Thanks for joining us today at Oppenheimer's Healthcare Conference. It's my pleasure to host this fireside chat with Aldeyra Therapeutics and CEO, Dr. Todd Brady. Thanks for joining us today, Todd. It's always a pleasure to chat with you like this, and, you know, it's great to have you.
Great to be here, Justin. Thanks for the invitation. Can't wait to get into our fireside chat, as always.
Yeah, so maybe just to begin, you know, for those maybe less acquainted to the story, you know, could you just give an overview of, you know, Aldeyra's approach, the sort of systems-based approach to drugging immune and inflammatory diseases, and maybe what the latest for the company has been?
For sure. Aldeyra was founded, gosh, I would say, 2004 or 2005 or so, based on a novel target that is systems-based, as you described. And what that means is, it's not a single target. Most drugs that we use today, essentially all drugs, target a single protein, whether it's a receptor or an enzyme, an agonist, antagonist, what have you. Or maybe some drugs are proteins or antibodies to proteins, but what we really don't have are drugs that target classes of molecules. And so, RASP is the name of the target that Aldeyra was based on originally, reactive aldehyde species, which is really a group of small molecules, which is quite unique, A, not a protein, B, not a single target, and that truly is systems-based.
I think what it allows us to potentially do is modulate large groups of proteins that respond to those small molecules that we call a RASP. We started in immunology, as you point out, because immunological disease is characterized in part by elevations in RASP. Sort of potentiate immunological processes and ramp up inflammation, and if we can modulate that process with our novel small molecules that we call RASP modulators, then maybe we can dampen a variety of inflammatory processes. So truly, it's the sort of this platform approach, where we attempt to modulate a lot of things at once, thereby minimizing the toxicity that you might see when you turn down or turn off, or turn on a single protein at once.
Great. And, you know, this has sort of crystallized into a number of key programs for the company, and I think, top of mind has been sort of the reproxalap story. So, can you just talk a little bit about, you know, reproxalap and sort of the recent updates over the past, I guess, month or so, regarding, you know, SPA agreements and initiation of trials, as well as when, you know, you think the company could be on track to plan a resubmission to the FDA?
Right. Well, I was hoping, Justin, that 2024 would be the year that we realize the Justin Kim vision of Aldeyra Therapeutics, which really, as you've been saying for many years, is about modulating RASP broadly across the body, not just in the eye. So if reproxalap is sort of the proof of concept molecule, where we've shown activity across a number of clinical trials, then, well, it seems like you could affect other parts of the body as well, and this is what you said many years ago. And I think the idea really is to develop this RASP modulating platform from the eye, really to the back of the eye, the retina, and then throughout the rest of the body. And we will one day get there.
However, last year, as you point out, we submitted a new drug application for reproxalap in dry eye disease. After a number of successful phase II and phase III trials, the FDA came back and said, "We've reviewed your package. We want you to do one more trial in symptoms that is showing that reproxalap is better than vehicle in improving the symptoms of dry eye disease." So yet again, reproxalap is back on the agenda, and I think it represents 75% of the questions I get from investors these days is, "How are you going to run this symptom trial? When is it going to be run? How much does it cost?
How much have you talked about the protocol in terms of the specifics with the FDA? Does the FDA agree, and so forth, and the timing, and when do you expect to resubmit and so on?" So, recently, in fact, as of some weeks ago, we updated our corporate deck, which is now available on our website.
In fact, we re-8-K'd the corporate deck today, highlighting the fact that we have not yet started the symptom trial for reproxalap, that we hope will remedy the Complete Response Letter issued by the FDA, requiring another trial. But we do expect to start that trial shortly. We remain in dialogue with the FDA regarding the protocol of that trial because we want to make sure that we're synchronized before we run off and complete another clinical trial and then resubmit the NDA. But the data from that trial and the resubmission should be available next half. So, we won't be waiting very long for those data. It's an interesting situation we're in, Justin, because this is a big deal for the company.
Obviously, we've been in dialogue with the FDA about the protocol, so they're not going to see anything they haven't seen before or discussed with us in some detail. One would expect then, if the trial is positive, that would bode well for approval of the drug. Anything is possible. The trial may not be positive or the review may not turn out in our favor. But having said that, we've spent a great deal of time with the agency. I think we know exactly what we want. I think we're at the tail end of figuring out how to run that trial, and we're just on the cusp of starting that trial, and so we won't wait very long. I think if the results are positive, it bodes well for approval.
But also, we have this deal with AbbVie, a co-promotion deal with AbbVie, where they can choose to opt in to the co-promotion. And that comes with it a $100 million upfront fee, less what they've already paid us for the option, which is $6 million to date. And then if the drug subsequently is approved, then there's another $100 million milestone fee. So I think, for the first time in our corporate history, we have a pivotal trial that you would think would be the last piece of the puzzle for approval, potentially, that is then tied to a significant corporate deal with a large pharmaceutical company. So I think, very meaningful for us, and hence, why 75% of the time, and speaking with investors these days, reproxalap is the topic du jour.
Mm-hmm. And maybe not to get too sort of into the nitty-gritty, but, you know, just in light of maybe the updates at the beginning of the year, you know, the company noted some, I guess, amended amendments, right? Like, in terms of its thinking for the chamber study. And, you know, can you just. Are you able to share? To what extent are you able to share, you know, what the current thinking is on a design for a chamber study to maybe address what was, I guess, around the pre-specified nature of the endpoint for the study that was submitted previously?
Correct. So, we've shown positive data from dry eye chamber trials in the past. We've showed positive data for redness and Schirmer score, which is a measure of tear production, and then finally, symptoms. So, you know, even before the complete response letter was issued, we were in dialogue with the agency about what kind of other chamber trials can we run to demonstrate activity and symptoms. And, you know, the question is, is this chamber trial a crossover trial, where every patient is treated with both drug and vehicle at different times? Or is it a parallel group trial, which is the other kind of clinical trial, that is, there's a group of patients treated with vehicle and a separate group of patients treated with drug.
I think that's sort of the crux of the discussion that we have ongoing. I think either way, my guess at this point, just based on where we are with the agency, is that a chamber trial is feasible. Again, the dialogue could change or shift course, but again, I think as I said, I think we're at the tail end of that discussion, and my guess is that a chamber trial is feasible. We're really interested in this concept of dry eye chamber trial, which is part of the FDA's draft guidance in dry eye disease, because the chamber trials are quick. Subjects are typically treated or exposed to the chamber for 90 minutes. So, this is really fast relative to the standard dry eye trial that takes many weeks and often months.
It's not just good for us as a sponsor running the trial, but it's good for patients, because you can demonstrate activity and theory within minutes of application, and that's really what I think the industry is lacking. What patients and physicians don't quite have yet is a drug that works super fast. I think we have drugs that work within weeks, but as a dry eye patient, I think you want drugs that work faster than weeks, and that's really what we're out to prove with the dry eye chamber trial.
Okay. In terms of the crossover versus parallel, sort of format, you know, are there meaningful differences between the two? Like, are they slightly different in size, or how long they might take to enroll or complete? Like, can you just sort of talk about, you know, when you think about sort of the timelines that you've sort of already articulated, are you already taking sort of the more conservative of the two, or just kind of how to think about, the potential outcomes following the discussions with the agency?
Crossover trials are interesting because they eliminate patient-to-patient differences, right? You compare yourself to yourself. Yourself on drug versus yourself on placebo or vehicle or what have you. Parallel group trials are typically larger, as you point out, because the patient-to-patient differences can be quite significant. So, if you're in a dry eye chamber, you may think, "Oh, my gosh, this is the worst thing that's ever happened to me." I may think, "Oh, it's okay, but not great," you know? But for the same level of discomfort, people react differently, and that's why parallel group trials are larger, because you need to average out those patient-to-patient differences. As I said, either way, I think though, we have a good path forward.
One option in parallel group trials is to compare patients to their own baseline chambers, either with or without a therapeutic intervention. And that allows some sort of intra-patient comparison, but in a parallel group fashion. So, all patients at the beginning may have no treatment or they may have treatment vehicle, and then they're randomized to vehicle or drug, and you can still have that sort of person-to-person comparison. But this is sort of what's at the heart of the dialogue with the agency at this point, and I expect that next month we'll have a press release. We'll outline the plans going forward for the drug, and I think many investors will be satisfied as to the timing and the nature of those trials going forward.
Okay, great. Sounds good. In terms of , I guess then sort of the next steps, right? I mean, getting this study initiated, enrolled, hopefully recapitulating the results that we've known to see and expect from studies of reproxalap. How do you think about sort of what happens afterwards, right? I mean, I think you've talked a little bit about how Aldeyra has been about, you know, broadening the scope, being a systemic RASP play, and simultaneously, you could be embarking on sort of this sort of commercialization with your partner. You know, have you talked with AbbVie on this sort of points? Like, is this more of a conditional thing? Like, is it sort of once you have that line of sight on a resubmission, then you sort of start to do that planning?
Can you just talk about sort of the you know, focus on commercializing in dry eye and sort of what role AbbVie you know, you think, or hope might play in that?
Well, certainly we're thrilled to have AbbVie as a partner. You know, in many respects, they're the only big pharma left in the front of the eye, that is, the ocular surface, and were the original creators of Restasis, which was the first dry eye drug. From our perspective, we, we couldn't have a better partner. AbbVie is, of course, synchronized with everything we're doing. We're very happy about that, just given the amount of experience that they've had in, in the dry eye space. As you know from what we've disclosed, the subject of the deal with AbbVie really is primarily reproxalap. However, AbbVie also has first look rights, regarding, drugs that have anything to do with immunology. That is, they get a period of time to look at the data before anyone else does.
And they also have right of first negotiation rights for anything else in the front of the eye, as well. So, it's a pretty broad deal, and I would think that AbbVie thus therefore has an interest in sort of a broader approach than just reproxalap. But obviously, the focus at this point is to get reproxalap approved and then commercialize the drug with maximal efficiency.
Okay, and I mean, h ow should we be thinking about allergic conjunctivitis then? I know we had talked a little bit about sort of the attractiveness of the indication, maybe ex-U.S. But sort of given the focus on dry eye, you know, AbbVie as a partner, like, is that sort of still, you know, on pause right now? Like, just kind of walk us through how we should be thinking about the potential to expand reproxalap's reach.
Well, I can't speak for AbbVie, but I can speak from our experience. We've traveled the world talking to other companies, and really, depending on where you are on this planet, the relative importance of dry eye disease and allergic conjunctivitis changes. I can tell you that in Asia, there's just a huge emphasis on allergic conjunctivitis. I think many, many millions of people in Asia suffer from ocular allergies. Today, we use topical antihistamines, that is, eye drop antihistamine drugs, to treat allergy, and they work in most patients, but not all. I think the latest numbers are still sort of a third of patients don't really respond to antihistamines. So then, what do you do with them? You can give them a steroid, a topical corticosteroid, but you can't use those long term.
So, there really is, I think, demand and medical need for something that's not a steroid, that can be used chronically, especially to treat patients that are refractory to antihistamines, and that's where reproxalap would fit. We announced last year our second positive phase III trial in an allergen chamber, much like a dry eye chamber, except instead of dry air, it's with aerosolized pollen. In terms of our view of allergic conjunctivitis versus dry eye disease in terms of the regulatory process in the U.S., I would definitely say that allergic conjunctivitis is in the back seat. We've submitted an NDA for dry eye disease. We are running at least one more trial to satisfy the FDA's needs in that regard. We intend to see that process through, and, if and when it's successful, we can think about, allergic conjunctivitis.
Okay, got it. Now, I promised that we'd sort of split the time, and I think let's, maybe we can talk a little bit about the systemic sort of platform. You know, can you just sort of remind us where things stand across the indications being pursued there, and I guess maybe the number of shots on goal as well, given that you're looking at a number of molecules as well to systemically address RASP?
You know, in the beginning, in the early days, it wasn't clear to us whether this sort of systemic RASP modulation would work, especially in diseases that affect multiple areas of the body. And so, we developed this, what we call sort of a signal-finding molecule called ADX-629. We tested in asthma. We tested in COVID, back when the COVID pandemic was raging. We tested in psoriasis. We subsequently tested in atopic dermatitis, in chronic cough, and alcohol toxicity, and so forth. And what we really found was that across the board, there were signals of efficacy. Now, they were small trials, and some of them were controlled with vehicles or placebo, some of them weren't. But overall, it feels like that RASP modulation represents a novel approach to treat these sort of immune-mediated diseases, and therefore represents a platform.
So, ADX-629 is now down to two diseases—one of them will read out this year, at least the first 10 patients of this indication, which is instead of MASH, Metabolic Associated Steatohepatitis, it's now moderate alcohol-associated steatohepatitis. These are our patients with moderate alcohol-induced hepatitis. Often, they're quite sick. What's interesting though for us is that when you drink ethanol or alcohol, you make a RASP, and that molecule is called acetaldehyde. Acetaldehyde is readily bound by our RASP modulators. In fact, we ran a trial we announced last year, where subjects drank high amounts of alcohol. They had to reach a certain blood alcohol level, and then we tested whether or not ADX-629 could modulate symptoms and signs of alcohol toxicity.
And indeed, we reduced flushing, and we improved balance time, and so forth. So ,I think, there's reason to believe that we'll see something positive in this alcohol-associated hepatitis trial. Again, the first 10 patients, open label, are expected to read out this year. The other thing left for ADX-629 is a disease called Sjögren-Larsson syndrome, which we talked a lot about in the past. Sjögren-Larsson syndrome is an inborn error of metabolism that leads to elevated levels of RASP, in this case, fatty aldehydes. And the notion would be that you could administer ADX-629 to these patients, and then over time modulate levels or reduce levels of these fatty aldehydes, which cause neurological damage. They cause dermatologic damage, so forth.
So, we've completed, or at least an investigator that works with us and is running his own trial, an investigator-sponsored trial, has completed the first three subjects. Those are adults. We announced in January that those results were positive from a biomarker standpoint. And then, he intends to approach the FDA to move to the pediatric cohort, where we could really, I think, in theory, make a difference. If you can, over time, as children are growing, prevent some of these fatty aldehydes from modifying tissue, then there might be a clinical benefit down the road. So that's ADX-629. ADX-246 is soon to initiate, we believe, a phase I clinical trial, followed by potentially a trial in atopic dermatitis, which would be randomized. ADX-246 is sort of like a more potent next-generation version of ADX-629, orally administered.
And the idea there would be to show some activity in patients with atopic dermatitis, like what was shown at the end of last year with ADX-629, except this time in a controlled fashion with a placebo control. And then finally, we have a preclinical program with a molecule called ADX-248, looking to begin clinical testing this year. In retinal disease, we'll probably start with the dry form of age-related macular degeneration, which has two issues. One is sort of this RASP-mediated inflammation, and the other is RASP-mediated aggregates or indigestible molecules that build up in the back of the eye, which can form things like drusen or lipofuscin. Big issues in patients with dry AMD, and geographic atrophy, and related conditions. So, we look forward to talking about that later in the year.
Okay, great. Maybe on the SLA point, sorry, SLS point, you know, we've sort of had the topical cream, right? That had sort of taught us some learnings there in terms of the agency's desire for controls for safety. You know, just wondering, do you think that the regulatory landscape has shifted any, like how should we think about the investigations with ADX-629 and, you know, the appetite or flexibility around control patients in this rare disease?
So, years ago, as you point out, you have a good memory, Justin, we actually used reproxalap, not as an eye drop, but as a dermal cream, applied topically to the skin of these patients, which is severe. I mean, they represent sick patients with skin that literally putrefies or rots simply because of these toxic RASP or fatty aldehydes that accumulate in the skin and related molecules. And, we showed activity. We even compared reproxalap to a vehicle cream, and were able statistically to show a difference between the two. I think the question there, though, was: Do we pursue reproxalap for dry eye disease as an eye drop, which is a large market and so forth, or do we continue to pursue reproxalap for an orphan disease for skin?
You know, there would be numerous clinical trials required and so forth for that. We focused reproxalap on the eye. Going forward, I think we're still enthusiastic about ADX-629, though, which is taken orally, because ADX-629 has the potential to benefit not just the skin, but also in neurological issues, which I think in many respects, are ultimately more important to patients, in terms of cognitive delay, and development, and spasticity, and the potential for seizures, and other kinds of things that affect these patients on a daily basis. We'll see. We had great biomarker data, which I think will be released by the investigator in the near term, in terms of improving fatty alcohol and fatty aldehyde levels in adults.
We'd look to see if that could translate also to the pediatric cohort, and whether there will be clinical changes associated with those biomarker improvements in the pediatric population as well.
Okay, great. We'll look forward to it then. You know, I guess ,the other thing that we wanted to maybe cover might have been on maybe just kind of feasibility around chronic cough. I mean, you know, when you think about that indication, you know, is the prioritization away from chronic cough sort of more a function of the regulatory landscape than sort of something in terms of, like, the development hurdles there? Can you just talk a little bit more about that?
Chronic cough's had a rough go. I know that Merck had a CRL, or a lack of approval of a new drug application in chronic cough recently. It's not quite clear to us where the FDA is gonna land in that direction, so that indication has been deprioritized. We had also thought about post-infectious cough, which affects us all, as we have upper respiratory tract infections, and we continue to cough long after the infection is cleared in many cases. But the challenge there often is that most of us get better, and really, it's a time to clearance or a time to lack of cough kind of issue, which are large, difficult trials to run. So, for the time being, chronic cough has taken a back seat.
Okay, got it. And maybe then just sort of shifting gears to ADX-246 and atopic dermatitis, which, you know, there is, there are some really intriguing results initially, and you know, it was really interesting to hear the clinician enthusiasm from the call the company hosted. You know, as you think about the product potential product profile of ADX-246 in this sort of particular indication, you know, it's obviously a very competitive field. I'm just sort of curious where you think ADX-246 can be most competitive, and how you think about sort of, you know, generating that sort of clinical signal as you embark on enrolling additional patients into additional studies.
Well, we were really lucky to work with Matthew Zirwas on that trial, who's sort of a nationally known clinical trialist in atopic dermatitis. And his whole point, to your question, is that what we lack in atopic dermatitis is a safe drug that can be given chronically in mild to moderate patients orally. So, today, we have injections, and the injections work pretty well, obviously not the preferred route of administration, particularly in children, where this disease, atopic dermatitis, is quite common. So, therein lies, I think, the Holy Grail. If a company can develop an orally administered, safe drug that works in mild to moderate patients, that is a space that has not been worked out, and I think there is just tremendous unmet medical need, which is why the ADX-629 results at the end of last year were so exciting.
They look just like the psoriasis results. Over 90 days, patients seem to improve, and many of these patients, as Dr. Zirwas pointed out on the call, are refractory. They haven't improved very much in a long time, and to see a group of patients get better over time, is quite amazing. And I think, you know, the idea would really be to replicate that in a controlled setting. If we can have a placebo group that doesn't do as well, at the same time, a drug group with ADX-246 that does do well, that could lead to compelling reasons to continue development down the road.
Okay. And just on the vein of sort of children and sort of safety, you know, when is the time to sort of peel back the age group to treat lower adding sort of adolescence? Is that something that, you know, sort of quickly drafts a primary program or something that you think, you know, once you go maybe to pivotal, you might have sort of a pretty broad inclusion, exclusion criteria?
Well, it's always a discussion with the agency, as we were talking about with Sjögren-Larsson syndrome. Typically, you want to start out adults, and that's what we've done in atopic dermatitis, and I think we'll do the same thing with ADX-246 in atopic dermatitis. You have data, you look at your adverse event profile, your tolerability profile, you discuss it with the agency, and as your trials continue to progress, you add in more and more younger patients. And again, it just depends on the profile of the drug and what that particular division, the derm division at the agency, thinks is appropriate.
Got it. And maybe just a final last covering point as we go back to the eye, but maybe the back of the eye. Is there anything we can sort of hope to look out for from ADX-2191 this year or next?
So, ADX-2191, the development there is that we've discussed proliferative vitreoretinopathy or PVR with the FDA. We presented the results of the GUARD trial, which were released last year. The FDA is requesting two additional trials in PVR. As you may recall from the data release around the GUARD trial, those trials are very difficult to enroll. Many surgeons really, quite frankly, hate to randomize patients because they want to treat them. There's a lot of belief that methotrexate is active, which is why we switched the GUARD trial to a historically controlled trial versus an internally controlled trial versus standard of care. But with that comes the need for two trials that presumably would be internally controlled.
We've decided that it's probably not the best use of shareholders' money to run two large PVR trials at this point. So, we've deprioritized PVR and are now focusing ADX-2191 on retinitis pigmentosa. We have a meeting coming up this quarter with the FDA to talk about a pivotal trial in retinitis pigmentosa. As you recall, we treated eight or so patients open-label with ADX-2191. Those patients improved in terms of peripheral, that is not central what you're focused on, but sort of peripheral vision, sensitivity in low-light settings, which is really a key issue in retinitis pigmentosa patients. We saw improvement where you wouldn't expect to see improvement in these patients.
And so, what we're doing is discussing a protocol with the agency, that we could run, to sort of confirm, perhaps in a pivotal setting, the activity of ADX-2191 in a controlled setting or a controlled manner. And, the results of that discussion, I think, will be out, next quarter, and that, I think, retinitis pigmentosa represents the future of, of ADX-2191.
Okay. Maybe just if I can squeeze one more last one, you know, just kind of reminded me. You know, given some of the changes at the agency, you know, have you felt that the messaging has been relatively consistent? I mean, I'm just sort of curious if you feel like there's still quite a bit of continuity, right? With sort of a changing of the guard and just any thoughts there.
That's such a great question. I hear that a lot. But Bill Boyd is the acting director at this point. Wiley Chambers, after 30+ years, the division is no longer there. I think it's too soon for us and other companies to know how that division will change, if at all. In the near term, I think, Dr. Chambers, you know, had his fingerprints on the written documents that we've generated to date, and I don't expect very much to change. Dr. Boyd has been there for many, many years. And, yeah, my guess is, in the short- term, we won't see very much that's this different, which I think is good news for us and other companies that have worked with this division in the past. As for the long- term, Justin, who knows? We'll just have to see.
Okay. Well, we'll just have to see, and, you know, thanks again, Todd. It's always a pleasure and look forward to the progress.
Good to see you, Justin. Thanks again