To Jefferies Healthcare Conference in London. My name is Clara Dunn. I am one of the biotech analysts here at Jefferies. Thank you for joining this session with Aldeyra Therapeutics. I am joined by Dr. Todd Brady, President and Chief Executive Officer of Aldeyra. Welcome, Todd.
Thanks, Clara. Great to be here. Man, what a conference. This is such a big conference these days, and I'm appreciative of all of you showing up on the last day. I know this has been a marathon, but we're deeply grateful for you being here.
Great, Todd. Yeah, so a lot of exciting milestones happening at Aldeyra with your Reproxalap upcoming for DOPHA in December. I'm sure we'll talk about it. Before we go into details, maybe it's helpful for you to give an audience an overview of Aldeyra's story first.
Absolutely. We are an immunology company. I and I, as they say these days, the letter I, not E-Y-E. We happen to start out in the eye. The eye is very important. It is immune privileged. It is what we use to see. It is one of the things that people rank most highly is vision. We are sort of pleased to be starting out in the front of the eye, at least. You mentioned our PDUFA date. We are just under a month for an FDA decision on our lead asset for dry eye disease, which is something we are all going to get eventually if we live long enough. Dry eye is endemic. We are all looking at our cell phones and our computer screens, and that is particularly true with the younger generation. I think we are going to see more and more of dry eye disease.
Behind dry eye, we have other immunology assets. We have an exciting orals compound in phase one for atopic dermatitis. We have an injection for the dry form of age-related macular degeneration, which is another disease we will all get if we're fortunate to live long enough. A lot of exciting things behind our most advanced product. We've been obviously getting a lot of questions about the PDUFA. I'm sure we'll talk about that.
Let's kick it off with the PDUFA then.
Yeah.
You recently resubmitted the NDA in June following the FDA's ratification of a baseline balance between treatment and RNA. Maybe just walk us through the background of this resubmission here, like the context behind that.
Right. This is why drugs are expensive, because they take a long time to get approved. In our case, we first submitted an NDA back in 2022. We got a CRL in 2023 saying, we want you to do one more trial. We did another trial. As you mentioned, the FDA found a baseline imbalance in that trial. That was back in April of this year. Fortunately, we had a trial right behind it. We submitted that in June, hence our PDUFA date six months later in December.
Maybe walk us through the recently resubmitted NDA package. What did you include in this package?
Yeah, that's an important question. The thing about CRLs, the C stands for complete. The complete response letter. The kind of thing that the FDA does is they tell you exactly what is, in their minds, deficient in the application. In both cases that I just mentioned, it was run another trial. It's run a trial in symptoms. I should back up. In dry eye disease, the FDA likes to think about symptoms, which is how you feel, what patients report in terms of feeling, and signs, which is how you look or what an investigator can assess objectively. Our sign trials seem to be good. Those are in redness. Redness may be the only sign that patients care about, right? None of us want to have red eyes. I think a potential commercial advantage for our label is not having a red eye.
That's going to be particularly important to patients. We did have to repeat a symptom trial. The symptom we use is discomfort. I mean, the FDA identified a baseline imbalance in discomfort before we started treating. In the last trial we submitted at the end of last year, the trial we just submitted in June had no baseline imbalance. In theory, we should be good in terms of baselines. The FDA is a very careful organization, and I think they're very thoughtful. This is the first time there will be this kind of data on a dry eye label. By that, I mean we assess patients in a dry eye chamber. We sort of torture people by putting them in a small room. It's forced hot air on their face. It's interesting because that environment simulates your bad days.
If you're a dry eye patient, you have good days and bad days. It's the bad days that people care about the most. We don't really care about our good days necessarily in terms of treatment. The bad days are what's simulated in the chamber. You can tell activity. You can assess activity within minutes. Within minutes, you start feeling dry, discomfort, pain. Your eyes get red, as you can imagine. I liken it to sitting on an airplane. I told the story last time with those two vents like blowing right in your face. The first thing I do is turn those things off when I get in an airplane. That's a particularly noxious challenge for dry eye patients. Like I said, you can assess redness and symptoms all within minutes. That's what's lacking in the dry eye marketplace.
Today, we have a number of drugs that are approved in dry eye. Most of them have activity in weeks. Who wants to wait weeks, right? If you're feeling bad, you come to see your optometrist or your ophthalmologist, and you have a hot eye that's red and painful. You don't want to wait weeks. You certainly don't want to wait months. You want activity rapidly. The kind of data we've been generating in dry eye chambers is rapid, potentially occurring within minutes. I think the FDA has been quite careful. This would be the first dry eye chamber data on a dry eye label. We're pleased to be a part of that because I think it's a commercial differentiator for our drug if approved.
I also want to talk about the data a little bit more at the recent R&D day beyond all the exciting pipeline updates. You also shared a little updates on the data from Reproxalap in dry eye as well. You presented post-hoc analysis with a new p-value. Maybe talk to us about that data. What's the importance of that?
We got two main questions for investors about this particular NDA review. One is, how is CMC going? There's a lot of CMC rejections these days. We disclosed that both our drug substance, that is the active ingredient, and our drug product, that is the eye dropper itself and the formulation, have been inspected by the FDA recently. Those inspections went well. I think in terms of inspections and CMC vendors, I think we're in good shape there. The other question we got was, hey, we read your CRL, and it talked about a particular analysis. Have you done that analysis? That's what we disclosed at our R&D day not too long ago. The p-value was highly statistically significant. It was similar to the primary endpoint assessment. It's difficult sometimes to interpret these complete response letters now that everyone can read them.
Now that the FDA has released all those letters, it's difficult to understand precisely what the FDA is talking about. That analysis that they seem to suggest went well for us. We submitted it in the NDA in June. As I mentioned, the outcome was positive. We were pleased to disclose that a couple of weeks ago.
Have you had any interactions with the FDA recently? I mean, we're not predicting the future, but do you anticipate the FDA decision will be made on time considering all the dynamics going on?
Yes. Fortunately, the shutdown is over. I don't know that the shutdown, at least in our experience, ever affected the review. The reviews are funded via PDUFA. I never got the sense that because of the shutdown, there was some sort of delay in the way they were processing information. That's been a fairly quiet review. We don't specifically update on the intricacies of the review and information requests and so forth. I would say the FDA is practiced at reviewing this kind of trial. We just submitted the same kind of trial at the end of last year. I think the learning curve is steep in this case, and fingers crossed for December 16.
Great. Very much looking forward to that date. Maybe tell us a little bit about your preparation for commercialization also ahead of the PDUFA in December.
Let me mention that we have an option agreement with AbbVie, which, in my opinion, is the only large pharma left in the front of the eye. The way that deal works is AbbVie has 10 business days after approval to essentially opt in to what is a co-development, co-promotion agreement. The opt-in fee is $100 million, less what they've already paid us, which is $6 million. $94 million upfront. If the drug is approved when they opt in, and I think that's the way things are looking at this point in terms of AbbVie's timing, it's another $100 million.
Opt-in after approval will be $194 million. After that, there are two other $100 million milestones. Aldeyra and AbbVie share the P&L on a 60/40 basis. 60 to AbbVie, 40 to Aldeyra. We are capped at Aldeyra on an expense basis each year. It's not like AbbVie can spend $2 billion launching this drug. I don't think they would anyway. It is a very good deal for us commercially. I think on a cash flow basis, it is particularly attractive given the expense cap, as well as the fact that two to three to four years down the road, whenever the P&L flips positive, we'll start generating cash from that deal.
Just to clarify, there hasn't been any changes following the previous Complete Response Letter on the partnership.
Correct. That's correct. There was some speculation along those lines. AbbVie is an excellent partner. We've enjoyed working with them. Your initial question was about commercial preparation. Without going into details, I can tell you that AbbVie is doing anything I would expect that any large pharma would do a quarter or so ahead of launch. AbbVie is a professional commercial organization. They are the owner of Allergan, which launched the first dry eye drug, Restasis, I believe back in 2006. In a sense, they have the team that invented dry eye disease. They truly do know what they're doing. It's been a pleasure and an honor to work with them. I always tell investors, you can assume that they're doing everything that would be needed to do this close to launch.
I know you touched on it a little bit earlier already, but maybe just to contextualize, how large exactly is the market opportunity for dry eye?
There are about 40 million people in the United States. I think what's interesting is about 5%-10% of those people are treated. The number being treated is going up for two reasons. One is we have more therapies available for the treatment of dry eye disease. The other is what I talked about, our cell phones, our screens. We're not blinking enough. We're not looking far into the distance enough. All these things we should be practicing on a regular basis. We're not. That's one of the downsides of technology. I expect the market will continue to grow. It's also a disease of aging. Every human will get dry eye disease to some extent if you live long enough, just because our ocular surface dries out over time. The more therapies to treat dry eye, the better.
Reproxalap is also under development for another indication, allergic conjunctivitis. How is that program progressing? Maybe just walk us through the status of that program as well.
For sure. Allergy is the second largest market in the front of the eye. Dry eye may be the first. Allergy, glaucoma, probably in the number two spot. Allergy is a problem, right? We're getting more pollen these days thanks to climate change. If your allergies, you feel like your allergies are getting worse, it's probably because they are, in a sense. We're all just going to get itchier, scratchier, and redder thanks to pollen and other particulate matter that's in the eye. We have antihistamines. You can go to the drugstore and buy antihistamines and drop them in your eye. That works about two-thirds of the time. 60%-70% of patients are probably satisfied with those. There is a good number of patients that aren't. For those patients, the only recourse you have is steroids.
You can take steroids for a couple of weeks, after which you risk cataracts, glaucoma, and other issues. We need a long-term therapy, a chronic therapy for ocular allergy for those patients that do not respond well to topical antihistamines. That is what Reproxalap is about. We have run a couple of phase three trials. In each case, redness improved and itching improved. Those are the endpoints for approval in allergy. At some point, there may be a supplemental NDA. If dry eye is approved, you go back to the FDA. You talk about an indication expansion on the label. Hopefully, AbbVie and Aldeyra are making that decision together.
Great. Let's also talk about your RASP pipeline. At the recent R&D days, you share a lot of updates, a lot of preclinical data, interesting findings. Maybe talk about your next-gen RASP modulators. You decided to prioritize 248, 246. Maybe tell us what's the difference of those next-gen modulators and what drove the decisions.
Let me take a step back and talk about RAS, which sounds bad. These are pro-inflammatory small molecules. They're sort of like leukotrienes for those of you who geek out in the inflammation space. They're a great target. They're small molecules. They affect a large number of proteins. As I said at the R&D day the other day, every drug you've ever heard of targets a single protein, pretty much, a receptor, an enzyme, something along those lines. This drug, this class of drugs, RAS modulators, Reproxalap included, target a whole bunch of molecules. They target a system of proteins. My view is that drugs of the future will be just like this. They won't be addressing one protein. Our grandchildren, their children will not be taking drugs that address a single target.
Instead, it'll be more like this pharmacology that I'm describing here, where instead you're affecting classes of proteins or systems of proteins, a single drug that does many things at once. That's what we believe Reproxalap does. That's what we believe ADX-248 does and ADX-246 does, representative of the future of pharmacology. I like to tell people, we're not an NCE company, a new chemical entity company. We're not just a new target company. We're a new pharmacology company. I'm actually quite thrilled to be part of this new way of thinking about treating disease. As I used to tell people, if we're right, we're going to teach medical school a little bit differently these days. Back to ADX-248, ADX-246. These are next-generation RASP modulators. Reproxalap is sort of the father. Sons and daughters would be ADX-248, ADX-246. They are more potent RASP sequestering agents.
They are also better PK, have better PK pharmacokinetics. They last longer in the body. ADX-248 is particularly minimal to oral administration. Unlike Reproxalap, which is an eye drop, 248 is a pill. We're in the midst of phase I as we disclosed the other day. We're getting excellent exposure. We keep escalating the dose. The drug seems to be well tolerated and safe. 248 is a candidate for systemic inflammatory disease. Atopic dermatitis is one. I'm happy to talk more about that. ADX-246, be injected into the eye for, as I mentioned at the beginning of the talk, dry AMD, a disease of aging, sort of like wet AMD, except more insidious, affects more people ultimately and leads to loss of vision.
Before we move on to atopic dermatitis, maybe I also want to talk a little bit about the preclinical data you shared at the recent R&D days. Very interesting finding in Parkinson's disease and ALS animal models. Maybe just tell us a little bit about the highlights there.
For sure. As we age, we're just getting more and more inflamed. And a lot of these diseases, including diseases of the brain and the central nervous system, are products of inflammation. So Parkinson's is a great example, clearly associated with inflammation. Amyotrophic lateral sclerosis, Lou Gehrig's disease, ALS, also associated with inflammation. Alzheimer's disease. We could just keep going. Multiple sclerosis. We've tested these RASP modulators in at least three of those preclinical models. And they all seem to work. This was the data we presented at R&D day. By the way, that slide deck is still on our website if you're interested in looking through those. For us, I think CNS could be the final frontier. It's the ultimate expansion of immunology as we think about classic immunological diseases like atopic dermatitis or psoriasis. We're moving more towards atypical neurological inflammatory diseases in the neurological system. This is where we intend to go as a company, sort of a broad expansion of I and I.
You're running a phase I study for 248 in healthy volunteer studies. Maybe just tell us a little bit more about this study and what will be the next step for the development for 248.
In phase one, you start low and you go high and higher until you reach what you think is either a maximally tolerated dose or you just can't make any more drug or it's not feasible to give patients more drug. I think the good news for phase one for us is we continue to escalate doses, meaning the drug has been safe and well tolerated so far. The bad news is that takes a little longer to test, right? As you initiate more dose cohorts, it just takes more time to develop. Hoping to be through phase one in the early part of next year. We'll start in atopic dermatitis shortly after that. With any luck, not too long, we'll have some phase two data.
Great. Then beyond the 248, 246, we just talked about, I also want to talk about the rest of your pipeline. You have some updates for your 2191 modulators, and you have the fast track designation in retinitis pigmentosa. Maybe just talk a little bit about that program. What's the progress right now and what's the next step?
We bought a company some years ago called Helio that had the world's only intravitreal, that is, ocular injection formulation of methotrexate, which is an old anti-neoplastic drug. What's interesting is methotrexate is injected all the time into people's eyeballs for a variety of different diseases. There's never been a formulation that has been acceptable, that's been approved. We aim to promote sort of the first formulation of methotrexate for ocular injection. Now, one disease is ocular lymphoma. It's a rare disease, fortunately. It's almost invariably fatal. The survival is less than five years in most patients. The standard of care is methotrexate. Today, you find an intravenous vial or some other vial of methotrexate. You break it open. You suck out just enough to inject into the eye. There are all kinds of problems with that, sterility being one, dose being another.
We have worked with the FDA to come up with a single pivotal trial for approval in ocular lymphoma. I hope to start that by the end of this year, i.e., next month. That would be exciting. I do not think the FDA is expecting any more trials, just a single trial. We could file for approval shortly after that. You also mentioned retinitis pigmentosa. We ran an open label trial last year in retinitis pigmentosa. We treated patients with intraocular methotrexate. That is a common orphan disease, if that makes any sense. It is a rare disease, but amongst rare diseases, relatively common. There is no therapy for broad use in retinitis pigmentosa. The patients we tested all got better than you would have expected, just looking at untreated controls in the real world. We're optimistic that this kind of treatment could improve the plight of those patients over time. They will invariably lose sight in retinitis pigmentosa. To have a therapy for that disease would be quite nice.
Maybe let's also talk about dry AMD and geographic atrophy. What's your development in that area?
Dry AMD, geographic atrophy is interesting only because we have two drugs approved today. They both treat lesions. And by that, I mean the endpoint for the clinical trials was lesions. What happens in this disease is you have accumulations of metabolites in your retina, which means you can't see as well because there's stuff in front of your photoreceptors that senses light. The way these drugs got approved is they showed a slower rate of development of these lesions in the back of your eye. That's interesting. However, patients don't wake up thinking about lesion size. They wake up thinking they can't see. They particularly can't see at night. As we get older, our night vision diminishes. We trip over our dogs at night. We can't drive as well at night, et cetera. This is exactly what we intend to assess. RAS in the retina are associated with low light vision, or I should say diminished low light vision. Our endpoints will be focused on seeing at night. It's one of the first symptoms that these patients complain of.
Here we really talked about a lot of programs and clinical, preclinical stage programs. How should we think about the prioritization of those programs?
I said at R&D day, we like to diversify across molecules, across indication, across stage, across mechanisms. I think we've been successful at doing that. Obviously, Reproxalap is our lead molecule. We'd love for that drug to get approved. We'd love to work with AbbVie to commercialize that drug, as I mentioned, because of redness, because of speed of onset. The market needs a drug like Reproxalap in dry eye disease. I think after that, you're thinking about allergic conjunctivitis for Reproxalap, potentially an SNDA. Probably the next major regulatory milestone would be what I was just talking about, ocular lymphoma, right? If we could get a single trial to work, if that trial worked, and we could file for another NDA for an indication that is fatal and has no therapy, we'd be pleased to be a part of that. I think behind that is the pipeline. Atopic dermatitis, dry AMD, and then finally, our diseases of the neurological systems would be our next efforts.
Great. Very looking forward to the upcoming PDUFA. It is on all of our calendars. Thank you, Todd, for sharing your time with us. We will wrap up the session here. Thank you, all the audience, for joining this session.
Thanks again for having me.
Thank you. All right.