chamber trials, 1 will be in the United States and 1 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 article is 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 effective 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 we have 2 models of symptoms, a chronic and an acute model, but also 2 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 in reducing redness. Our 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. Frank.

Right. The question is we're running 2 chamber trials, 1 in the U.S., 1 in Canada. Is there any difference between the 2 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. Hey, Matt. 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 results that I just presented regarding the 3 trials, the 2 chamber trials, the field trial, obviously, was derived in conjunction with AbbVie. And AbbVie is a dry eye leader, RESTASIS, which was their drug, now generic was the first dry eye drug, so obviously, they know what they're doing. Yigal, I think you had a question. The question is about of the 3 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 6 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's last visit? The seasonality is really important during field trials. So if you're testing patients over 12 weeks, or in our case, 6 weeks, the last thing you want is for a patient to start an 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 they're -- 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 symptom 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're going to -- we plan to resubmit this NDA in 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?

The conduct of the trial, patients show up. And what fraction get in for the trial, going through some exclusion criteria? And then you have a first round where you compare a vehicle against vehicle. They don't get worse. They'll get into the trial. What's the cost there? Kind of curious how good your population is going to [ fail ]?

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 4 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 2 different time points. I think they have to have a score of 15. So this is a 0 to 100 scale, 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, that work. Hey, Yigal. 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 trial at all is -- 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 and in our case, backup plan to this backup plan. 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 determined that there are 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 now cytokine assay, we go in an in vitro drug ability characterization. And so that's really ensuring that the drug-ability 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. And 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 -- to 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-finding molecule. And 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, for the models and the mouse that I'm going to show you. And we can really highlight how we've taken that -- 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 are going to talk about ADX-246, probably our most active, our sort of hottest RASP trap and maybe our most hydrophilic. And then 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 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 and 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 signal finding ADX-629 molecule. And 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. And 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 prior -- 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 0, we shaved the backs of the mouse, and we sensitized with a 5% oxazolone solution. That upregulates these T cells and causes the induction of the immune response in the mouse. On day 4, we start treating orally with our molecule. On day 7, we challenged the animal by painting a little bit of this oxazolone or 3% solution of oxazolone on the ear of the animal. And then on day 8, we do histopathology and that drives the outcome for this model. So what do these results look like? We looked at our single molecule, ADX-629, which we had already shown was active in the clinic and characterize that side by side with the 2 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 3 molecules, highly significant in that outcome with ADX-248 in particular, showing a very strong response. Epidermal erosion. Again, all 3 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 in all 3 -- for all 3 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 [ pharmaca-4 ] is broadly applicable across 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 finding molecule, ADX-629. And of course, in alcoholic hepatitis, the causative agent is really acetaldehyde, a very basic RASP molecule. And we had 3 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 the study. So we really challenged these subjects with a very high bolus of ethanol. So we dosed the drug at 1 p.m. We dosed the drug at 6:00 p.m. Between about 8 p.m. and 10 p.m., we were feeding the subjects very high dose of ethanol based on their body weight and based on the [ Widmark's ] equations and so forth with a target DAC for each subject of about 0.14, which is pretty intoxicated. 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 growth intoxication, before there's a ton of acetaldehyde on board, you can see that we don't really have an effect until the following day with 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., et cetera. So how does this translate to the mouse model? So with the mouse, we're giving ethanol plus controlled diet for 10 days. So they have a steady chronic exposure to ethanol. Then by day 10, give them an ethanol bolus, so a very high dose of 31.5% ethanol. And then we conduct histopathology 9 hours after that ethanol bolus. So -- and they were treated on day 10 with the 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 what we're all familiar with, we have a very significant decrease in the 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 adducts. So malondialdehyde and acetaldehyde are 2 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 the -- 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 agent-stained liver slice looks like. At top, that's what a healthy liver looks like. And then underneath that, you have serious red staining. As you introduce ethanol in the middle 2 slides, you have those white circles. 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 serious 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 liver -- the lipid deposition is reversed and there is far less fibrosis. We can quantify, of course, those images. And this is what the column slots 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, but 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 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 substance model that I described early in the funnel. We also measured that in this ethanol mouse study, and 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-opioid analgesia. This is a relatively new indication for us. We don't have clinical data underpinning this. But the Carrageenan Pain Model is very well established. So you take this molecule, Carrageenan, and inject into a paw pad of a rat and then there are 3 outcomes: there's the Von Frey test, Hargreaves test, and ankle caliper. Von Frey is a mechanical pain tolerance outcome. So you take a wire and you can measure the force that's required before an animal withdraws its paw. 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's exposed to 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 injection. You administer the Carrageenan and then over the course of 4 hours, you assess these outcomes and the results are in, area under the curve or AUC. So in all 3 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 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. And 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, the high-fat meal, 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, changes in acetates by aldehyde dehydrogenases. These acetates go straight to Coenzyme A and go into lipogenesis cycle. So the fatty acid synthase and diglyceride acyltransferase readily change the products of these aldehydes into triacylglycerol. So what does the high-fat diet induced obesity model look like in a mouse? So we acclimate the animals for 6 days. This was done in collaboration with a collaborator. Fat mass assessment is characterized at a minus 2. Daily body weight is assessed and then we treated either control -- vehicle control, 629, a GLP-1 agonist or 629 in combination GLP-1 agonist. And 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% to 10% or more. And then when we combine 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. We thought we would do is have a RASP free for all here. I feel a little bit like we're sitting in front and getting interrogated by the police with these bright lights and this is 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 to extend our pipeline and I see Tom is already raising his hands.

The GLP-1 synergy isn't odd, right? We're seeing the same thing with NLRP antagonist. So if you block inflammation, [indiscernible] out there, it kind of makes sense. Two questions. Your NSAID comparison study, are they additive also? You didn't have the combination…

Yes. We haven't looked at that yet.

You follow TNF outlook. You talking about it in 1 model. Is it a good marker everywhere? Isn't it at some level, they're all inflammatory?

I think that does vary. So the question is, does TNF alpha a good market across all of our models or it's a model in particular? I think there are some differences between models, depending on the mechanism of pathology in that particular model with whatever the inductions for that model, whether or not TNF alpha will be a prominent one. That said, I think TNF alpha is a common signaling molecule for inflammation in general.

I have a question on TNF alpha. Just wondering about sort of real-world patient [indiscernible].

So we actually have a -- so I think the question -- let me make sure I have the question. What is the real world indication look like for the ethanol toxicity model in terms of administering this drug. So we actually have a Phase IIa signal finding study ongoing as we speak in ethanol 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. And then it's actually completely unmet. There's really no treatment at this time. So you use steroids to some extent but steroids are relatively ineffective. And unfortunately, the outcome is it's more [indiscernible] mortality in many of these patients. So that's, I think, the short answer. Patients are coming with acute hepatitis. They're really no longer drinking. They're 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 act of the hepatotoxicity in that disease. And if we can stop that immune response, then maybe we can save these patients.

Catherine, thank you for that question. I think 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 brittle, severe patients with alcoholic hepatitis and the outcome is mortality. One of the things based on pending the 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. 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 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. Frank?

So I assume you would discuss different amounts or levels for severity of the ailing patients. But how do you handle enrollment of a trialing then if they are more mild? And how does the patient present? Do they even present to the hospital when they have mild AH? Or is it just moderate to severe? Because I just know between the patients presenting to the hospital with an almost 30% mortality rate, so fast. How do you -- it's hard enough to enroll moderates 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. And these are patients that are followed by their internists. They probably have 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 in female, so I'll note there is no safe dose of alcohol. I would assume, Frank, that, that's the kind of trial we're on, and we would look to our colleagues who are trialing MASH and NASH. More to come as we work through that and evaluate the data from the ADX-629 trial.

Do people understand if [indiscernible].

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 very beginning, that's probably the same phenomenon happening with alcohol. Yigal. 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, Yigal. However, obesity trials and/or dyslipidemia trials, folks with hypertriglyceridemics, folks with hypercholesterolemia are not 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 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.

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The question is the activity of ADX-629 alone versus the activity of ADX-629 plus GLP-1 agonists when compared to GLP-1 agonist alone. I was involved as an investor in, what I would say, the first wave of obesity drug development. And those drugs that were ultimately approved, reduced weight, I would argue, in the 5% to 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, inhibits appetite and patients eat less. As a result of eating less, however, patients lose both fat and lean mass, which is a problem. So we have, not by accident, entitled our approach lipogenesis modulation. Our idea is to target fat directly. And as Adam showed here, there's a good biochemical basis to believe that RASP potentiates fat, RASP makes 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 GLP1 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 assuming in Aldeyra could be of great strategic [ piece ].

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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 is toxic. That's what makes you flush. That's what makes you nauseous. That's what gives you cancer. There are certain populations, due to these polymorphisms that you referenced, that just simply aren't as capable as 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. Your idea is a really good one, and 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 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.

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Yes. 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 629 looked like it had less of an effect relative to ADX-248, 629 performed rather strongly in the clinic. So I think to some extent, that model demonstrates that our [ pharmaca-4 ] is quite active across all 3 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 form. Do we think it's the best molecule for oral systemic administration, the cost of goods sold, just the entire sort of suite of questions that go into drug-ability of the molecule and the best molecule going forward. So I think the short answer to question is that there's no one model that we're going to focus on to pick our molecule for that indication across those suite of different models and it becomes toxicology, pharmacology, et cetera.

So Adam, there really is no difference between, statistically, molecules that we've seen. And you mentioned the [ pharmaca-4 ]relative to the backbone, we're thinking about structure activity relationship or SAR. Maybe you could talk about the similarity across [ pharmaca-4's ] relative to backbones and how you think about those 2 things in our selection.

Sure. So we understand our structure activity relationship very well for this [ pharmaca-4 ]. So as I mentioned, 246 is sort of our most juiced-up hottest molecule in terms of rapid binding at an extent of binding to RASP in vitro. ADX-248 is intermediate and ADX-629 is on the lower side. In addition to that, 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 we have the molecule that's going [ yield ] us with tissue distribution, bioavailability and the right 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 [ pharmaca-4s ], our characterization of 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 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 once-a-day administration. We'll know more when our Phase 1 completes, which is about to begin imminently for 246. Those are the kind of things we're thinking about when we think about indication and molecule selection.

[indiscernible]

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 and that's the same question that he asked. Just a bit of history, and I'll allow Adam to comment further. But a long time ago, and this is on our website, we tested reproxalap in inflammatory pain. In fact, the same model, Carrageenan injection. And 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 does reproxalap reduce 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.

Yes. We haven't exactly decided that yet. We're obviously an inflammation company. And so I think our first reflux or instinct might be to think about inflammation-based pain. But 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 camp.

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 -- or all know, our joint 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, well.

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Should we assume on the pain side, the RASP? Well, I think that what we've shown with reproxalap, at least topically applied to the eye, is that if we're able to find 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 at that, and all of those seem to go in the same direction. Presumably, that's because reproxalap is finding 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 that's 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 up 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 chronic. 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 osteoarthritis. Okay. Any other questions before we take a break and move to the back of the eye. Excellent. Okay. [ Take ] a break and be back shortly. [Break]

Welcome back, everyone. We're running a little bit ahead of schedule, which is always good news. Maybe we can finish up and then have lunch afterwards. It's my distinct pleasure to introduce to you Ramiro Maldonado, who runs the inherited retinal disease service at Duke. A few interesting things about Ramiro, as of last night, except for last night, it's the first time he has not seen me wearing shorts. And the reason for that is my son is an undergrad at Duke. He's a sophomore. And I come down to visit him, and he never wants to see me, so then I said I just go see Ramiro. It's been such a pleasure to get to know Ramiro over the years. He was our lead investigator or the principal investigator for our Phase II trial in retinitis pigmentosa with ADX-2191. He has a fascinating background. His father was the first retinal surgeon in Ecuador. And he told me -- Ramiro told me last night that what he really wanted to do is be a soccer player, but he went to medical school because he didn't want to disappoint his dad. And then loved it -- and here he is now at one of the premier institutions that practices medicine as it relates to retina. He also had an interesting idea last night. He said, Todd, instead of Research and Development Day, why don't you have Retinal Dystrophy Day and you don't have to change abbreviation? So it is with great pleasure that I introduce to you our keynote speaker for the 2024 Aldeyra Retinal Dystrophy Day, Ramiro. I'll stand for Ramiro.

So good morning, everyone. Thank you very much for the invitation, Todd. I'm going to leave the podium and then be a little bit more active here to burn all the calories from the last night's dinner. But I'm here to tell you about retinitis pigmentosa, but not from the all point of view we had about retinitis pigmentosa. I'm going to tell you about the new vision that we have for this condition. And I hope you get a sense of how exciting is this field nowadays. So this is going to be an overview of retinitis pigmentosa. And a little bit about myself. I'm at the Duke Eye Center, I'm Co-Director of the Pediatric Retina and the Ophthalmic Genetics Center. And I had the blessing to -- a little bit about myself. I had the blessing to start my career at Duke. I was fortunate to be part of the group that developed the first intraoperative OCT and brought the first handheld OCT for the diagnosis of retinal diseases in children. So all this technology was available for adults, nothing for children. The children, they also have retinal diseases. They can also go blind. They didn't have this technology to be able to get a diagnosis. So we were able to make it compact, portable and available for children. So that was my initiation. I stayed at the Duke Eye Center for residency. And at that time, when I was in residency, I got a phone call from a friend of mine in Ecuador, telling me that his wife was diagnosed retinitis pigmentosa. He was told that his wife was going blind. There's nothing to do. And he calls me -- you are in the United States, maybe there's something there you, can you check for me, and I went ahead and I did my search and there was nothing, no cure, nothing going on. And that brought my interest into this field. I mean, I always like to be in places where we still have questions to answer. And that's how I end up going to NIH to do my fellowship in ophthalmic genetics. At that time, NIH was the only place doing gene therapy. And so I thought that, that was a good place to go, did my fellowship there, I say, for retina as well. And after my fellowship, my first job was actually at University of Kentucky. The Chairman there had this vision that it was time to have someone that can see patients with retinitis pigmentosa. So there I was the only IRD specialist in the entire state and is a fascinating experience to build a service from 0 because patients didn't have anyone to guide them or see them for so long. They were traveling to other states and so there was no one to take care of them. After that, I came back to Duke, kind of feel that that's my home and where I made. The majority of my friends and my colleagues and mentors are there. So very happy to be back. So on financial disclosures. And let me start by telling you a patient real story there, this will help you to understand why we are concerned about retinitis pigmentosa. This is a 42-year-old patient in the prime of his life. He's at the best point of his career. He has children, he wants to see them growing and he is diagnosed with retinitis pigmentosa and the doctor tells him you are going blind. You are going blind and of course, this is devastating for him, and this is a common scenario for these patients. Can you imagine that at this stage of your life, you're told that you're going to go blind, devastating, right? This is an example picture of the back of the right eye of a patient with retinitis pigmentosa. And you see all that pigment there, and that's why this disease is called retinitis pigmentosa because of all that pigment, but we know that, that pigment takes 10 years to develop. So the process has started probably 20 years before. We are diagnosing so late, so late, and now we are much better. I'm going to highlight in this picture, the macular area. This patient has been doing well and driving and working because that central portion is still in fairly good shape. And that's why he has been able to compensate things, but you can see the massive amount of retinal destruction present in this retina. This is autofluorescence. This is a functional technology that we have, where essentially cells that are still in good shape, they have some fluorescence and they appear in this bright gray there. But all the cells that you see in black, they are cells that are not working, they don't have the normal fluorescence there. So this technology is amazing to help us to understand the amount of disease in the retina. That's the right eye and the left side of the same patient there. But we can also do living in histology, and that's one of the points that I want to make, not only that we can see the big panorama of the retina, but we can do live histology. This is an OCT image, kind of like, I tell my patients that this is like an MRI that we can take in 5 minutes there and see the photoreceptors. We can see the cells that are still working or not working there in the clinic without having to do anything more special, and we can do measurements of these and we can study these patients very well. And these are visual fields of the patients. So inside the red line is the area where the patient can see. Normally a patient without vision problem should go all the way to the edges of that circle there. So the fields are constricted, very likely this patient is bumping into things, tripping, falling and so forth and most importantly, at risk of having accidents while driving, right? These are other tests that help us to measure the amount of light that the patient can see. So even though the patient -- a patient with normal vision perception will -- the test will draw a line here. And as the patient loses the capability to see light, the curve will go to the right there. So this is very useful because some of the patients in advanced stages, they cannot read the letters anymore. So the visual acuity tests are not good anymore and we can use these other tests to monitor patients. The main point is that IRDs, inherited retinal diseases, are a group of genetic diseases that are characterized for being progressive, irreversible and still in the book, it says that for which there is no cure. We don't have cures for these diseases. And there are about 7 million people in the world with inherited retinal diseases. In the U.S., there is an estimate about 300,000 people with inherited retinal diseases that are affected by these conditions. So that's the big picture, 7 million in the world, 300,000 in the U.S. We only have 1 treatment for 1 gene for insignificant amount of patients there, unfortunately. So that's the first message. It's a big problem. We don't have cures yet. We are getting closer, as I will demonstrate, but we still have a lot of work to do. Inherited retinal dystrophies is a group of genetic eye diseases that affect the retina in different forms. The most common one is retinitis pigmentosa. So you can see in this graph, 47% of IRDs have retinitis pigmentosa there. More than -- we have discovered more than 350 genes already causing these IRDs. So it's a large number of genes. The thought is that we have discovered all the genes. We're still discovering new variants there, but we think that we have discovered all the genes that cause retinitis pigmentosa there. From these 350 genes that was IRD, 60 are thought to cause retinitis pigmentosa there. And there can be multiple inheritance form. And the most common one is the recessive one in purple and the second most common one is the green, 25% autosomal dominant there. This slide is very important because nowadays with genetic testing, we know that retinitis pigmentosa can be caused by multiple genes and 1 gene can cause different diseases. So this genetic testing is helping us to refine our diagnosis. So nowadays, I don't charge patients with retinitis pigmentosa. I say patients with rhodopsin relating -- related retinitis pigmentosa. I identified the gene to the disease, and that's getting a little closer to what we call precision medicine, right? And I think that in a few more years, we're going to be naming in the charts also the variant. A little bit in the field, we are getting bored with naming the genes. Now, we are getting closer to naming the variants, and that's pretty exciting. So genetics is really changing the name of the diseases. My resident fellows they still bring questions from the traditional books that are out there for ophthalmology and it's amazing how those concepts are gone and not valid anymore because genetics has changed the name that we are giving to diseases there. This is a picture of the Duke Eye Center and the reason why I'm showing this is because I wanted you to see how academia is working nowadays. The building in the back is the research building where we have laboratories working in retinal degenerations, macular degeneration, retinitis pigmentosa gene therapy. And here, we have the clinical building where we see a high volume of patients that I've referred from the community. And in the middle, we have the research unit there. So it's this integration of facilities there that's helping us to advance the field. In the Ophthalmic Genetics Center, we see about 5,000 patients a year, that's a large number. We're a referral for 5 states, as I mentioned, Kentucky, I left there and no one was able to take my position there. So there is still no one seeing patients in Kentucky. So we still get referrals from there. We need more IRD specialists for sure. And this slide is to help you to understand how we are integrating patient care with clinical research and basic science. In the clinical research unit, we have the IRB process, the research unit and everything integrated with basic science. But the most important thing is that academia is now ready to welcome industry. We have a research unit that has dedicated clinical coordinators, people that go under regulatory staff, specialists on recruitment, on reimbursement for patients and so forth. It's a dedicated team that is ready to welcome the clinical trials from industry. And so we finally think that this is very beneficial for patients, the integration of academics with the industry. So the patient journey starts with a patient with inherited retinal diseases. Eventually, the patient sees an eye care provider. It could to be an optometrist, a retina specialist or a pediatric ophthalmologist. Eventually gets to generic service, but there could be a big delay here, and that's the problem there. And then we do genetic testing, we do specialized testing. And that's where we get to classify patients now by genes and by variants. And that's the final outcome because by understanding the variance and the genes is that we can get closer to having some therapies there. Of course, this is where ophthalmologists we play -- or we remember that we are doctors and so we analyze more than the eye because many of these conditions are syndromic and can affect other systems there. But, yes, we run through a battery of tests that I showed you already, including electrophysiology. It's very interesting how we can measure the signals coming from the eye, and this is very important to test therapies, the functional aspects that we can measure there, not only the structure, but also the function there. And of course, I told you that these diseases can affect children, and we are at Duke focusing on providing better care to children. And so we have developed several portable units that make things more friendly for patients, including virtual reality in these portable devices that I mentioned to you. Everything with a hope to get better diagnosis to children as well including these mobility testing. So we have headsets where we can have the patient walk into a virtual room and see how they manage and we modify the lighting level to see how they perform in real life, and we put obstacles there and they get a score on how they do here. So we have gotten to this point where genetic testing is a standard of care. I remember when I did my fellowship, it took 1 year to give results to a patient, and we were testing for 1 gene sometimes or when in gray days, 30 genes. Nowadays, we can give a result of a panel of 300 genes in 6 weeks. So things have changed a lot. Genetic testing is more affordable. And now it's the standard of care. We do it in all the patients there that have an inherited retinal disease problem. But for a long time, there was no hope for these patients. And I think that although we don't have treatments yet, we have some hope and that's one of the messages that I wanted to bring. NIH was one of the first centers having this first-in-human plans. Basically using genetic testing for some diseases there, and they had the first gene therapy for X-linked retinoschisis. And all that process took more than 30 years to -- for us to be able to finally have gene therapy here. And gene therapy is a reality nowadays. We have 1 FDA-approved therapy and several in clinical trials. In '19 -- in 2017, the FDA approved the first gene therapy to treat a form of retinitis pigmentosa. Remember, I was telling you that we just have a treatment for 1 gene. Well, this is the treatment for that gene that has been proven to be highly beneficial for patients. The problem is that it is a very rare gene and we don't have many patients with that. And so it's the contradiction, but certainly, we -- all the field is very thankful of these -- of Luxturna because Luxturna brought all the momentum, all the excitement about gene therapy that's finally working. And if it works for this gene, it happens to be very rare, it can work for other genes. And so the amount of clinical trials keeps going up, and it's very exciting over the years, more and more clinical trials. In reality, we have to become very selective about the options that were presented, we are contacted by industry. We have to be very selective because it's a huge amount of time and resources and it's -- we don't have the capacity to take all the trials here, even though with all the research units that nowadays we have. So we have a treatment. This is a new era. That's what I would like you to remember. Gene therapy is a reality, but this slide is very important because I think that we're missing the boat here, gene therapy, it is maybe not the answer for this and I'll explain why. There is a huge amount of studies that are failing in the -- and I don't know if there is a risk of losing the momentum. I thought this -- a couple of years ago, I think that the excitement is coming back. Essentially, early detection means everything. Gene therapy is not going to be able be successful in a patient that is almost blind. Gene therapy has higher chances of helping someone that is at the beginning of the disease where we can stop the progression there. So early detection is very important. And that's why we are investing a lot in diagnosing children with these conditions. These retinal dystrophies can happen at any point during the patient's lifetime. So that's why you have a representation on the left of LCA, leber congenital amaurosis, that's the most aggressive form of retinitis pigmentosa, can leave a baby blind. And then the second most common wave comes when the kids go to kindergarten. And the teacher tells the parent, I think that your kid is not seeing well and that is when we have the second wave on these diseases that are very called early-onset rod-cone dystrophies. And later on, the third wave is when patients have to get the driver license and they cannot get the driver license because they fail the driving test and so that is the most common one, the rod-cone dystrophy is there. And there's a last group of patients that get the diagnosis in their 60s -- when they are ready to retire and enjoy life and then they get the diagnosis there. So the point is that retinitis pigmentosa can affect at different stages, depending on the gene that is affecting them. And the thing is that we are diagnosing a little bit late, those purple arrows kind of represent the timing of the diagnosis. We really need to make the diagnosis early on, early on to save the patient's vision. That's the point. There are multiple therapies, multiple therapies in the market, anti-oxidants, gene therapy, RNA therapy, stem cells and of course, methotrexate. It's also one of the options, pretty exciting options. We are very happy to participate in that trial where we saw significant results in patients there. It is a remarkable experience where -- when physicians, we have been seeing these patients without any treatment and we do something, and we see the emotional impact in patients. I had several stories that I shared with Todd where patients were extremely happy to be able to see for the first time the stars in the sky and navigate a little bit better in the -- at home without having to put intensive light and be able to have better visual fields. There's 1 patient that participated in the methotrexate study, she was doing her own visual fields. She decided to put some magnets in the fridge and mark where was the limit of her visual field. And as she was receiving the treatment, she was expanding the visual field by herself and pretty exciting. And we have a mother and a daughter that participated in that study and it was so emotional to see how the mother was in tears not only because she was receiving a possible successful therapy, but because her daughter was able to receive it, and she didn't want her daughter to go through what she went through and so pretty remarkable what we can do for the lives of these patients. The number of therapies that are available for these inherited retinal diseases is pretty significant. It's pretty significant, and I don't want to cover all of them. Some of them, they tackle genes, some of them they tackle oxidation, other that tackles inflammation. And so we can discuss more about that. Stem-cell is also coming to the market there. But Luxturna is the treatment that I told you that is FDA approved but what is beyond this Luxturna that is certainly not solving the problem? We have more genes that can be -- that are currently in clinical trials. So RPE65 is the gene for which Luxturna has the option to treat, but there are other genes in clinical trials already. There is RNA therapy, stem cells, as I mentioned, chemically induced photoreceptors, retinal prosthesis. And we can keep elaborating more and more on all the possible treatments that we have for these patients. But an important concept is that I don't know if the slide is bright enough to see, but we have from left to right representation of the histology of the normal retina on the left and different stages of progression or degeneration of the retina as we got to the right. And so here we have severe degeneration of the cells here in Stage 4. And so the thought is that we need to intervene early with gene therapy. It doesn't make sense to intervene with gene therapy here in Stage 4. And so here's where I wanted to talk about the methotrexate because specifically in autosomal dominant retinitis pigmentosa, which has a very common mutation in the U.S. There is this misfolded protein that gets trapped into the ER of the cell and causes the degeneration of the cells. So methotrexate has this concept of helping with the clearance there of this misfolded protein there. And I think that it's important to have these alternative therapies that are not gene-specific, that's the main thing, not gene-specific or what we call gene agnostic there to help with the prevention of this degeneration there. So vision sciences is living a huge momentum. We are bringing -- this field is becoming one of the most interesting in ophthalmology nowadays. When I did my fellowship, no one wanted to go into IRDs. It was the very obscure field and now it's like many, many fellows they want to go into this field because it's -- we have treatment options and is becoming very exciting there. We have courses, I have been able to put some courses at the major national meetings and to be able to get these courses approved, the organizers they want to make sure that there's enough audience. So the fact that we are in the 3 major meetings there speaks of the excitement in ophthalmology for this IRDs. So there is a bright future for patients. Certainly, there is hope, there's future, but we are at the beginning of this. And so I think that academia in general is ready to partner with the industry to move the field forward, and it's going to be in benefit of our patients, and that's what we want to help them. With this, I wanted to thank you for your attention, and if you have any questions, I'm happy to answer them.

If we go through the Phase II data first. And then what I'll do is have Dr. Stryjewski and Dr. Maldonado, answer questions, and I'm sure there'll be a lot of them. These data from the Phase II methotrexate trial retinitis pigmentosa has been previously disclosed. But I thought before we go into next steps, it just might be helpful to review the data. It turns out there was an investigator who screened something like 40,000 compounds, known and unknown, approved and unapproved from a compound library and in vitro and animal models of retinitis pigmentosa, particularly rhodopsin mutations. And surprisingly to her, the winner was methotrexate and that's well described in the paper that we cite here. In fact, we have a copy of that paper with us today if any of you would like to see it. But there was a pretty clear response to methotrexate and then she investigated why? Why would methotrexate effect patients or improve patients or animals with retinitis pigmentosa. And her conclusion was that mutated rhodopsin is dysfunctional and that methotrexate promotes degradation of that mutated rhodopsin allowing the bulk of rhodopsin in the eye to be wild type or normal and thus, in theory, the vision would improve. The trial was an open-label trial. It compared 2 doses of -- or dose frequencies of methotrexate to baseline. There was a monthly cohort for 3 months. So it was a 90-day trial. And then there was a twice monthly cohort of 6 injections over 90 days. And as Dr. Maldonado described, we assessed a variety of endpoints, the primary endpoint safety. Never before had methotrexate been injected into retinitis pigmentosa patient. So it's appropriate that we first assess safety and tolerability. I'll just say that methotrexate, as some of you know, has a long history of being injected into the eye. It is the standard of care for ocular lymphoma and it's been used in other conditions such as posterior uveitis and proliferative vitreoretinopathy. The first thing we noticed was that visual acuity improved. Now this is interesting because as Dr. Maldonado described, the central part of the retina that part that you use to appreciate fine detail is spared in retinitis pigmentosa. At least initially in the early phases of the disease, so your acuity per se, that is your ability to focus on certain letters wouldn't be as affected, I'd say, your peripheral vision. And Dr. Stryjewski and Dr. Maldonado know far better than I, but the physiology of the eye is such that your cones are in the center of the eye, they are responsible for color vision and fine detail and then your rods are in the periphery of the eye and they're responsible for light perception. So the fact that retinitis pigmentosa is primarily a rod disease and yet we saw improvement in vision was at least to us remarkable. The effect of the improvement in vision was fairly stable during dosing, but after dosing ended at least for normal lighting, as you can see on the graph on the left. Treated patients returned to baseline and look similar to untreated patients, supporting the idea that treatment improves the vision. This is a retinal function and relates to some of the graphs that Dr. Maldonado showed previously, this is the electroretinogram where you can independent patient sensation or perception assess the function of the retina. It's a little bit like an electrocardiogram or an electroencephalogram, where you're simply just measuring response to a light stimulus -- electrical response to light stimulus. And you can see both the peak response and the time to response improved. And then most importantly, because this relates to our announcement we made in our press release this morning, there was a significant improvement in visual field. This is a central visual field particularly, and you would think would be more spared in retinitis pigmentosa and then the peripheral visual field which is what really is affected in these patients. The green stimulus is typically more rod mediated and the red stimulus is typically more cone-mediated, but both seem to improve in dark adaptive settings. And I'm sure we'll talk more about that with Dr. Stryjewski and Dr. Maldonado later. So we have been in active discussions with the FDA as we announced this morning. We have what we believe to be in agreement with the FDA on a potentially pivotal Phase II/III clinical trial of ADX-2191 in patients with retinitis pigmentosa. The dosing will be a very low dose of drug, 40 micrograms versus the standard dose of drug of 400 micrograms. The reason for that is that saline injections are not thought to be always ethical given the safety issues that could be potentially associated with injection. So a very low dose of drug is used. Instead, this will be a 12-month trial. There was really no difference as you saw between monthly activity and twice monthly activity. And so there's no reason to dose patients twice monthly instead we'll dose them monthly here. And the endpoint will be this sort of peripheral sensitivity to light or peripheral visual field, if you will, to the green or rod-mediated stimulus. We'll continue to look at visual acuity and other endpoints such as safety, but the primary endpoint will be as specified here. We're looking forward to initiating this trial in the second half of this year. We've added a new milestone along those lines. And for all the reasons that Dr. Maldonado highlighted, we're very excited to be part of this because there is no broadly active retinitis pigmentosa treatment. So why don't I invite Dr. Maldonado and Dr. Stryjewski up here to our table, and we'll open up the floor to questions.

[Technical Difficulty]

Let me begin the answer, and I'll turn it over to our expert panel. Some patients came in with basically normal visual acuity. And because the trial is a small, 4 patients per group, 4 patients per monthly, 4 patients twice monthly, those baseline balances really sort of show up here. So if you have perfect vision, it's difficult to get better. But statistically, when you compare twice monthly to monthly, there's no difference between the dosing. But maybe our panel can discuss why the focus on dark adapted fields or scotopic vision?

I think as Dr. Maldonado said earlier, one of the challenges with RP is that many patients are walking around with 20/20 vision, but they're walking around looking through a funnel. For the registration study that we're describing here, the primary endpoint is going to be this unique endpoint of assessing essentially the peripheral vision under dim conditions. The complaint that patients with RP have is that I can't navigate in a dark movie theater, I can't see the stars at night. How does one quantify that in a trial setting. And so there's this very innovative and clever visual field machine that we're utilizing made by a company called Medmont and its assessing kind of that ability to see dim lights that are increasing in intensity that can be then quantified and it is under a dark setting, which in an investigational way, kind of simulates that ability to see the stars at night or navigate in a dark room. The issue of monthly or bimonthly, I think some of the data which you have seen is, again, the visual acuity gains, many of these patients were close to 20/20, maybe to 20/25. So there's somewhat of a ceiling effect of the ability to improve, but that's not really like their problem, unlike a lot of other macular diseases or central acuity is the issue. The issue here is the ability to see subtle features in the periphery, and that's really the problem with this condition.

Maybe if I just last one on it. There are 2 parts there that I was wondering, 40 versus 400 after may be ethical reasons or how strong we feel at least is a true placebo [Technical Difficulty] we can really differentiate what the drug does [Technical Difficulty] that surprising? Or if there wasn't ceiling would there be some [Technical Difficulty]?

Yes. So the classic control group for most intravitreal studies for the past 20 years has been what's called a sham injection, where the patient's eye is anesthetized and the doctor presses the hub of a syringe against the eye. And if your eye is properly anesthetized, you will not know whether any needle is actually penetrating your eyeball or not. There has been generally a change in the views of the FDA of the applicability of using that as a control group. There's concern that patients are being essentially unmasked. And so I think this is not necessarily unique to us, but many other companies are developing intravitreal products. There's a need to do a different control group than kind of what's been done for the last 20 years. So this decision is largely from their guidance to change the dose and this is essentially the lowest detectable dose that we could provide. It is such a -- the activity -- the level is so low that we would not expect there to be any activity.

Yes. Frank's question is really about why not just give 0 methotrexate in the control arm. And obviously, there is some morbidity associated with ocular injections. You don't do that lately. And in addition to everything that Dr. Stryjewski just said, I think there are some ethical issues of injecting saline in the patients where you know there's going to be no effect. The risk is that 40 milligrams is active. But we would argue that's highly unlikely, the standard dose of methotrexate is 400. That's what's typically used for ocular lymphoma. Lower doses haven't appeared to be active in the past in other diseases. So we're pretty comfortable of where we are. The other thing we heard from the FDA is after an ocular injection, there is a little bit of an impairment in vision because you're squirting something into the vitreous, and you have this sort of waviness. So patients know or at least injection familiar patients know whether something has been injected into their eye because they see this disturbance in vision, which you wouldn't see after the sham injection that Dr. Stryjewski described. Tom?

[Technical Difficulty]

We proposed -- the question is how well recognized is the primary endpoint of scotopic or dark adapted visual field or retinal sensitivity periphery. We proposed this endpoint because it was by far the most active and tractable from the Phase II trial. The agency's response was of unambiguous that this is something that they would consider. And I think the reason for that, Tom, is that visual fields have been used in other conditions, glaucoma comes to mind and the way visual fields are measured and clinically relevant responses and so forth, have all been worked out, but I would say largely in glaucoma, I don't know if the panel agrees or disagrees with that.

And I think that this is not regular visual fields. This is a super wide visual field technology that uses different wavelength to just measure the rods. And in a disease where rods are primarily affected, you really need to dark adapt to have better sensitivity of them. And by using this special wavelength, you are really, really assessing rods. So I think that this is a very good test for the target.

I'll just add to that. As Todd said, it's been 40 years that visual fields have been used primarily in glaucoma. The first really characterization of using this specific testing sequence with a dark adaptation with these different wavelengths of light to stimulate rods versus cones. And that history has been about closer to 8, 10 years. So there's very good characterization of using this. A lot of this was pioneering work was done by Dr. David Birch. He's also been a consultant of the company. And there's has been primarily in academic, I guess, academic literature context. There have been other sponsors who have done studies in RP who've used this test as well. And for a number of operational reasons and just clinical relevance, it's really the most sensible endpoint for the study.

Yes. So Katherine's question is, what is the rationale for calling the Phase II, III. I don't think the FDA distinguishes between Phase II/III and Phase III and Phase II. Their question is whether the trial is adequate and well controlled? Does it have a control? Is it randomized? Has it been discussed with the FDA? We are calling this a Phase II/III because it's the first time methotrexate has been dosed in retinitis pigmentosa patients with a control in our case, a super low dose as the control. But we could also call it a Phase III. Our point with the FDA was to make sure that the trial design we presented up here is adequate and well controlled, and therefore, might qualify as a pivotal trial if successful.

In terms of the [Technical Difficulty].

The importance when thinking of the design of a study like this is you really need a Goldilocks approach. If you enroll patients whose retinas are totally extinguished and then you're going to have a floor effect. If you have patients who are too young and the retinas are too healthy, there will be a ceiling effect. So there's really this intermediate zone of which we're trying to capture it. The endpoint selection, which we've received agreement with the agency with is, there is going to be minimum requirements of 5 low side points in the vision. There's 144 points of the vision being tested, and there is a range where it's not 0, it's still a responsive area of retina, but not kind of too good. And those are going to be essentially the baseline features for that patient. So we're basically looking for the areas of kind of medium vision. In retinitis pigmentosa, it's rarely clear vision or black gone. Most people have intermediate areas and some areas are excellent. Some areas are very hazy and they're different across every patient. And so that's kind of the nuanced approach we need for designing this. So for this study, we're looking at those intermediate zones. And then the way these algorithms are described in terms of the intensity of light, they describe the intensity, the unit is called decibels, okay? But it really -- it comes down to the intensity of the light. And for long-standing agreement in the field with the FDA's blessing, what they call 7 decibels of change is considered to be clinically meaningful across really all diseases that affect peripheral vision. So that is the mean change that is expected to be obtained versus the control.

[indiscernible]

That's correct. So the study is powered to greater than 90% to detect this difference.

The beauty about this patient population with rhodopsin gene is that it just happens to be that it's a subset of patients with RP that have fairly good central vision and are more reliable in testing, testing like these perimetry testing. So they are better at doing -- performing on the test and have reliable results.

[Technical Difficulty]

I think a question just for the audience listening in is, who are we going to enroll? And the answer is patients that are not too sick and not too mild. And then the follow-up question really is about, what's the clinically relevant threshold? And that's typically 7 decibels. We approached 10 in terms of change from baseline after 3 months and made various assumptions about powering to be in the 90% power range. And then maybe the panel can answer sort of the clinical relevance question to that patient, what do they complain about and how might their lives improve?

Yes, I think that the -- in real life, the major benefit for these patients would be to perform better at night or when there is no great lighting like in the winter, and depending on where they are in the disease, it may mean being able to drive at night versus not feeling comfortable driving at night or just having less scanning effort. Some of these patients would have to be scanning to see things. And so by having better perception on their field, they may be more comfortable doing daily activities and overall feel more independent. And -- but in reality, the major goal is to stop the disease progression or help to stop disease progression because if you don't do anything is just going to get worse and leading to complete blindness.

I have to tell a story. I know someone whose mother is 90, and she just started dating again, and she asked her mother, she said, what are the criteria for who you're dating? And her mother who was 90 said, I need him to be able to drive at night. And as we get older, we can't see as well at night. I think that's just a natural thing I tell people that I -- my dog insists sleeping on the floor between the bed and my door, and I just always tripping over my dog and maybe that's just me. They may have other issues besides not seeing at night, but that's probably not helping the matter. And I think dark-adapted vision or seeing at night or dark adaptation itself is a common complaint, as I understand it, for all kinds of disease, not just retinitis pigmentosa.

There's -- classic example is macular degeneration. It affects also the rods. And that's why patients they don't see well at night. But I would like to emphasize that really the major benefit here is not the night vision, it's kind of preventing more degeneration that will lead into blindness.

[Technical Difficulty]

So the question, by the way, is their Phase II was 3 months. Why is your Phase II/III, 12 months? So it gets to a number of factors, including the natural history of the disease and pathogenesis. This therapy, if approved, would likely be a lifetime therapy obligation for the patients because they have a genetic mutation that is preventing clearance of a protein that builds up and develops toxicity. As best as we understand the activity of 2191 is promoting via the lysosomal pathway clearance of these misfolded proteins. So the healthy proteins can function. But if you discontinue therapy, the idea is that the toxic misfolded proteins will build up again. So it really comes down to just creating a delta of having an extended period of time where you can allow patients under treatment to continue to clear the misfolded proteins, kind of strengthen, if you will, the rods. It's -- RP peculiar disease, and that even though it's a rod disease, people eventually lose their central vision, the cones. And this is what Dr. Maldonado is getting to is that the chronic buildup of these toxic metabolites creates an inflammatory picture in these patients that's probably part of the mechanism of methotrexate in the eye. And then eventually, the codes are affected and then there's complete vision loss resulting. So it really just comes down to creating a spread between the control and what we believe is the effective dose.

And I think there's something else at play is that patients when they perform these visual fields, which is a complex process. I've actually seen the facility at Duke of dark adapting patients, having them with, I guess, a clicker kind of thing identify when they see something in their periphery. So you have patients fixate on a point and then there's little dim flashes of green light that occur and you sort of click with it. And that's just a -- it is a -- it's just a difficult thing and only certain centers can do it, but ultimately could translate to clinical benefit. Now one of the challenges is patients learn. So as you -- if you've never had a visual field, the first time you do it, especially if you're older, you're not very good, but over time of serial visual fields, you learn, and we think that happens over 2 to 3 to 4 assessments. So one of the things we're going do in this trial is to get those 2 to 3 or 4 assessments done ahead of time so that by the time we're looking at drug effect, the learning period is over.

That's a great idea to do because visual fields have a learning curve. And so doing that ahead of time to make sure that patients are reliable in testing is very important.

Yes. The 2 questions are, are these bilateral diseased patients and the other question was about volume per dose.

So we are enrolling 30 patients. Patients may choose to have 1 or both eyes injected assuming each eye independently meets the inclusion criteria, as I described, the key inclusion criteria is having these Goldilocks areas that are neither too good or too poor. In terms of the volume of injection, there's going to be -- the volume will be the same. There will be a controlled dose that will be manufactured essentially. So it will be 40 micrograms and 50 microliters, the standard injection volume as ADX-2191.

Kelly, so the question is there a variety of rhodopsin mutations for retinitis pigmentosa, would we expect to see or did we see a difference in those mutations?

So I think I'll also just take your question maybe to one level above that. The study is focusing on RHO-associated RP. RHO mutations are the most common form of RP in North America. So the inclusion criteria, you have to have an RHO mutation, and it can be any variety of genotypes that are accepted. Probably the most specific one is P23H. In the study so far, we did not see a difference in responsiveness and we would not expect that going forward. So the requirement is to have an RHO mutation. But beyond that, the specific mutation characterization as there's no specificity towards that.

We really didn't see anything in the first trial. We had a variety of them, including PT23H, but we just didn't see any differences along those lines. If [ Dr. Chen's ] thesis is correct about methotrexate leading to the degradation of mutated rhodopsin. It may not necessarily matter how it's mutated the rhodopsin. It's just as long as it is mutated I think I'd like to emphasize something that Dr. Maldonado said in his talk, gene therapy is amazing for specific genes. How many Luxturna patients have you treated gentlemen?

So far, in 4 years, in my time in Kentucky, I couldn't find not even 1 single patient there. At Duke in 3 years, we have treated 5.

So a gene-agnostic treatment, if you will, assuming you have a rhodopsin mutation, a gene-agnostic treatment would be in high demand. So look, you wouldn't have to worry about the specific.

Not only because of that, but there is also a very important fact that after doing genetic testing, which includes a panel, sometimes we go to whole exome sequencing. Even with that, we are estimating that 40% of patients with retinitis pigmentosa do not have a final formal genetic diagnosis. We are not able to uncover the pathogenic variant. It's just not there in the capabilities of the testing. It could be intronic. we don't know. But 40% of patients don't have a genetic identifier.

[Technical Difficulty]

The question is, why restrict ourselves to rhodopsin mutations and then, b, what percent of RP patients have rhodopsin mutations?

I'll take the first part of that question. And the reason to restrict it is really just the bulk of the preclinical work was focused on that. So we think it's the most likely to work. I think if it does, it's an interesting question just because of the other causes. I mean retinitis pigmentosa, the unifying also issue in that is also just the inflammatory component. So I think that could be so interesting to look at in the future, but right now, I think the strength of the preclinical work is in that. So we're focusing on that. And Ramiro, do you want to comment on that genotype composition and RP?

Yes. Roughly 15% of the patient population has a [ ReSoMal ] dominant therapy. And from that, the most common gene is rhodopsin. So it is 1 of the top 5 genes in the patient population here.

[indiscernible] Phase II data based on the gene-agnostic approach makes a lot of sense. But were you surprised by the strength of the [ results in the Phase IIa trial ]? Would you expect the gene therapy to be more efficacious? Or it makes sense [indiscernible]?

The question is, were we surprised by the strength of the results in the Phase IIa trial? And then for a particular mutation, would we expect a gene therapy to be more active?

Yes, certainly surprised. Yes, it's a positive surprise that we had. I was involved in an RNA therapy as well. I didn't see this effect there. So gene therapy really has this freezing effect. That's it. So the patient is not going to necessarily refer improvement. That's my take there, maybe these other alternatives, which I think that at the end, could be combined, why not combine this with some form of gene therapy as well.

I think there's also been an evolution in the thought of selecting these endpoints and analyzing the endpoints in these diseases because in many other trials, the assessment even though we know visual field sensitivity is what matters in many other studies, they've just essentially looked at like the average of all the points. As I said before, some areas are affected by a floor effect, other areas are affected by ceiling effect. And if you shoot out a target, you're one foot under the first shot, one foot over the second shot, you didn't on average hit a bull's eye, you just missed and so I think -- and how we're approaching the analysis of this, which, again, we've received agreement with the FDA is like we're focusing on the disease areas that have a chance for improvement. And I think that's where this may differentiate from some of the other programs.

Maybe if you think into the basic science gene therapy, which RNA -- with RNA and perhaps solve the mutation problem there, but the misfolded protein is still there trapped. And so having the clearance mechanism could have an important role.

And there probably is something to be said about treating patients early. As you mentioned in your presentation, Dr. Maldonado, that gene therapy may work, but only for patients when they're treated sufficiently early in their disease course. Any other questions? I have some questions. I hear from our investors or many of them that in the dry AMD landscape or geographic atrophy landscape, that the therapeutic area is crowded. Now that we have 2 drugs approved, do you think -- for these retinal diseases we're now treating, do you think that they're crowded therapeutically?

The approval of the 2 complement inhibitors for dry AMD, GA, I mean, no doubt, it's a landmark because it's kind of the only thing we have, but it's an incredibly -- I still continue to practice as a retina specialist, and it's an incredibly unappealing sell to patients because there's been no demonstrated visual benefit for either the drugs. It's based on anatomical landmark, but across like the 5 secondary endpoints, reading speed, visual acuity, low-luminance visual acuity, microperimetry, none of them improved. I think it's a good kind of like philosophical potential that these drugs should work. But I mean, when I'm selecting patients in my clinical practice to receive one of these drugs, it starts to become kind of like a niche population. If they already have the geographic atrophy in the middle, there's nothing to preserve. Other people maybe are not progressive. And when you inject anti-VEGF, okay, for wet AMD, for DME, people come back the next month and they say, "Doc, I saw better. Let's keep going. I don't like the injections." The problem with the therapies we have for geographic atrophy is no one -- I don't get any hugs from those patients, okay? No one is coming back the next month because they're not seeing better. Okay, 5 years from now, we think by slowing down the progression of the atrophy, you'll see better. So there's a tremendous need for a therapy that's going to give people a functional benefit. And there are many ways that can be assessed whether it's acuity or sensitivity to light. Again, we've said several times in the last like half hour about macular degeneration patients complain about, "Oh in a restaurant, I can't see. I should turn on the light." That's common to a lot of other issues as we age, but it's really an issue for patients with macular degeneration. So there's a tremendous need to create a therapy that creates a more immediate functional benefit, not something that, oh, we think in 5 years, the lines will diverge enough that it will make a difference.

Absolutely. And it's -- but it's also remarkable, the amount of patients that come asking for that therapy. And yes, I agree, it's not great therapy. I tell them it's not a cure. It's what we have. It's not perfect, far from perfect. It will only slow down this process and maybe help you buy some time until we have something better. And maybe when they hear that, they are committed to come. And so I bring them back for on the injection, on the appointments to at least reduce the time that they spend in clinic, but yes, I agree, they just come in out of pilot. They get injection, they are not feeling any benefit, but they are hoping that they are doing something to save their vision.

So on our pipeline, we have a different set of drugs, RASP modulators for the dry form of AMD and geographic atrophy, both of you have been involved as architects of that program. I was hoping Dr. Stryjewski you specifically could talk about the rationale in dry AMD for the use of a RASP inhibitor.

So the major part of the pathogenesis of dry macular generation is the accumulation of lipofuscin, which are these yellow deposits that we can see when we look into the macula, and those deposits are comprised of byproducts of the visual cycle. And as part of the visual cycle, there are free aldehydes that are created. And then for some reason, in elderly individuals with some kind of genetic predisposition that's not entirely understood, there's a higher generation of those and then they begin to covalently bind and then accumulate, and that is, we believe, what leads to then the inflammatory cascade that creates what we call dry macular degeneration and its advanced state geographic atrophy. A lot of the other -- the therapies that have been approved are kind of targeting some of those middle steps of the inflammatory pathway to complement pathway, but there is a highly rational approach to exposing those photoreceptor segments to a molecule that's going to soak up the free aldehydes and prevent their accumulation before they form those tight covalent binds -- bond molecules that comprise lipofuscin. And so that -- a therapeutic approach that could affect that pathway would not only potentially be beneficial for the long-term kind of progression of geographic atrophy, but there's, I think, a lot of opportunities to improve short-term visual function because the accumulation of these toxic byproducts affects things like dark adaptation, reading speed, contrast sensitivity. So I think there's a lot of -- I talked earlier about the limitations of current therapy is they don't produce a visual benefit. And I think there's a lot of opportunities by intervening at that part of the pathway that leads to geographic atrophy to improve patients.

And the drugs that are approved today for geographic atrophy are complement inhibitors in a sense, anti-inflammatories. And I think, as we've talked about today, RASP, our pro inflammatory. Another argument we might make is that not only with RASP modulators prevent the accumulation of lipofuscin, but also diminish the inflammation associated in this condition as well. It's a marvelous paper, and I'm happy to send it to any of you if you'd like to see it, correlating at least preclinically, the accumulation of these RASP adducts in the eye with a deficit in dark adaptation and scotopic vision. And so one of the things we're thinking about now as we design our next steps in RASP retina is what is the end point. Is it similar to the one we've talked about in retinitis pigmentosa with a dark-adapted peripheral field? Is it lesion growth? But I think the fact that RASP are related clinically, to some extent, to dark adaptation, it gives us a real-life endpoint that patients might care about. Any other questions? Yes?

[indiscernible]

The question is, are we concerned about methotrexate compounding. And Dr. Stryjewski, maybe you can just talk about that a little bit.

Yes. I think there's several ways to think of it. The most like a practical, I guess, the easiest barrier is that it's extremely difficult to do. It can only really be done in a tertiary care medical center and it has a use time, usually about 6 hours. And so whenever a patient comes, who needs this, it's like a whole-day affair because the patient shows up, someone has like run from the clinic to the pharmacy. It's pharmacist time dedicated to doing this. There's drug shortages as you may have read in the times very frequently with methotrexate. So it's a very -- logistically, it's a very complex thing to do. And most retinal care in the United States is done at like private practices in the community, which is basically impossible to get methotrexate in those places, whereas the 2191 formulation has a 2-year shelf life, likely could be 3 years. So that's, I think, just like the practical aspect of it. I think no one would even like care to. The second is a legal and regulatory framework and that the FDA and Congress want drugs to be GMP-manufactured and facilities to be inspected. And there was a law passed some years ago called the DQSA Act, the Drug Quality Safety Act (sic) [ Drug Quality and Security Act ]. And that's if a formulation has been approved for a specific route of administration, it is not permissible to compound it. And that's Outlook Therapeutics is developing the first branded version of bevacizumab and that's kind of the reason there, is not on label for use in the eye right now. So this has been kind of a, I don't know, well-trodden path of the regulators have thought about. And again, specifically in our case, it's just like very complicated to do this cancer drug to dose it just right to be safe in the eye.

I think there are 2 other practical concerns. One is methotrexate in abortive patient. So in states that are restricting abortion, it is very difficult to acquire any methotrexate. It wouldn't be the case with an injection because of the -- ocular injection because of the volume. The second other practical issue is storage of methotrexate. There are USP regulations that specify very strict methods that need to be employed for storage of methotrexate given the nature of the drug itself. Anything else? Great. Well, thank you, Dr. Maldonado, and thank you, Dr. Stryjewski. I think we will take a break. We will grab lunch for those of us that are here and for my schedule, we'll resume at 12:30. See you everyone then. Maybe 12:15. We'll let folks know. Thank you. [Break]

Okay. Before I lose my voice, I think we should continue. We're going to wrap up today with a discussion of pipeline and milestones and then a final set of questions. Here is our pipeline. We have modified the ADX-2191, retinitis pigmentosa bar, by extending that into the early part of Phase III, but I thought I would run through the other programs, particularly the areas we haven't touched on yet today. So one is reproxalap in allergic conjunctivitis. As many of you know, we've completed 3 Phase III trials in allergic conjunctivitis that were successful in our view. We have not discussed with the FDA submission of an NDA for allergic conjunctivitis. I think to the extent that reproxalap, dry eye disease, is partnered, and as a reminder, AbbVie has an option on reproxalap that would be our partner's decision. I often get questions as to why not just go ahead and submit an NDA for allergic conjunctivitis, your data look good, go ahead and do it. And I think there are all kinds of reasons to think about doing that or not doing that. And they have to do in part with the label, the breadth of the label, the competition in allergic conjunctivitis. As many of you know, you can go to your Walgreens or CVS and buy a top line of histamine over-the-counter, which is relatively inexpensive. And thus, our message has been reproxalap allergic conjunctivitis will be reserved for those patients that are refractory to topical antihistamine use. Now it turns out, at least based on our market research about 1/3 of patients with allergic conjunctivitis do not adequately respond to antihistamines. I'll tell you a real story that happened a few years ago. I have a medical school classmate who came to me and she said, "Well, I heard you were developing a drug for allergic conjunctivitis." And I said, "That's interesting you bring that up." And she said, "I have allergies, and I'm going to claw my eyes out." I have been on every topical histamine. They don't work for me. I can only stay on top of steroids for so long. And thus, I have -- I'm running out of options. And so I suggested cold compresses. She didn't like that suggestion very much. So there clearly is an unmet medical need in allergy. However, how the reproxalap label evolves, particularly with dry eye first will then impact and our partnership situation will then impact whether we or our partner discuss with the FDA allergy for the eye. And I'm happy to answer more questions about that afterwards. We actually have a late-breaking announcement on ADX-629 in Sjögren-Larsson Syndrome. But first, let me tell you what Sjögren-Larsson Syndrome is. For those of you that don't know, some of you have been involved in our story for so many years. Sjögren-Larsson Syndrome is like second nature. This is a rare inborn error of metabolism that involves mutations in fatty aldehyde dehydrogenase, which means that these patients sadly have very high levels of fatty aldehydes. And the 2 clinical manifestations of that. One is ichthyosis, which can result in petrification or death of your epidermis. Epidermis actually sort of falls off, it cracks, it's not hydrated in a sense it petrifies or it rots and these patients have terrible itchy, dermal compromise. The other clinical manifestation is CNS. So cognitive delay in some patients. And so I was just having a conversation earlier during the break, it would make sense to treat the skin condition topically, which we've done in the past with reproxalap before reproxalap started working in dry eye, but it would make more sense to treat the whole disease orally or systemically. And so some years ago, last year, maybe we worked with an investigator, Bill Rizzo, who is the physician that really discovered the biochemical basis of Sjögren-Larsson Syndrome, which is this mutation, fatty aldehyde dehydrogenase to start treating adult patients with oral ADX-629, as we've disclosed previously, those 3 patients that were treated actually did have near normalization of their biochemical parameters as they relate to fatty alcohols and fatty aldehydes. We also disclosed that Dr. Rizzo is going to speak with the FDA about then testing children. Now the reason to test children is the same reason that Dr. Maldonado described about treating children. And that is if you can influence the disease earlier, you can prevent many of the refractory clinical issues that occur down the road. These children are often diagnosed fairly young, some are even diagnosed in utero. And so there's an opportunity to intervene early in the course of the disease. The FDA has now allowed Dr. Rizzo to proceed to children. Our plan is to treat 3 to 5 children in the near future, and we look forward to updating you on that as Dr. Rizzo completes that trial. This is an investigator-sponsored trial, so we don't have control over the trial or the data or the release of the data, but we are happy to keep you updated at a high level. We mentioned alcoholic hepatitis in response to the good questions this morning. That is still on track to produce results in 10 patients open label by the end of this year. As I mentioned, those are severe alcoholic hepatitis patients. Among many endpoints, the primary of which being safety, we also plan to look at mortality, MELD scores, other measures of hepatic function. ADX-246 is on the cusp. As I mentioned earlier today, beginning a Phase I/II trial for atopic dermatitis. That Phase I part of the trial is a single ascending dose, followed by a multiple ascending dose, which is a standard Phase I protocol and pending results from that part, we would intend to extend the protocol to treat on a randomized basis 20 to 30 atopic dermatitis patients based on the Phase I results. The timing of that depends on Phase I. We do typically dose as far as we can in terms of tolerability and toxicity. We have not really identified certainly with ADX-629 orally any consistent toxicology or side effects of dosing. That's all good news, but it does mean for longer Phase I, as you continue on to your next dose and your next dose and so forth. With any luck that happens with 246, and we're able to give a considerable amount of drug, which gives us more flexibility of dosing in diseases down the road. And then the metabolic disease piece we discussed earlier today that's still in preclinical mode. As we mentioned, I think we need to evaluate our data with potential partners versus go-it-alone scenario with a clinical trial. And I think you'll hear more about that shortly. As you know, and as Adam Brockman described, something else we're considering as a trial in pain, we were talking about different kinds of pain, acute chronic neuropathic, if we do decide to initiate a trial in pain, my expectation it would be in chronic inflammatory pain. But we need, I think, to characterize the molecule more fully preclinically in terms of activity and different kinds of pain first. And then finally, with our esteemed KOL panel in retina, we discussed the dry form of age-related macular degeneration, geographic atrophy. And if it were up to me, I would put on their dark adaptation. Because, as Dr. Stryjewski mentioned, this is something that's intimately related to RASP adducts, a; and b, is clinically important to patients who are today tripping over their dogs at night and cannot drive at night. So these are interesting times for the GA and dry AMD field. I think as we move from anatomic endpoints, to functional endpoints that matter to patients, there truly is a brighter future as Dr. Maldonado said for future drug development in that regard. We've added a milestone at the bottom. This is the initiation of the Phase II/III clinical trial in retinitis pigmentosa. We expect to start that trial in the back half of this year. All the other milestones are the same. We have a busy second half of the year, highlighted by reproxalap results. And if positive, an NDA resubmission, but also potentially alcoholic hepatitis data and in the Phase I/II trial in atopic dermatitis as well as the initiation of our dry AMD or geographic atrophy trials that I just mentioned for ADX-248. So with that, why don't I stop and just note that we're thrilled with all the interest we've received of late. I just had an investor call with a front page holder of Aldeyra last week, and their comment was, "I don't want to hear about reproxalap," which I was thrilled. I said, "You have made me so happy." Not because I don't care about reproxalap or believe in reproxalap, it's that the RASP platform and ADX-2191 are so exciting. The breadth is tremendous, potentially for these other assets. And I think what we've talked about today really represents the future of Aldeyra. We don't intend to be a commercial company, marketing reproxalap for dry eye disease, hence, our partnership. What we do intend to do is develop new and novel drugs for unmet medical need. And I think that's been the focus of today. And as always, we look forward to continuing to keep you updated along those lines. Why don't I take any questions before we wrap up? And no questions are fine. Good. Well, thank you all again for coming today. This has been certainly enjoyable for us as a management team, I hope you've had a chance to speak with our management team members that are here today, and it really is a pleasure to see everyone in person again. Thank you.