Hey, well, welcome back everyone to H.C. Wainwright's 26th Annual Global Investment Conference. My name is Matthew Caufield. I'm a senior biotechnology analyst here at H.C. Wainwright, and we're very grateful to be joined by Dr. Todd Brady. He's CEO of Aldeyra Therapeutics. So thank you very much for joining us today, Todd.
Pleasure to be here. Another great Wainwright conference.
Thank you. It's great to see you again.
Yep.
So there's a lot of moving pieces in the pipeline. Obviously, we'll try to cover as much as we can. But maybe to start off, most recently, we were excited to see the achieved successful primary endpoint for the dry eye Chamber phase III for Reproxalap. This was the pre-specified ocular discomfort primary endpoint, the FDA-accepted symptom for dry eye, which was great to see. Can you take us through this achievement and what's coming next in the near term for the anticipated NDA resubmission? F or that program?
For sure. Dry eye is an interesting condition from a regulatory standpoint because you really sort of have to do four clinical trials-
Right
... for approval. Two sign trials, two symptom trials, and we submitted an NDA back in 2022. The FDA wanted one more symptom trial, and that's the trial that Matt references. We just completed that trial, which we believe enables a resubmission. It's nice when the FDA asks you for one thing, you do it, and it works.
That's where we are. We're hoping to get that resubmission in pretty shortly. I get asked all the time, "What does the resubmission mean? What does it entail?" Obviously, the bulk of it is the clinical trial. I mean, the clinical response letter was, "Do another trial," and there's really nothing else in the letter of any substance, and so the bulk of the resubmission is the trial, but there's some CMC updates, you know, stability studies continue on, and those will go in the package.
There's a safety update. We had 66 more Reproxalap patients in that last trial so that requires a little bit of a safety update. And of course, now the label, the draft label that's submitted with the NDA changes. It's updated with the new chamber trial. What's so nice about chamber trials in terms of labels is timeframe is minutes.
You know, we have drugs approved for dry eye disease and this is a condition, by the way, we're all gonna get it eventually, right? We're all staring at screens. We're looking at computers and phones, and our kids are doing that even more. It's sort of this endemic issue, and fortunately, we have several drugs now on the market that can treat dry eye, but they work in weeks, and no one wants to wait weeks. Our new data suggests that patients will feel better in a matter of minutes, which is a paradigm shift in the field.
In a way, sort of perversely, the CRL from the FDA enabled us to get symptom data on the label that's achieved within minutes, and that's really quite novel for the field.
Yeah. No, it's fantastic. I mean, that kind of goes into my next question. So as we think about the resubmission package, there's been several trial examples for Reproxalap demonstrating benefit for the signs and symptoms of dry eye. Can you describe the significance of the potential broad signs and symptoms dry eye labeling? We've seen ocular discomfort, ocular redness, obviously, the timeframe. Can you speak to the importance of having both, ideally, within labeling?
On the label?
Yeah.
For sure, and we have drugs today that are approved, and the clinical data is Schirmer test, which is a strip of paper in your eye. It shows you how much tear is being made.
Mm-hmm.
I like to tell people we're really good at making people cry, right? We have drugs that make you cry. And you know, what we need are drugs that make you feel better. And there is one sign of dry eye disease that patients care about, and that's redness. Who wants to have red eyes?
Mm-hmm.
And so on our label, we're gonna have symptoms, discomfort being one from the latest trial, that are achieved within minutes, but also ocular redness control, and that's also unique. There's no chronically administered dry eye drug that improves redness, but matters to patients. So I think we'll have two important clinical pieces of clinical data on our label, which is you feel better and your eye is less red.
Yeah. No, very hopefully. And then looking back, there was additionally the announced positive phase III INVIGORATE-2 trial in allergic conjunctivitis patients, which notably represents upwards of 50% overlap with dry eye. What do you think are some of the Reproxalap implications for having applicability in allergic conjunctivitis?
You're right, Matt. There is a huge overlap between itching and dryness.
Mm-hmm.
In fact, there was an optometrist, Milton Hom, who years ago took the people that came in his office that complained of dryness, and he asked them: "How many of you itch?" And then he took the people that came to his office complaining of itching, and he said: "How many of you have dryness, feel like your eye is dry?" And there is truly a 50% overlap.
Mm-hmm
... between dry eye disease and allergic conjunctivitis. He was the first person to really describe that, which is why Reproxalap is in development for those two diseases. Combined, they're the two largest anterior segment, you know, inflammatory diseases that affect the eye, and given the comorbidity, the fact that Reproxalap could get approved for allergic conjunctivitis based on the INVIGORATE trials that you mentioned-
Mm-hmm
I think it's really quite a large market differentiator for dry eye disease. So you could, as a sales rep or an MSL or, promote this idea that your patients may also itch. Your dry eye patients may also itch. They may also have this comorbid allergy, and there's really only one drug for chronic use, reproxalap is approved for both indications t hat you could give.
Mm-hmm.
You can give steroids for two weeks.
Yeah, exactly.
Yeah. Which is the problem, because if you keep taking steroids, you can get glaucoma and cataracts and other issues.
Mm-hmm.
So I think this is a huge market differentiator for dry eye disease.
Mm-hmm.
Probably all of us have some form of those two diseases in some combination, and a drug like reproxalap that could be used chronically to treat redness, itching, dryness, could be quite significant.
Yeah. No, absolutely. I mean, what do you consider the greatest topical reproxalap differentiators within the landscape of current dry eye therapies, and even their limitations? I mean, clearly, there's rapid effect, acute benefit.
Mm-hmm.
What do you think are some of the greatest drawbacks in current standard of care that can be addressed with reproxalap?
I would say reproxalap is fast-
Mm-hmm.
It's anti-redness, and it works on itching.
Mm-hmm.
Those are three things that are really not in the marketplace today. Like I said, we have drugs that work in weeks.
Right.
We're good at making you cry over weeks, no doubt about that.
On ramp, yeah.
... or after weeks of therapy. We really don't have any chronic therapies to treat redness in the dry eye space, and we have no drug that's approved for both itching and dryness.
Mm-hmm.
So I think those are the three major holes in the market that reproxalap fills or could fill.
Do you feel like there'd be any step-through potentially with standard of care, or is that sort of a given, or just from a reimbursement standpoint, from kind of a high-level view?
The grandfather of dry eye disease was a drug called Restasis.
Yeah
... that AbbVie and its precursors developed some years ago.
Mm-hmm.
Restasis is the first major dry eye drug to go generic.
Mm-hmm.
And so I think that a lot of patients that come in today complaining of dry eye will be offered a generic Restasis. This is cyclosporine-
Mm-hmm
... the transplant rejection drug. It's been around forever. So to some extent, I think we may see some step-throughs or prior authorizations for new drugs. The thing about moderate dry eye patients is they've already been on these drugs.
Right.
They've already been on Restasis, they've already been on Xiidra, so the need to step through-
It's like that box has already been checked-
It's already been checked.
and they're still looking for alternatives.
Exactly.
Yeah.
Exactly. I think in allergy, it's a different situation. One piece of good news about allergy, for those of us that suffer from allergic conjunctivitis, is you can go to the drugstore and buy antihistamines, stick them in your eye you feel better in some cases. About a third of those patients don't respond, and they're left with steroids.
Right.
I think there is, at least for two-thirds of the market, a good solution at Walgreens or CVS, but not for one-third of the market, and that's where reproxalap would fill in on a chronic basis.
Mm-hmm. No, understood. I mean, it's also worth mentioning the option agreement with AbbVie, for the possible development and commercialization of reproxalap in the U.S. market. We've continued to view this as possible upside with option execution potentially before approval, I mean, hypothetically speaking. Where do things stand with that agreement in terms of prospective timing, at least currently?
For sure. I was just at AbbVie yesterday. They had their partnering conference-
Mm-hmm
... in Chicago. How great is it for us as a small company to be working with a company that invented dry eye?
Mm-hmm.
Right? And marketed Restasis for all those years. That was the old Allergan group.
Right
... subsumed by AbbVie, and they're still very much intact and eager to build ophthalmology and-
Mm-hmm
... we were highlighted as one of the companies, yesterday. So it's, it's been a real pleasure to, to work with AbbVie. The deal, as you point out, is that they have an option on reproxalap. For all indications, it's an option to what is technically a co-promotion agreement. The option expires, at the end of April or ten days after approval-
Mm-hmm
... whichever comes sooner. We're hoping to submit the NDA shortly.
Sure.
Maybe a Q1, Q2 PDUFA date.
Okay.
Relative to AbbVie, they pay us $100 million upfront, less the $6 million they've already paid us, so $94 million upfront, and there's a different $100 million milestone at approval. So at near term, a couple hundred million bucks from them if all goes well.
Mm-hmm.
Like I said, we couldn't be working with a better group in the front of the eye with their sales force and marketing presence.
Sure.
I'm sure they'll do great with the drug if it's, if they option in.
Amazing. A very exciting catalyst, potentially.
Yep.
So obviously, there's a lot more moving parts in the pipeline. I wanted to make sure we covered some of those. So thinking more broadly about RASP, or reactive aldehyde species, modulators, there's several shots on goal across ADX-629, ADX-631, ADX-248, ADX-743.
Mm-hmm.
Just pick a number.
Yeah, pick a number.
Recently with ADX-743 and preclinical assessment in obesity, the candidate or an alternative could have an IND submission in 2025-
Right
... in obesity, or hypertriglyceridemia.
Right.
Can you talk a little bit more about that program or that development for the mechanistic approach?
Right. Well, we try to be a diversified company, Matt.
Mm-hmm.
You know, we're not just a dry eye. And let's say that AbbVie does exercise the option. Reproxalap is mostly managed by AbbVie at that point, and so we're left-
Right
... to focus on what I describe as skin, liver, and retina.
Mm-hmm.
The liver program is the one you're mentioning with seven four three. All of our RASP modulators are related to reproxalap structurally-
Okay
... to some degree or other. So it's not like we're reinventing the wheel with these new indications. I think in the obesity space or the liver space, the hypertriglyceridemia space, there's still some unmet need.
Mm-hmm.
We have the sort of requisite animal model data showing that our drugs facilitate weight loss, especially in conjunction with GLP-1s, but there are other things we can do. I mean, we've had phase I/II data showing that in human subjects that have drank too much alcohol, that the symptoms and signs are lessened with RASP modulator treatment, so there's an opportunity to combine sort of this liver aspect or obesity aspect with substance abuse.
Mm-hmm.
And you can imagine enrolling a trial with obese subjects with hypertriglyceridemia because RASP are precursors to fat.
Mm-hmm.
So if you can inhibit RASP, you can inhibit fat, preserve lean mass, while at the same time modulating substance abuse. So there's a lot of different angles I think we can take in the liver and obesity market, and look forward to talking more about that next year.
To leverage that mechanism.
Exactly.
So just one follow-up then. So when you mention, sort of, or an alternative could be brought forward in that indication, does that mean there are other sort of products being or assets being worked on, or that's if that particular one doesn't play out as you expect?
Right.
Or-
We have a whole stable.
Yeah.
Quite a large pipeline of RASP modulators. I think we're the only company in biotech that's working on RASP-
Right
... as a target, which are totally unique. You know, I don't think it's hard to find drugs that work on proteins, but it's really hard to find drugs that work on small molecules.
Yeah.
You know, a small molecule to small molecule interaction is quite unique, and that's what we have. And, this sort of bullpen of candidates-
Mm-hmm
... is sort of interchangeable in a way.
Mm-hmm
... depending on, pharmacokinetic properties and so forth. So we're excited about really expanding from the front of the eye to the back of the eye to-
Mm-hmm
... to systemically.
Yeah, absolutely. And hopefully, with the validation for the mechanism through Reproxalap.
Exactly.
Yeah, that'd be fantastic.
Exactly.
So, for ADX-248 in preclinical development for atopic dermatitis, that one's moving forward into phase I/II clinical testing, and expected to begin second half-
Mm-hmm
... of this year. Can you tell us a little bit more about the clinical implications of RASP modulation in atopic derm? Kind of your thoughts in that indication.
First of all, I think the oral space in atopic dermatitis is still wide open. For a safe, novel, orally administered therapy, I think there's a lot of room for development. Atopic dermatitis commonly affects children, so safety is key. You don't want black boxes for your atopic dermatitis drugs.
Mm-hmm.
We have some oral drugs, but there's also safety liabilities, and that's sort of something we're attempting to avoid. We announced data with ADX-629, one of our signal finding RASP modulators l ast year, with really fantastic reductions from baseline in ten or so patients across the board: itching, and EASI scores, and all the kinds of things you mention, you test symptom and sign-wise in atopic dermatitis. So 248 is our new version, our second generation. ADX-629, phase I should start this year, as you mentioned.
Mm-hmm.
And then we're going to roll into a randomized phase IIa in atopic dermatitis, again, looking at all the standard endpoints.
Mm-hmm.
Hopefully, things pan out, and we're in larger trials by the end of next year.
That'd be great.
Yep.
Amazing. And then for ADX-631 preclinical testing, that's been initiated in models for retinal diseases.
Mm-hmm.
So it was announced that the candidate or an alternative could have an IND submission first half of next year in dry AMD or geographic atrophy.
Mm-hmm
... or GA. What are important differentiators for such candidate selection, and what more can you tell us about the retinal direction for RASP?
I think the dry AMD field is remarkable-
Mm-hmm
... in that it relates-
Focus on complement.
... GA complement.
Yeah.
There's sort of like one route that drug companies have taken.
Mm-hmm
... which is the complement space.
Mm-hmm.
Whereas, very few companies have attempted to affect symptoms or modulate symptoms, or something that patients can notice. Today, we measure lesions.
Mm-hmm.
I don't know how many patients wake up thinking about: How are my lesions today? I think they're thinking about: How well can I see?
Exactly.
As we, as a field, attempt to move closer toward vision endpoints, we're going to be part of that. I think we'll start with clinically relevant changes in vision, particularly scotopic vision or low-light vision-
Mm-hmm
... which is principally affected in these patients. Patients that have dry AMD come into their physicians and say, "I can't see at night," or, "I'm stumbling over the dog," or, you know, "Running into things when,
Night driving.
Night driving is difficult.
Yeah.
And so I think there's a real clinical need there that may be addressable with RASP modulation. So RASP are connected to dark adaptation-
Hmm
... or low light sensitivity, and we look forward to exploring that next year as 631 makes its way towards clinical testing.
Great. Very exciting. And then kind of thinking more generally, so across possible RAS indications that also include the moderate alcoholic hepatitis for 629, there's several administration routes for RASP, from ophthalmic solution, to oral, to intravitreal, potentially in the eye. How is the RASP profile possibly impacted or refined across these different delivery mechanisms?
Yeah, we try to be delivery agnostic, and I think, you know, for retinal disease, it still probably makes sense to inject-
Okay
... into the eye.
Yeah.
We've toyed over the years about oral administration, which possibly is the holy grail there. I think topical is probably more difficult.
Sure.
But for now, we're going to treat the retina with injections. We're going to treat skin with oral administration. Like I said, I think the market for atopic dermatitis is really unsatisfied with where it comes to oral administration, and that's something we're going to pursue.
Mm-hmm.
And then also with obesity, liver, hypertriglyceridemia, substance abuse, that sort of constellation of issues is probably also optimally treated orally.
Okay. And then kind of along those lines with the multiple RASP shots on goal that we've discussed, where do things stand from a cash standpoint, and how does the current runway look for kind of this variety of programs?
Believe it or not, we're well-financed. All that, all that we've discussed is funded.
Mm-hmm.
We've announced, at least in our last Q, I think we reported $120 million in cash. We have runway through 2026.
Mm-hmm.
From that vantage point, I think we're well-financed. None of that includes any AbbVie dollars.
Right.
No milestones, no exercise, no revenues from the P&L. So I think, sort of a conservative estimate is through 2026. And-
Okay, great.
The good news is, everything we've discussed today is all funded.
Amazing. And then I know we're kind of short on time here, but I just want to draw attention to kind of outside the RASP platform for ADX-2191, vitreous methotrexate in retinitis pigmentosa. Can you tell us about where that program is or what you're looking towards for the near term?
We bought a company some years ago called Helio, and they had developed this-
Mm-hmm.
Vitreous-compatible methotrexate, which, we took into the clinic, or we're taking into the clinic for, an orphan disease called retinitis pigmentosa. I think amongst inherited retinal diseases, retinitis pigmentosa is one of the more common ones.
Sure.
but still orphan, still no approved therapy that's widely used, and-
Mm-hmm
... I think a big unmet need. So we had an open label trial with ADX-2191, which is what we call this compound, last year, and the data are compelling. I think
Mm-hmm
... in a syndrome or a condition where you wouldn't expect patients to improve, they are improving on drug, and so hopefully in a randomized setting, that pans out. That phase II, III trial should start at some point this year.
Specifically, that mechanism is obviously separate from sort of the RASP approach.
Different from RASP.
Yeah.
Methotrexate actually leads to the degradation of mutated rhodopsin-
Mm-hmm
... which is the issue in many retinitis pigmentosa patients. It's good to have rhodopsin because you need it to see, but it's bad to have it when it's mutated, and that's what-
Sure
... methotrexate takes care of.
Very helpful. Now, I know we have less than a minute left here, but what are you most excited about in sort of the near term over the coming quarters? There's obviously a lot of irons in the fire. Obviously, reproxalap-
Yeah
Is sort of top of mind, but what are you most excited about, sort of in the next quarter or two?
Yeah, today's my day off.
Okay.
Tomorrow, I go in and work on the NDA resubmission.
Okay. Okay.
I think first and foremost, we resubmit the NDA.
Yeah.
Hopefully, that goes in in a matter of weeks. We need to make sure the FDA accepts that submission, that there are no holes in the submission.
Mm-hmm.
Wait for, you know, draft label and PDUFA dates, and all these kinds of things you expect over a six-month resubmission review process, first and foremost. And as we've talked about over the last 10 minutes or so, the pipeline is robust.
Mm-hmm.
I think next year is Aldeyra's year to move beyond the front of the eye.
Excellent.
Maybe the next time we have a fireside chat, we'll be talking about that pipeline first.
Everything outside of reproxalap.
Exactly. I look forward to that.
Yeah.
Great.
Absolutely.
Yeah. Thank you.
Todd-
Yeah, good to see you.
Thank you very much.
Yeah.
Thank you to Aldeyra Therapeutics, and thank you to all everyone that tuned in.