Hey, welcome everyone to the H.C. Wainwright & Co. Global Investment Conference. My name is Matthew Caulfield, Senior Biotech Analyst here at H.C. Wainwright & Co., and we're pleased to be joined by Dr. Todd C. Brady, CEO of Aldeyra Therapeutics. Todd, great to see you as always.
Thank you, Matt. Pleasure to be here.
Absolutely. Maybe to start things off, Todd, you could give us a high-level view of where things are for lead candidate reproxalap in dry eye disease, and then also some of the main progress you've made for the broader RASP pipeline.
Matt, I thought we were going to talk about reproxalap. That was our agreement, yes?
No, reproxalap is our lead asset, and I would say 95% of our conversations with investors are about reproxalap because we have a PDUFA date coming up, mid-December. That's December 16th, and if the drug is approved, our commercial partner AbbVie has 10 business days to exercise an option, which if they exercise post-approval is worth $194 million in cash to us per the terms of the option agreement. By the way, 10 business days plus December 16th is December 31st for those of you that are interested during your break of keeping track of where everything is. That's why our investor conversations are about reproxalap. We resubmitted the NDA in June, as you know, because it's a resubmission. It's a six-month review process. The issue with the last submission was a baseline imbalance that the FDA had identified between treatment arms of seven points on a 100-point scale.
You can read about it in our newly released CRL that the FDA issued last week. The new trial, though, didn't have that kind of baseline imbalance, only two points between treatment arms. Thus, given the highly statistically significant result, we think we're in good shape from the trial side with this submission. Very exciting. The accepted NDA package includes the phase 3 dry eye chamber trial for ocular discomfort, along with support for benefiting ocular redness and providing dry eye impact measured in minutes instead of waiting weeks or months for a response, which is kind of more the standard of care. Do you believe the inclusion of additional materials such as the dry eye field trial safety, for instance, makes the review any more nuanced?
Right. That's a good question, Matt. I mean, we had run two trials to satisfy the CRL. One was a chamber trial, which worked well. I just described the results there. The other one was a field trial. A field trial is when you go home and you take the drug for weeks and patients report how they feel and so forth. That didn't reach statistical significance. The FDA allowed us not to submit that trial in the last NDA submission. However, the safety data does, of course, go in as part of the 120-day safety update in that submission. We only have safety data from the field trial there, and I think, as we've consistently disclosed, we're not aware of any safety issues.
That's great.
In any product, any patient that's been treated with the product, we've had over 2,000 patients treated to date.
Oh, that's great. Obviously, investors have been excited about the near-term PDUFA date for reproxalap on December 16th that you mentioned. Can you help us best understand the current limitations for treating dry eye disease considering the varied products and OTC options that are out there?
You mentioned, Matt, two of our greatest attributes. Thank you for that commercial there. One is redness. Eyedrops that do well make you look better. If you have an eyedrop on the market and you make patients look better, those tend to sell very well. Redness is our so-called sign. In dry eye disease, you have signs and you have symptoms. Signs are things that investigators assess or optometrists assess or physicians assess. Maybe the only sign that patients care about is redness. No one wants to have red eyes. That will be in our label. We have two positive redness trials. I think that's a commercial boon for the product. In fact, reproxalap, if approved, would be the only drug for dry eye disease used chronically and has redness data on the label. The other part is discomfort and dryness. Those are two common symptoms of dry eye disease.
I like to say in theory, you'll look better and you'll feel better at the same time with reproxalap use. Today, we don't have that necessarily in other dry eye disease drugs unless you want to wait weeks or maybe months for those kinds of changes to take effect. No drug in a chronic setting is proven to improve redness. I think we're commercially advantaged for those two reasons that you mentioned. I think in large part, I would guess that's why AbbVie entertained the option on reproxalap because with those kinds of commercial advantages, there's a potential for the drug to sell very well.
Absolutely. As we consider reproxalap's novel mechanism as a reactive aldehyde species or RASP modulator, what is most important to appreciate about how the mechanism can improve upon standard dry eye treatments and ocular inflammation?
Our target is something called RASP. We're the only company involved in RASP at the moment that I'm aware. RASP is unique in that unlike every other drug you've ever heard of, they are not a protein, right? Every drug you take, you have taken probably affects a protein, a receptor, an enzyme in some form or other. RASP are small molecules. Not only are there, there's not just one RASP, there's many RASP that modulate inflammation. They modulate your blood vessel dilation. They modulate how you feel and symptomatology. If you could affect RASP, you affect a lot of different proteins at once. This is probably one reason why we're improving signs and symptoms of redness and discomfort at the same time. Given the breadth of RASP as a target, with one drug, we have the potential to modulate a lot of different signs and symptoms.
I actually think when our grandchildren or great-grandchildren are taking drugs, they won't be taking drugs that do one thing. They'll be taking a single drug that does a lot of things. This sort of systems-based approach where you're attacking not just one target, but many targets, where you're modulating not one protein, but many proteins, that's sort of the future of pharmacology. We haven't quite gotten there yet, but I think reproxalap and the RASP modulators we'll talk about later in this chat are a step in that direction.
Mm-hmm. Understood. You alluded to this, but another key piece for reproxalap is the outstanding option agreement with AbbVie. You know, it's a very, you know, interesting and, you know, important opportunity for the program. What do you think are the top considerations for investors in the near term? Obviously, sort of a binary event with the PDUFA, but what comes to mind in terms of considerations?
The top two questions I get are, are you going to get approved and is AbbVie going to exercise? Right? Those are the two questions I get. We've talked about the potential for approval. AbbVie obviously is very engaged on a commercial front. You can see that per the terms of the option agreement that have been disclosed. They have rights to participate in development, to participate in any regulatory activity. We expanded that option late last year to include more commercial supply, that is more eyedrops. As you would imagine, if you're a large pharmaceutical company and you're tasked with launching a product, you're going to be very busy right now because we're three months ahead of PDUFA.
In fact, when this fireside chat ends, I'm going to run to the airport and fly to Chicago so that I can participate in the AbbVie partnering meeting, which is being held tomorrow. You can expect that they're very engaged and have been not only on a pre-commercial front, but also on a development front as well.
That's very exciting. And then kind of thinking about the dry eye market overall, can you tell us a bit more about the market opportunity within dry eye disease and how you see reproxalap being able to penetrate that market? Do you think patients would have to step through standard cyclosporine eyedrops, for instance? What are your thoughts there around the market?
I think that pillar research has been done in terms of thinking about now that we have a generic dry eye drug out there, which is cyclosporine, the generic Restasis, which by the way Allergan invented, which was then bought by AbbVie. I like to say that AbbVie invented dry eye in a sense. They're the perfect partners for us, they're the only big pharma left in the front of the eye. We're all going to get dry eye. We just will. I mean, we're all staring at computer screens, we're staring at our phones. Our kids are staring at phones more than we stare at phones. It's just this endemic, behavioral pattern that's going to lead to more dry eye. On top of that, we have global warming. We have pollen. We have pollution. All of these things are contributing synergistically to increase dry eye.
I tell people if your eyes aren't dry yet, they will be. You just wait. Today we have eyedrops you can buy over-the-counter, artificial tears, very temporary relief. For patients that fail eyedrops over-the-counter, you then go to your doctor. Now we have several kinds of drops on the market that are scripted. The problem is they take weeks or months to work. If you ever just look at the drug labels, no one describes activity in days. No one describes activity in minutes. What we need is a drug that works fast. When a patient comes into the doctor's office or the optometrist's office with a hot eye, the last thing they want to do is wait weeks or take a drug for weeks.
I've taken some dry eye drugs, and the last thing I want to do when I have a flare or a bad day is wait another two weeks for taking these drugs. I think what characterizes dry eye is bad days. It's not like every day is a bad day. Many days are bad days, and you want to treat your bad days. You don't want to treat your good days. That's flare. That's the definition of flare. What simulates flare is the dry eye chamber. That is a room much, much smaller than this, with no humidity, dry air being blown in your face. They tell people it's like sitting on an airplane with those vents. This just happened to me yesterday. I sat down and for some reason, the guy next to me aimed both vents at me.
The first thing I did was turn them both off because it dries out your ocular surface. I'm always looking at my computer screen on top of that. These are bad days. These are flares and exacerbations. This is what our clinical data are based on. They're based on dry eye chambers simulating these bad days. There is no dry eye drug out there that has dry eye chamber flare data in their label, period. I think this is a major opportunity for reproxalap and drugs like reproxalap to capitalize on.
Absolutely, in terms of the onset, efficacy, and durability benefit over time.
Right.
Even looking beyond reproxalap, obviously that's a big focus for investors, but there have also been recent announcements for intravitreal methotrexate candidate ADX-2191. There's the Fast Track designation in retinitis pigmentosa and also the EMA orphan designation, including primary vitreoretinal lymphoma. What more can you tell us about this non-RASP side of the pipeline?
ADX-2191 is the first that we're aware of intravitreal methotrexate. Why is that interesting? Methotrexate injected into the eye is the gift that keeps on giving. There are many conditions that are treated with intravitreal methotrexate. The primary one is ocular lymphoma. Some people, believe it or not, develop lymphoma in their eye. That's where it starts. The problem is that if you don't treat it, it metastasizes to the brain. Your ocular nerve is part of your brain. It's just an extension of your brain. In fact, the back of the eye is the only part of your brain you can see with an exam. You have to treat that lymphoma before it metastasizes to the brain. Nonetheless, these patients have about a 4.5 year median survival. Today, what you do is you take intrathecal methotrexate, that's methotrexate injected into your spine.
You break open the vial, you take your little syringe, you pull a tiny amount out, and you inject it into someone's eye. You can imagine all the issues there: potential for dosing irregularities, potential for infection, and so forth. First intravitreal methotrexate, this is ADX-2191, is the subject of a special protocol assessment agreement with the FDA. They've agreed to the protocol. It's a single trial for approval in theory, or a single trial to support an NDA submission. We have all of 20 patients in the trial by design. We hope to start enrolling at the end of this year, data potentially end of next year. You can't use placebo in these trials. The patients will die. Instead, we have eight doses a month in one arm and one dose a month in the other arm. Comparing the two arms, the endpoint is clearance or remission.
Cells from the back of the eye. It's exciting because today there's no product approved for lymphoma, and beyond that, I think there's a true unmet medical need. First, you lose your sight, and then you lose your life eventually. We're pleased to be part of that program. You mentioned retinitis pigmentosa, another orphan disease that in theory could be treated with methotrexate. We ran an open label trial some time ago. All patients improved versus baseline. There's another disease that essentially has no approved therapy and will inevitably lead to loss of sight. I think there's good clinical and preclinical evidence that methotrexate can make a difference. Hopefully over the next couple of years, we post a positive result there. I think there's another indication that really demands a product.
Absolutely. With several other candidates in the RASP pipeline, how do you plan to prioritize the different programs? Maybe first focusing on the clinical work, that includes ADX-248 in atopic dermatitis and ADX-629, the alcohol-associated hepatitis program, Sjögren-Larsson syndrome as well. How do you kind of think of these separate programs within the clinical space so far?
Broadly, RASP are pro-inflammatory. Anti-RASP molecules like we have are anti-inflammatory. I just continue to be impressed with inflammation and immunology broadly. Talk about drugs that have multiple indications. Think about Dupixent. Think about AbbVie's drugs, Rinvoq and Skyrizi. Think about Humira, before those drugs. I mean, a drug that is active immunologically, there's a lot of different indications that you could exploit. That's the idea behind ADX-248. Instead of an eyedrop, it's a pill. ADX-248, we hope, could be the first drug taken orally to treat mild to moderate atopic dermatitis. That's important. Today, we can treat severe atopic dermatitis with injections, but who wants to get injections? Particularly not kids. Atopic dermatitis is a disease that is common in the pediatric population. There's a huge unmet need for an oral. There are no drugs that are orally administered that are approved for atopic dermatitis.
We're in the middle of phase 1. The good news is the drug to date appears to be remarkably safe. The bad news is, it's taken more time to dose escalate and test higher and higher doses. I'd much rather be in that position, though, than the alternative, which is an unsafe drug with a narrow therapeutic window. Hoping to wrap up phase 1, if not end of this year, early next year, we'll move into atopic dermatitis again as one of the first drugs. I hope it's approved for oral treatment of atopic dermatitis. Behind that, we have a future phase 1 program in ADX-246, which is another injectable, ocular injectable for dry age-related macular degeneration. Dry age-related macular degeneration or the dry form of age-related macular degeneration is another disease that we will all get. We're into the dryness. The front of the eye, it's dry eye.
In the back, it's dry age-related macular degeneration. It's a disease of aging. There's no approved therapy for dry age-related macular degeneration. We have approved therapies for geographic atrophy. Those are complement inhibition therapies, but nothing really shown to improve vision, which is key. I was just telling Matt earlier today, I'm sold now. I can't see as well at night and I trip over my dog. That kind of thing. This is the main symptom in dry age-related macular degeneration. If you can't see as well at night, particularly peripherally, it's the periphery of your retina that's responsible for dark adapted vision. Those are some of the first symptoms of the dry form of age-related macular degeneration. We need a drug that has been shown clinically to improve symptoms. How well can you see? How well can you appreciate light, dark adapted environments, particularly periphery?
That's where we aim to go. RASP are at least preclinically intimately linked to dark adapted vision. In fact, if you have higher levels of RASP, your dark adapted visual capacity goes way down. That's what we intend to test clinically. Hopefully, it'll be in the clinic next year.
Excellent. That's some very exciting work on the pipeline side. Maybe in our last minute or so, I just wanted to ask, you know, beyond, obviously, there's the December 16th PDUFA for reproxalap that's kind of front and center. What else can investors watch for during the end of 2025 into 2026? I know you've mentioned a couple trial timelines. What would you think would be the top maybe one or two catalysts to keep in mind?
I think beyond the December PDUFA, beyond the potential AbbVie exercise, beyond the reproxalap launch, you'll have the initiation of lymphoma, mm-hmm, again, which is a single pivotal trial designed to support an NDA submission. Data possibly as soon as the end of next year. Beyond that, initiation of phase 2 trials and the two programs I just talked about, atopic dermatitis and the dry form of age-related macular degeneration. Data depends on when we start those trials, but our goal really is to have a series of late-stage catalysts initially followed by earlier stage catalysts so that we have a regular news flow from here into the visible future.
Excellent. A lot to be excited for. Thank you. With that, I'd like to thank everyone. I'd like to thank Todd and Aldeyra Therapeutics. Thank you very much.
Thanks.