Good afternoon. Thank you very much for coming to Jefferies Healthcare Conference. My name is Yun Zhong, and I'm a member of the Biotech Equity Research team, working with senior analyst Kelly Shi. It's my great pleasure to be moderating the next session with Aldeyra Therapeutics, and joining me is President and CEO Todd Brady. Todd, thank you very much for coming. So, maybe before we dive into the details of each program, would you like to provide an overview of the company and including the technology platform, please?
For sure. Thanks, Yun, first of all, for having us here, and I know that, Kelly and you have been great supporters of the company, and Jefferies Conference is always amazing, robust list of investors, and so forth, so we're thrilled to be here. Thank you for the opportunity. Aldeyra is a company centered around novel therapeutics for immunology and metabolic diseases. We've been around for some years now, and are, I would say, pre-commercial stage, at least with one asset. We have a partnership with a large pharmaceutical company.
We have a robust pipeline of assets behind that in clinical development and look forward to the next several quarters as we have a pivotal readout coming and many more exciting Phase II kind of readouts, not only with ocular disease, which is sort of where we started, but also systemic disease.
Great. So maybe I will just start from the lead program, reproxalap, in dry eye disease. I believe that you announced last month the enrollment of the first patient in the new Phase III study. So are you able to provide an update on the current status of the study, and also maybe you can remind us of the design of the study, please?
For sure. Yeah, I think half of our company, or at least half of the interest we receive from investors, is about reproxalap, which is a novel molecule for the treatment of dry eye disease. We submitted a New Drug Application last year. We received a Complete Response Letter. The FDA wanted another symptom trial, and so the trial that Yun is referencing is that symptom trial. We're actually running three symptom trials to make sure that one of them works. The first one that works, we'll resubmit the NDA in conjunction with our partner, AbbVie, on dry eye disease.
So we did announce the first patient is enrolled. This trial is relatively fast, so these kinds of dry eye trials are performed in chambers, which I liken to sitting on an airplane and having both of the air vents directed at your face, and no humidity, a lot of drying. There's forced visual tasking, so you have to look and keep your eyes open, and that's the nature of this trial. The FDA allows dry eye chambers as a methodology for proving that your drug works. We have a couple of ocular redness trials that have been successful in the dry eye chambers.
We're trying to now replicate that with symptoms. So this is a symptom or ocular discomfort dry eye chamber trial, hoping to resubmit this next half coming, which starts next month, right, the next half of the year. Which means that probably in the third quarter or so, you can expect to see clinical data from the trial that we hope will remedy the CRL.
Yeah, I was going to ask whether you'll be able to provide guidance on the data readout, but I think you.
There you go.
Touched on that.
It's pre-provided for you.
Okay, great. But then you mentioned three Phase III studies. So why three? And so are you going to wait for the top-line data from the first one before you initiate the other three, sorry, two, and I think the other one, too, maybe you can talk about the design, whether it's identical, similar, completely different.
I get that question a lot: Why three trials? Well, dry eye is an interesting disease. I mean, there's two issues with testing dry eye patients. One is a placebo effect that we all know and love, and that's sort of up here in your brain, "I'm treating my eye, I feel better." The other is a vehicle effect, and that means you're putting something wet on your eyeball, and whenever that happens, you feel better. As the U.S. FDA dry eye guidance states, even water is effective in dry eye. So with those two things compounding on each other, it's a difficult clinical trial to perform, which is why we're running three.
I think there's a long, long history, not across Aldeyra's trials, but many other trials and other companies and other drugs, where you've seen some trials work and some trials not work, hence three trials. So the trials are running in parallel, all of them. We have two dry eye chamber trials that I just described. We also have what's called a field trial, which is a longer-term trial over a number of weeks, where patients take the drug every day, and they rate their symptoms, and so forth. That's sort of the traditional approach in dry eye disease.
Now, we've submitted two field trials in our first NDA. One of them was deemed acceptable by the FDA, so we'll have a field trial in the label. Now we're trying to get a chamber trial on the label, and that's important because the time frame in chambers is minutes. There is no dry eye drug that works quickly. All dry eye time frames today in the commercial marketplace are measured in weeks. This drug may work in two weeks or four weeks, but as a community, I think we need to shift that conversation from weeks to minutes, and that's what the chamber does.
So we're hoping that one of these two chamber trials is successful. Then, in the label, the trial will be described. It could be that sales reps could use the word "minutes" for the first time, and that's what patients care about. No one wants to take a drug and wait weeks for activity. You'd rather wait minutes, and that's what reproxalap is about, and that's, I think, its main angle, potentially in the marketplace.
Okay. I believe you said before that the two chamber trials, they have identical design. Is that just to save proof? Also, would you say that the field trial would be a higher bar or not necessarily?
Well, let me take those questions in turn. So there are two dry eye chambers in the world that have been used for clinical trials that are fixed, that are in buildings. So one is in Canada, that's trial number one, and one is in the United States, just outside of Boston, that's trial number two. So those are the two trials we're running. They're with different CROs, but the protocol, as you point out, is identical. There's essentially no real difference between the protocols of those two trials. There is heterogeneity in dry eye disease, as you mentioned.
There's geographic heterogeneity, there's pollen, there's pollution, there's communicable diseases that happen and influence our dry eye responses. So, a way of hedging those bets is to run two different trials, same protocol, different locations, and that's exactly what we're doing. The field trial, I think, typically is a higher bar in our hands. I'll just point out, though, there is no commercially available drug for dry eye disease that has chamber data, and the reason for that is drugs typically take a long time to work.
Reproxalap is different, and there again, a potential advantage in the marketplace. If you can convince healthcare providers and patients the drug works in minutes, that's a paradigm shift. You could dose in the office, and a patient could feel better walking out of that office, in theory, whereas today, with the drugs available, that's just not possible.
Field trials are notoriously more variable in a way because, well, it really depends on all those environmental conditions that I mentioned previously: pollen, pollution, temperature, seasonality, especially when you're crossing seasons and so forth. Either way, I think three shots on goal is sufficient to mitigate all those variabilities.
Okay. Maybe I'll just another question on the phase three study. So, if anything happens, will you be able to combine the two chamber trials together to improve the statistical power? And, so in case that you have to rely on the field trial, how will that impact your timeline for NDA resubmission?
That's a good point about. The trials being run in parallel doesn't mean they finish up at the same time. So in fact, the opposite is true. Each trial is designed to finish up at a different point in time than the other. So if the first trial works, the chamber trial I've talked about, then that will go into a resubmission for the NDA.
The other two trials, in theory, would read out after the NDA review. If trials read out during the NDA review, those trials need to be submitted to the NDA, and that gives the agency an excuse to extend your PDUFA and so forth. So it makes, I think, most companies, not just us, we'll submit a single trial. Any ongoing trial will remain ongoing until the review has been completed.
Now, in our case, because this is a resubmission, it's a six-month review, relatively rapid. So if, let's say, we have clinical data early in the first half, the first half of the second half of this year, say, Q3, we resubmit, say, in the latter part of the second half, say, Q4, then you're looking at a PDUFA date in the Q2 timeframe.
Okay. I think you kind of already provided answer to my next question again. So the label, I think you mentioned that you included a draft labeling talking about acute and chronic. How important is that? I know that you mentioned, you know, the immediate symptom improvement, but how critical is for you to include that label into your official labeling?
That's, that's a great question because I think it gets to how has the dry eye marketplace evolved. Over the past four or five years, we've had a variety of products get approved in dry eye disease, really for the first time. I think Restasis was there forever, and then came Xiidra, and those two drugs were sort of, you know, competing against each other for many years, and then we had a steroid that got approved. Now, steroids can only be used acutely, so that steroids are not for chronic treatment of dry eye, otherwise you get potentially glaucoma or cataracts or infection or ulcers and so forth.
So we have a steroid, which can be used acutely, and then we have chronic therapies that have come out since then. Many of them are variants of Restasis. Cyclosporine is the active ingredient there. But in our case, we have a drug that can be used chronically. We have a 12-month safety trial, which turned out well, but then has activity, in theory, within minutes.
So the redness data is derived from chambers, chambers are measured in minutes, so patients could, in theory, be told in minutes in a dry eye chamber, redness improved. Well, if the symptom trial works in minutes, in theory, within a dry eye chamber, you feel better, and that's really quite different from anything we have on the market today, and there gets your acute and chronic relief.
Okay. For the next question, I wanted to ask about your collaboration agreement. You talked mentioned earlier, so with AbbVie, I think it was announced around the same time when you heard the negative opinion from the FDA. So can you remind us the structure or the terms of the agreement? What has happened, what has not happened, is yet to happen, depending on what kind of outcome from the study and maybe your discussion with the FDA?
The rapid activity of reproxalap, at least in clinical trials, has been described for some period of time, and obviously, we had been talking with a variety of larger companies interested in the dry eye space, including AbbVie, for many years, actually. So as the FDA situation was evolving, we were in touch with all of those companies so that by the time it was clear the FDA was gonna require another trial, I think a variety of companies were up to speed, including AbbVie.
So we announced that we thought we were going to have to do another trial before the CRL was issued, based on FDA correspondence. And then subsequent to that, we signed the deal with AbbVie, which is an option. So AbbVie has an option on reproxalap, with $1 million upfront, and then $5 million later in December to extend that option. This is an option to a co-commercialization deal, where the P&L for reproxalap is split 60/40. So AbbVie has 60% of the P&L, there's 40% for Aldeyra.
Now, in the meantime, to exercise said option, there's $100 million upfront, less what they've already paid, which is $6 million, so $94 million additional dollars. And then if the drug is approved, another $100 million. There's some other milestones that have been described, publicly as well.
So for us, given that AbbVie is a large company interested in the front of the eye, given that they were behind Restasis, which was the first dry eye drug, we're absolutely thrilled to have them as a, as a partner and, you know, we need together, AbbVie and Aldeyra, to get a positive trial to resubmit the NDA, and hopefully, the FDA agrees with the package, and then, I think we'll have a very successful collaboration going forward, should AbbVie, exercise.
Great. Thank you. I think you had another indication in the past. I think it's allergic conjunctivitis. Can you remind us the status and what's your plan going forward?
I'd like to say that I have allergic conjunctivitis right now, sitting in front of you. Given all the pollen, I don't know how it has been in New York City, but in Boston, we have been smothered in pollen, and I've suffered from this condition for a very long time, and many of my colleagues are as well. I'll tell you, today, typically, for allergic conjunctivitis, we go to the drugstore, and we buy topical antihistamines, and they work in most patients, probably 2/3 of patients, but a third of patients, they don't work. So we some time ago initiated a clinical trial program in allergic conjunctivitis in parallel with dry eye disease.
That's important because about half the patients with dry eye have allergy, and about half the patients with allergy have dry eye. There was an optometrist on the West Coast that figured this out a long time ago. When patients came in and complained of dryness, he said, "Do you also itch?" And that's the sort of the classic symptom of allergy, and half of them said yes. And the patients came and said, "I have itchy eyes, doctor." He said, "How many of you have dryness?" About half of them. So this is a, this allergy concept is really a boon for dry eye disease.
So there is no drug today that can be used chronically, that's approved for both ocular allergy and dry eye disease, and yet, 50% of the roughly 40 million patients in the US with dry eye also have allergy. So from a marketing standpoint, from a commercialization standpoint, there may be some benefit of getting allergy on the label.
We've completed two allergy chamber trials in allergic conjunctivitis. That's sort of like a dry eye chamber, except instead of hot, dry air, it's air filled with pollen, if you can imagine. I don't think you could pay me enough to sit in that room for three hours or however long it is. But patients rate itch, and then a third-party observer will evaluate redness. So in two Phase IIIs, we've shown versus control, reduction in itching and redness. And there's the potential, should Aldeyra and/or potentially AbbVie decide to submit an NDA or an sNDA, a supplemental NDA for ocular allergy if dry eye is approved.
Okay, so you have everything ready, just need to submit officially?
As far as we know, I mean, I think that requires a discussion with the agency. There are different safety trials and so forth. Obviously, we've done a lot of safety for dry eye. As I mentioned, a 12-month trial is part of that package, but, the whole, allergy submission plan is something that needs to be discussed formally with the FDA, and whether that happens, again, I think will depend on Aldeyra, and I hope AbbVie together.
Okay. And then, probably moving on to the rest of the pipeline, I, I think you hosted an R&D day recently and reviewed a wide spectrum, really, a lot of programs. And, maybe starting from the retinitis pigmentosa program, it's injection of methotrexate. Can you go through the, go over the biological rationale behind, injecting methotrexate into the eye, and, what kind of patient population do you intend to target?
We bought a company called Helio some time ago, and their main product was this reformulated methotrexate for ocular injection. We didn't know this at the time, but it turns out that there was a scientific investigator in Pittsburgh who had discovered that in animal models of a rare disease called retinitis pigmentosa, which can lead to blindness in humans, methotrexate was one drug out of about 40,000 that she screened that really seemed to work, and she figured out that it works because in retinitis pigmentosa, you have these mutated proteins.
One in particular is rhodopsin. Methotrexate leads to the degradation of rhodopsin. It clears mutated rhodopsin, and thus, at least in animals, methotrexate's been a beneficial effect. So last year, we announced open-label data from a methotrexate trial in patients with retinitis pigmentosa.
Patients improved fairly dramatically from baseline, particularly as it relates to visual fields in the periphery. This is not what you're looking at; it's what you see in the side of your eyes. That's what's affected in retinitis pigmentosa, especially in dark conditions. So you really have this sort of tunnel vision in retinitis pigmentosa. You can't see on the side. We saw dramatic improvement there, so suggesting that the investigator was correct about methotrexate. And so we've now reached agreement with the FDA on a potentially pivotal trial, where patients are treated for 12 months.
There's a control in this trial, which is an extremely low dose of methotrexate. It's really become sort of semi-unethical to give saline injections into the eye for obvious reasons, or sham injections into the eye. Patients can often tell if you're injecting something into the eye because your vision gets blurry as that is squirted into your, to your orbit. And so, that's the trial we're running, low dose versus high dose over 12 months, and, I think that'll take a while to run.
We're hoping to get that initiated, shortly. We've announced second half of this year for initiation, but very exciting because there's nothing for this disease, and yet patients are going blind. We have orphan designation for methotrexate and, the associated exclusivity that, that comes with that. So I'm excited for patients. I hope it works, and, if it does, certainly that'll change the way, a lot of patients, are, are treated with this disease.
Okay. Have you disclosed the primary endpoint, and have you reached an agreement with the FDA? 'Cause a lot of gene therapy company, they tried, but I think a lot of program have failed.
That's correct. Yeah, so it's a difficult disease, like dry eye disease. We seem to only pick difficult diseases. Well, those are the diseases where there's unmet medical need, right? We don't do things because they're easy, to paraphrase a former president. So I think in this case, there is one approved product called Luxturna, which is a gene therapy for a very rare form of retinitis pigmentosa, but otherwise, there's really nothing to use to treat these patients.
So we met with the FDA. We did a Type C meeting, which has now been minuted, and we have in our corporate deck the protocol that resulted from that meeting. And the endpoint is exactly as I described. It's not central vision, but it's peripheral vision, especially under dark-adapted conditions. It's also an issue with dry AMD, the dry form of age-related macular degeneration, which all of us will get if we live long enough, not the wet form, but the dry form.
That's something else we intend to explore later with our RASP program, since RASP are associated with dark adaptation deficit and vision in low light regions. So that's those two programs are eerily correlated in terms of endpoints, but in terms of RP, we believe we've reached agreement with the FDA on a potentially pivotal trial design.
Okay. Well, I feel we have to move on because too many programs to cover, and, sorry, 629, I think you have been using that product as a kind of a signal finding. So can go, maybe talk about the data so far and, what's your plan with this specific candidate and, maybe the next generation compound, the plan in terms of indication?
Well, I think many of you know RASP are pre-cytokine, early-stage mediators of inflammation. RASP modulation, which is really the key platform behind Aldeyra Therapeutics, is about binding those mediators to prevent inflammatory changes or aberrant metabolic changes, and therein lies our platform and list of indications that Yun is referencing here. So everything we're talking about today, liver, retina, skin, that's all RASP modulation. ADX-629 is our signal-finding molecule. It's a relatively old RASP modulator. The idea was run a variety of clinical programs to see if 629 is active.
We've completed asthma, psoriasis, atopic dermatitis, ethanol toxicity. We even ran a trial on COVID back in the day. Every program, the molecule was safe. It was well-tolerated, based on the data we generated, and there was activity, at least signals of activity in small, uncontrolled trials. So now we're moving on to the second-generation RASP molecules. ADX-246 is one for atopic dermatitis, potentially hepatitis if ADX-629 generates positive results, in the alcoholic form of NASH or MASH.
Hopefully, data end of this year, maybe the first part of next year in that condition. Then finally, I mentioned the RASP retina program, where newer molecules will come in, and we'll evaluate these dark-adapted peripheral fields, in dry AMD.
Okay. Are there any particular indications that you feel might be more interesting or exciting than others, or are you still trying to decide which ones to really pursue?
Which of my children do I like the most? I can tell you that investors mostly want to, after dry eye, mostly want to hear about atopic dermatitis and retina. Those are two areas where there's clear unmet medical need. There is still today no accepted oral approach for atopic dermatitis, particularly in mild to moderate disease. We have great injectables, but children don't want to get injected, and atopic dermatitis features a lot of pediatric patients, unfortunately.
And so as we continue to progress, I think we've gotten a lot of interest in an oral or an orally administered approach to treating atopic dermatitis for those, for those reasons. Retina, same kind of thing. You know, if you have problems in your retina, you go blind. You can't see, and that leads to an unmet medical need, a high motivation on the part of providers and patients, but also probably on the part of payers and regulatory authorities as well.
Okay. I think last question, you provided a business update in January, laying out a lot of catalysts. So other than the NDA resubmission, anything that you think our investors should be paying attention to?
Well, in short, the list is dry eye, followed by alcoholic hepatitis, followed by atopic dermatitis, followed by retinal disease. So we're starting in the front of the eye, we're going backwards and down, is what I tell people. So a lot of different catalysts. We have quite a bit of cash relative to a company of our size, $130-something million at this point. All the programs we've discussed are covered, so RASP, retina, RP, hepatitis, atopic dermatitis, and the three dry eye trials. So for a company that's 10 or so employees and a big pharma partner, I think we're well-capitalized.
Great. Thank you very much.
Thank you.
Thank you, everyone, for coming to this session.