Everyone, welcome to the 2024 Jefferies London Healthcare Conference. My name is Klara Dunn from Jefferies Biotech Research. It's my absolute pleasure to have Aldeyra CEO Dr. Todd Brady here with us today. Very welcome.
Thank you. Great to be here, Clara. Thank you.
So before we start discussing the pipeline, maybe for those who are not so familiar with the story, could you please give us an overview of the company and what's been happening with the company for the past 12 months?
For sure. Well, thanks again for the invitation. It's great to be here. This conference is amazing now that it's grown in popularity and so forth, so we're thrilled to be here. I always start off by telling people that Aldeyra is an I&I company. At our heart, we're immunologists, and our first indication, first late-stage indication, happens to be dry eye disease, which is an immunological disorder of the front of the eye. And that is now obviously the subject of an option agreement with AbbVie. And at NDA stage, we just received our PDUFA date last week.
Congrats.
Thank you. April 2nd of next year, and so fingers crossed we have an approved drug next year. Probably worth going into the AbbVie agreement because that's what everyone wants to know about, so AbbVie has a right to a co-promotion agreement with us on Reproxalap, all indications. Dry eye disease is obviously the subject of the NDA, but also allergic conjunctivitis. We believe we've completed phase three testing for that indication as well, which is important because the overlap between dry eye and allergic conjunctivitis is about 50%. That is about half the patients have both conditions. Anyway, the exercise is $100 million less what AbbVie has paid us. That's $94 million at approval. It's an additional $100 million milestone, and then we split the P&L 60/40 AbbVie-Aldeyra after exercise, assuming exercise occurs.
And then finally, there are a couple hundred million more milestones in addition to the ones that I've described. So that's our late-stage product, I would say the tip of the iceberg as far as our eye and eye portfolio is concerned. Behind that, with the same series of targets, which we call RASP, a novel small molecule target in immunology, skin, liver, and retina. So atopic dermatitis, alcoholic hepatitis, metabolism, and then finally a retina condition called dry AMD. We've heard a lot about geographic atrophy, what people don't talk about as much as the precursor to geographic atrophy, which is equally damaging, and that's called dry AMD, and that's another target of ours that we hope to talk more about next year.
Then finally, we have an asset called ADX-2191, which is the subject of phase 2/3 trial in retinitis pigmentosa, another rare retinal disease, which again, hopefully talking more about later this year.
Great. So maybe let's start with reproxalap for dry eye disease first. And you mentioned the PDUFA, so congratulations.
Thank you.
I guess I would just start by asking, what are the next steps while we're waiting for the PDUFA decision? How do you think about the possibility for potential outcome? If so, how are you preparing for this possibility?
Right, so Reproxalap was the subject of a CRL last year. Unfortunately, the FDA said they would like to see one more clinical trial assessing the symptoms of dry eye disease and how our drug may or may not affect symptoms. We did that trial. The trial worked, highly statistically significant. This is a trial that we discussed with the FDA as part of the SPA, or Special Protocol Assessment Program, and obviously have had many interactions with the FDA since the CRL to discuss the program, so certainly the FDA is familiar with the trial, and the fact the trial seemed to work is a great sign. The nice thing about resubmissions for NDAs is you address what's specified in the complete response letter. That was one more trial. The submission is very straightforward, so primarily consisting of the trial.
We had a few, I would say, perfunctory CMC updates having to do with stability primarily. We updated the safety database with a whopping 66 more patients out of the 2,500 patients that have been exposed to Reproxalap. And finally, a new label, or a draft label, I should say. So our draft label includes two signs and two symptoms. The signs that we're assessing in dry eye are ocular redness. I always like to say that amongst the dry eye signs, redness is one that's quite important. People care about how red their eyes are, right? They care less as patients about staining or tear volume, but we don't have red eyes. And so to have redness on a label in dry eye disease, I think could be quite advantageous.
We'll have two symptom trials, a 12-week chronic study looking at symptoms over 12 weeks, and then finally a trial we just completed, which is in a dry eye chamber. So dry eye is characterized by flares. So we have the vents on the airplane. We have ceiling fans. We have dry days. We have days with pollen or pollution, and all those exacerbate dry eye. And so the chamber is a small room designed to simulate some of those flares. That was the trial we just completed. Ocular discomfort was our symptom, and obviously ocular discomfort was less in Reproxalap patients than in vehicle patients. We're thrilled to see that. So I would say a fairly straightforward resubmission. The FDA, in theory, doesn't have much to review other than the trial. Because the trial has been through the FDA, we've discussed it with them.
Because the trial was positive, we have high hopes for approval.
Fantastic. So you briefly touched upon the draft label. So I want to ask, what kind of label would you consider as ideal? And how would the label be differentiated versus other approved products on the market? And how do you think about the label? Yeah.
The label's important, right? That's what your sales force can promote on. I think dry eye disease, anterior segment ophthalmology, is very promotion sensitive. So what's in your label is critical. I mentioned the importance of redness. I think redness is a key differentiator. There is one drug out there indicated for dry eye where redness is on the label. That's a steroid, which you can only use short term. You can't use steroids chronically because of cataracts and ocular pressure issues that lead to glaucoma in theory and so forth. So we'd be the only drug for chronic administration with a safety package consistent with chronic administration where redness is decreased. Honestly, we all care about how we look. Just look at GLP-1 drugs these days, right? I mean, whether it's weight or redness, I think that's a key differentiator from the drugs out there today.
And then symptoms. We're actually going to have two different symptoms on the label. Traditionally, dry eye drugs have worked on the symptom of dryness. How dried does your eye feel? In our latest trial, we switched to discomfort after discussing with the FDA the primary endpoint. Honestly, we mostly care about discomfort. What does dryness mean? Are we dry? Are we not dry? Well, what we really care about is how comfortable are we or uncomfortable are we? So I think we'll have the first dry eye label if the drug's approved with two different symptoms for chronic use with redness. I think that makes for a compelling proposition relative to what's out there today.
Gotcha. So now that Reproxalap is one step closer to a regulatory approval in dry eye disease, so maybe could you walk us through your commercial readiness activities ahead of the PDUFA and your launch preparation?
The beauty of the AbbVie deal is that in theory, AbbVie, which was the first company via its acquisition of Allergan to market a dry eye drug that was Restasis for many years, the only dry eye drug, would take over the bulk of the commercial activity. And we're a small company. I think we had nine people as of our latest Q. Whereas AbbVie is an expert in commercializing eye care. Eye care is one of AbbVie's top five drug areas. They are truly experts in the space. I must say it's been a pleasure to work with them under the option agreement. I have full faith that should the drug get approved, should AbbVie choose to exercise the option, they'll do an excellent job across the board, just given their experience as sort of the inventors of dry eye disease.
Terrific. Let's talk about the market opportunity in dry eye disease. So maybe walk us through how do you think about the market opportunity in this disease and where do you see Reproxolap really fitting in this market?
At peak, Restasis, which again was the first dry eye drug, was about $1.5 billion. I just saw the script volumes earlier this week. They continue to grow in dry eye. We will all get dry eye disease at some point, right? We're all looking at phones. We're looking at computers. Screen time has become a major precipitant of dry eye disease. And as we get older, our eyes naturally dry out. So it's truly a mass market in terms of drug markets. And I think the challenge has been to date, there's no drug that works quickly. So when we come in, we see our optometrist, we see our physician, we want immediate relief. And one of the beauties of using a dry eye chamber is you can measure activity in minutes, not days, not weeks, not hours, but in minutes.
And there's the key differentiator for Reproxalap. It's really the first drug that has shown, at least in a dry eye chamber, activity within minutes, both redness and symptoms, how you feel and how you look. I think that's tremendously important. I think the space will continue to grow as we all age, as we all continue to use screens and our cell phones. It's just remarkable walking out there in the lobby with so many people staring at their phones, or even on the streets of London walking around. And this is a condition that's not going away. It's only going to get bigger. And I think the recent script volume I've just seen supports that notion. So I think there'll be a place for many drugs, not just Reproxalap, but if approved, I still think it's the only drug that has been shown to work quickly.
Perfect. And also Reproxolap is also being studied in allergic conjunctivitis. So maybe remind us what's the current status in this indication and what's the plan forward?
Right. So I mentioned I think we're done with phase three testing in allergic conjunctivitis. Those trials are also done in chambers, except with dry air, it's pollen. It's sort of aerosolized and sprayed in your face. I can't imagine who, as a sufferer of allergic conjunctivitis, I can't imagine who volunteers for these trials. But you measure itching. The symptom there is itching. That's the primary issue with allergic conjunctivitis, itching, but also redness. And so we have two phase three trials in allergy chambers showing reductions versus vehicle in itching and redness. And as I mentioned in the very beginning of this fireside chat, about half the patients with dryness have itching, and about half the patients with itching have dryness. So the comorbidity between allergy and dry eye is significant.
I think why that's important is because if you're going to market a drug for dry eye disease, you want to be able to address those patients that have allergy as well because of the overlap. And I think that's a real market differentiator. Having allergy potentially on your label really allows you to market to a broader group of healthcare providers and patients that have both conditions.
Given the patient overlap with dry eye disease, how should we think about the market opportunity for this indication?
Right. Well, I don't know exactly how AbbVie's thinking about it. In the past, our thinking has been dry eye takes pole position. It's the disease that probably has the most number of patients. It's the disease that healthcare providers are most concerned with these days. We do have over-the-counter treatments for allergy, antihistamines that are generally effective, but about a third of the patients just don't respond. So I think it's difficult to sort of tease out allergy from dry eye, again, because of the overlap. And in this case, the idea would be dry eye would be the first approval, layer on a supplemental NDA potentially for allergy, and then the market size of dry eye grows.
Gotcha. So maybe let's move on to alcoholic hepatitis with 629. So for phase two top line data of 629 in this indication, when should we expect the data? And could you help us set the expectation for the data and also walk us through how large is this market?
For sure. Let me back up and talk about RASP, which is the small molecule target I mentioned. It's amazing. If you think about drugs today, almost every drug targets a protein, an enzyme, a receptor. In fact, it's difficult to think of any drug that doesn't target a protein. Either it is a protein, it's an antibody against a protein, it's a receptor agonist or antagonist or an enzyme inhibitor. So as a medical field, we've targeted proteins, but RASP are a series of small molecules. So a new pharmacology that we have here with Reproxalap, with 629, with 248, 631, other drugs are developing in the RASP modulator class. And I think it has the potential to change not only the medicines we're using, but how we think about immunology and maybe even how we think about pharmacology. So Reproxalap is the beachhead.
This is the drug that we developed many years ago, now the subject of the front-of-the-eye diseases we've been talking about. Behind that was 629, sort of a relative of reproxalap, is ADX-629. We call that our signal-finding molecule. That's currently in a trial for alcoholic hepatitis. We'll update on timing towards the end of the year. It's a 10-patient open-label trial. It's fascinating to me that we talk about MASH, which we used to call NASH. We talk about obesity. We really don't talk about alcoholic liver disease, which is probably something that many of our obese patients have. Many of our MASH patients have alcoholic liver disease. Alcohol is a toxin. When you drink alcohol, ethanol is metabolized to acetaldehyde, which is a RASP. It's an aldehyde, a reactive aldehyde, and that's what gives you cancer. That's what causes you to flush.
That's what causes you to feel nauseous and so forth. And so by binding acetaldehyde and other pro-inflammatory molecules like acetaldehyde, I think drugs of the ilk of ADX-629 have the potential to open up a whole new treatment paradigm for these patients that suffer from alcoholism or maybe some of the rest of us that occasionally drink too much. And the resultant medical issues are significant. So we'll update later in the year in terms of timing, but I am excited about the potential to sort of think more broadly about metabolism as it relates to alcohol.
Fantastic, and then let's move on to 248, ADX-248. Maybe could you provide us an overview of this program and how it's different from the previous two programs we mentioned, and remind us about your plan for this program and the indication?
I always tell people that we start in the front of the eye and we've gone backwards and down. So moving to other parts of the body, these are oral drugs, all that ADX-629, ADX-248, even ADX-743, which is our follow-on to ADX-629 in the metabolism space. They're all really interesting. RASP do two bad things. One is they're pro-inflammatory and the second thing is they make fat. So we don't really want inflammation or fat and RASP therefore represent a target for inflammatory disease and other diseases that relate to metabolism. ADX-248 in theory is a once-a-day oral. It's a pill. We're currently testing in atopic dermatitis, so phase one should begin shortly. I think the market for atopic dermatitis is satisfied if you're injecting, particularly if you're injecting an antibody. People don't want to inject themselves, so hence the need for an oral product.
I think the oral space in atopic dermatitis has not been well worked out. We're excited to be a part of it. Hopefully, phase one gets going shortly and phase two A data next year.
Terrific, and given you have this RASP platform, so could you please broadly talk about how do you plan to leverage this platform and to support your development of many candidates across various indications?
Yeah, I think the other area that we really haven't talked about yet is the RASP Retina program. So we're in front of the eye with Reproxalap in allergy and dry eye. We've got our oral compounds such as 248 for atopic dermatitis or inflammatory skin disease, which may apply to other inflammatory diseases in theory. Inflammatory bowel disease comes to mind and pulmonary fibrosis. I mean, I think the list in innate immunity is sort of endless if you have a safe, orally bioavailable, broadly active molecule. But then there's Retina. So it turns out that this company was started back in 2004, so based on the Retina. So vitamin A actually is a RASP, has a RASP form. When vitamin A escapes the light cycle, it's reactive, it's pro-inflammatory, it forms aggregates, which are part of drusen. Many of you may know drusen, which is part of dry AMD.
That is another disease we're all going to get. If we live long enough, we'll have some form of dry AMD as these aggregates accumulate in our retina. There is really nothing indicated for dry AMD today. We talk a lot about geographic atrophy, which is a form of dry AMD. We have a couple of complement inhibitors approved for that, sort of the anti-inflammatory side of things. What's interesting to me about those compounds is there's no change in vision that's been shown. Patients don't know that they're getting better or not. What's the endpoint? Has been lesions, lesion size. I don't think people wake up thinking, how are my lesions? What's my lesion size? They wake up thinking, I can't see at night. Everything's wavy. My vision's deteriorating as I get older. That's the direction we want to go.
So vitamin A derivatives, these RASP that are associated with vitamin A are associated with dark adaptation. As we get older, we can't see as well at night. And this is something that we look to test directly as an endpoint with ADX-631, which would be injected into the eye as a RASP modulator. So excited about that. You'll hear more about that next year.
Fantastic. And also I want to talk about the 2191 in retinitis pigmentosa. You recently presented data at New York Retina 2024 symposium. So could you talk about what kind of data you presented there and how do you think about the development of this program and what kind of data you want to see in order to qualify the study as a pivotal study for discussion with the FDA?
Right. ADX-2191 is the world's first injected methotrexate, or at least intravitreal injection for ocular injection methotrexate. Methotrexate has been shown at least in animal model to be active in retinitis pigmentosa, as you mentioned, and as we recently presented at Retina 2024 a few weeks ago, that drug was active in humans, at least in an open label setting with retinitis pigmentosa. That's one of the more common inherited retinal diseases, retinitis pigmentosa. There's no cure, there's no therapy. Patients eventually go blind. I've known several people with the disease, and so there needs to be something, and there needs to be more companies working on that condition. Although it's rare, I think, just given the nature of the disease, the fact that it's the vision loss that occurs, that there's no therapy, we're really pleased to be part of the RP community and working on something new.
We have a phase 2/3 trial in the works. Now that we've demonstrated positive open-label data, we'll have a control in this next trial. We've discussed that trial with the FDA. We'll be guiding on that initiation and completion probably later this year.
Great. And lastly, can you remind us what are the key data catalysts or events in 2025 for the company and what should investors focus on next year?
I can tell you the questions I get asked, including today, is the drug going to get approved? Is Reproxalap going to get approved? I think that's the major milestone that we're all focused on. Again, PDUFA date is April 2nd. As we discussed, should AbbVie choose to exercise that approval, it's associated with $194 million in milestones. We're currently sitting with $113 million as of last quarter, $113 million in cash. I think we're well financed to fund everything we've talked about today, skin, liver, retina. We're thrilled to potentially initiate commercialization with AbbVie in dry eye disease. So I think Q1 is a really interesting time for us, right? As the PDUFA date looms on April 2nd, I think we're attractively positioned from a stock price standpoint.
I don't think the market has appreciated the potential milestones, the impact of the drug approval, the timing of the PDUFA, which we just announced, so I'm really feeling like our most important milestones are probably just a quarter away.
Fantastic and looking forward to it. And thank you for the great discussion and I'll wrap up here. Thanks everyone for attending the conference.
Thank you, Clara.