Ladies and gentlemen, thank you for standing by, and welcome to the Aldeyra Therapeutics Full Year 2022 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After speakers' presentations, there will be a question-and-answer session. I would now like to hand the call over to -- the conference call over to Mr.

Bruce Greenberg, the company's Interim Chief Financial Officer. Please go ahead, Sir Bruce Greenberg..

Thank you, and good morning, everyone. With me today is Dr. Todd Brady, our President and Chief Executive Officer. This morning, we issued a press release reporting recent corporate highlights and our financial results for the year ended December 31, 2022.

A copy of the press release is available on the Investors & Media section of our website at www.aldeyra.com. Please note that this morning's conference call contains forward-looking statements regarding future events and the future performance of Aldeyra.

Forward-looking statements include, but are not limited to, statements regarding FDA review of our drug applications -- of our new drug applications, potential commercialization, the anticipated timing of initiation of results from our clinical trials, our projected cash runway, our possible or assumed future results of operations, expenses and financial position, and potential growth opportunities.

These statements are based on the information available to us today and reflect our current views concerning future events. They are based on assumptions and subject to risks and uncertainties, including the development, clinical and regulatory plans or expectations for Aldeyra's product candidates and systems-based approaches.

The risks that result from clinical trials or portions of clinical trials may not accurately predict the results of future trials for the same or different indications and Aldeyra is continuing review and quality control analysis of clinical data. Aldeyra assumes no obligation to update these statements as circumstances change.

Future events and actual results could differ materially from those projected in our forward-looking statements. Additional information concerning factors that could cause results to differ materially from our forward-looking statements are described in greater detail in our press release issued this morning and in our filings with the SEC.

I will now turn the call over to Dr. Brady..

proliferative vitreoretinopathy, a rare condition that is a leading cause of failure of retinal reattachment surgery; and retinitis pigmentosa, a group of rare genetic eye diseases characterized by retinal cell death and loss of vision.

We plan to conduct a Type C Meeting mid-2023 with the FDA to discuss the completion of clinical development of ADX-2191 for the prevention of proliferative vitreoretinopathy. In addition, we plan to report top-line results from the Phase 2 clinical trial of ADX-2191 and patients with retinitis pigmentosa in the first half of this year.

With respect to Reproxalap, the PDUFA date is November 23, 2023. We continue to engage in potential partnering discussions with multiple parties for Reproxalap and are also preparing for commercialization internally.

Our commercial preparations are designed to exploit the unparalleled rapid onset and breadth of activity observed in clinical trials of Reproxalap in patients with dry eye disease. Last week, we reported top-line results of the vehicle-controlled 12-month safety clinical trial for Reproxalap in dry disease patients.

Ocular safety was similar across Reproxalap and vehicle-treatment groups and no treatment emergent serious adverse events deemed at least possibly related to treatment were identified.

What we believe to be particularly significant about the results is the potentially landmark evidence that visual acuity in patients treated with Reproxalap was statistically superior to that in patients treated with vehicle. Visual acuity in the Reproxalap group improved by approximately 37%, resulting in a P-value of less than 0.0001.

Coupled with demonstrated broad activity and rapid onset of action, the positive visual acuity data observed in the safety trial potentially further differentiate Reproxalap in what we estimate is a $23 billion addressable market in the U.S. Now, I'll turn the call back over to Bruce for the financial review..

Thanks, Todd. Let me begin with our liquidity profile. Cash, cash equivalents and marketable securities as of December 31, 2022 were $174.3 million.

Based on our current operating plan, we believe that existing cash, cash equivalents and marketable securities will be sufficient to fund currently projected operating expenses into the second half of 2024.

This includes the initial commercialization and launch plans for Reproxalap and ADX-2191, if approved, and continued early- and late-stage development of our product candidates in ocular and systemic immune-mediated diseases.

Net loss for the year ended December 31, 2022 was $62.0 million or $1.06 per share compared with the net loss of $57.8 million or $1.07 per share for the same period in 2021. Losses have primarily resulted from the cost of our clinical trials and research and development programs as well as from general and administrative expenses.

Research and development expenses for the year ended December 31, 2022 were $47.3 million compared with $44.9 million for the same period in 2021.

This increase was primarily related to an increase in drug product manufacturing expenditures, personnel costs, consulting expenditures and external preclinical development costs, which were partially offset by a decrease in external clinical development costs.

General and administrative expenses for the year ended December 31, 2022 were $15.4 million compared with $11.3 million for the same period in 2021. This increase was primarily related to higher consulting expenditures and higher personnel costs.

Total operating expenses for the year ended December 31, 2022 were $62.7 million compared with total operating expenses of $56.2 million for the same period in 2021. Now, let me turn the call back to Dr. Brady for closing remarks..

Thank you, Bruce. 2022 was a transformational year for Aldeyra, highlighted by the achievement of key clinical and regulatory milestones across our drug development pipeline, including the submission of two new drug applications.

That momentum continues in 2023 as we move closer to our goal of validation of our platforms for immune-mediated systemic and retinal diseases. In our industry, success comes from forging one's own path based on evidence and science, that is precisely the course we're charting at Aldeyra.

The development of Reproxalap has created a strong foundation for our RASP modulation platform, which now features our orally administered candidate ADX-629 and five Phase 2 clinical trials, representing varied designs and two new drug candidates poised to enter the clinic.

Through ADX-2191, we are creating a potential first-line therapy for rare retinal diseases without FDA approved therapies, beginning with ocular lymphoma, proliferative vitreoretinopathy and retinitis pigmentosa, all indications for which our drug has received FDA's orphan drug designation. And with that, we'll be happy to take your questions.

Operator?.

Thank you very much. [Operator Instructions] Our first question today comes from Marc Goodman of SVB Securities. Marc, please go ahead. Your line is open..

Hey, good morning. Todd, can you talk about the side effect profile that you've seen of the oral? And how you think about that product and just the profile relative to what's on the market today? Obviously, the excitement is a broad spectrum oral.

Just give us a sense of how you're thinking about it? What should we be looking for as far as just the profile -- the side effect profile? Thanks..

Thanks, Marc. Very much appreciated fireside chat we had together the other day. And thanks also for highlighting our oral RASP modulation pipeline. I would say broadly that inhibiting or activating single proteins tends to lead to toxicity. There's a reason why we have such proteins.

There's a reason why they are neither consistently turned off or constitutively turned on, and therein lies the value of RASP modulation. ADX-629, ADX-246, ADX-248 are all molecules that influence a family of mediators that in turn influence a family of proteins. So, we're not turning any protein on or off.

We like, in RASP modulation, to a master volume knob where we're dialing down inflammation, say, from a 7 to a 2. The value of that is safety and tolerability. Not only do we have breadth of activity, but we have drugs that aren't individually affecting proteins and, therefore, should lead to less toxicity. We have seen that in trials observed to date.

With ADX-629, we have very few side effects. As I mentioned in my prepared comments, we have no serious adverse events that have been deemed related to drug. So, as we continue to test patients in other indications, I expect that safety profile will continue based on the mechanism of action of the drug..

Thank you. Our next question is from Yigal Nochomovitz from Citigroup. Yigal, please go ahead. Your line is open..

Hi. Thanks very much for taking the question. Todd, with respect to the PDUFA for Reproxalap for dry eye, obviously, that's filed. Could you comment to an extent on the partnering discussions there, and [indiscernible] does that has a clear target date for FDA approval? And then related to that, obviously, you have the second Phase 3 for AC coming up.

I think in the past you've indicated that it may not necessarily -- be necessary to file there, given the extensive overlap between the AC and dry eye patient populations.

I'm just wondering how are you thinking about that? Is it potentially a situation where the partners may want to see that data and then make a determination as to whether it'd be necessary to file in that second indication? Thank you..

Thanks, Yigal. Happy to comment on partnering discussions and happy to comment on allergic conjunctivitis. As you know, the Reproxalap NDA for dry eye disease has been accepted and thus, to some extent, regulatory risk has been removed at least as it relates to the FDA's review of that FDA.

As we've said before, we believe the NDA submission is the most comprehensive ever for a dry eye disease drug with three different signs and a variety of clinical trials that feature acute and chronic administration up to 12 weeks for efficacy and now 12 months for a safety.

All in all, the data continue to suggest that Reproxalap is the only drug in development that can work quickly. And I think that's a major commercial differentiator.

Also, as I announced in my prepared comments, Reproxalap appears to be the only topically administered drug ever to demonstrate an improvement in chronic visual acuity, something that normally doesn't happen as we age over 12 months. Therefore, I would think that there are many potential partners that are interested in Reproxalap.

I can tell you that our partnering conversations are robust and, as I mentioned in my prepared comments, involved multiple parties across a wide array of terms. I do expect that partners would want to be involved with Reproxalap prior to label negotiations, which, in our case, I would expect to occur in the September to October timeframe.

Regarding allergic conjunctivitis, we continue to see that indication as a major differentiator for any dry eye disease drug. As you mentioned, there's a considerable overlap between dry eye disease and allergic conjunctivitis. And it's difficult for many healthcare providers to distinguish between those two diseases.

Thus, a compound or drug that can treat both of them simultaneously should be of considerable value. Our main goal, at this point, Yigal, is to demonstrate the activity of Reproxalap in allergic conjunctivitis.

We have two published papers, one of Phase 2 trial, one of Phase 3 trial, demonstrating activity of Reproxalap in patients with allergic conjunctivitis across two different clinical trial models.

The INVIGORATE II trial, which is our second allergen chamber trial, will be announced, as I mentioned in my prepared comments this morning, in the first half of this year.

And I think pending the results of those trials, pending the partnership discussions with Reproxalap, that we can then make a decision about the -- a need to submit a new drug application for Reproxalap in allergic conjunctivitis..

Great. Thank you..

Thanks, Yigal..

Thank you. Our next question comes from Justin Kim from Oppenheimer & Co. Justin, please go ahead. Your line is open..

Hi, good morning, Todd and team. Thanks for taking the questions and congrats on the progress.

With Reproxalap and 2191 sort of locked in for regulatory review over the course of the year, I just wanted to ask how you think about commercialization for these assets, how they sort of may differ and how to think about the timeline for investment or commercialization as sort of a review process progresses?.

A, retinal physicians are already using methotrexate to treat at least two of the diseases we've highlighted this morning; and B, there's a limited number of physicians that treat these diseases. I think there are something like 50 to 60 ocular oncologists in the United States.

And therefore, I don't really consider ADX-21 to be a sales and marketing effort per se, but rather more of a market access effort, making physicians aware that compounding methotrexate is no longer necessary and making physicians aware that ADX-2191 is in theory clinically superior to compounded methotrexate because the volume is lower, the volume for injection is lower, the density is higher, all of that designed to reduce the side effects that you typically see with methotrexate injection into the eye, which is something called punctate keratitis.

As we announced last year as a result of the Phase 3 GUARD trial in proliferative vitreoretinopathy, the adverse events of keratitis was significantly lower than what one would expect with compounded methotrexate at least as has been published in the scientific literature.

So, I'm really quite thrilled about the commercial prospects of ADX-2191 for all those reasons, the advantages of the drug combined with the fact that there's a targetable physician population combined with the fact that there's no therapy approved for these indications.

For Reproxalap, one of the efforts we're pursuing internally is initial commercialization. You can expect that, that is a very thorough process that we will be prepared, if necessary, to launch internally. As I've said before, with mass market drugs, it's not always optimal for small companies to launch.

But in the ocular space, it is certainly feasible. We've seen it many times before. I think we're right on target to the extent that we need to do that if we're unable to secure the partnering deals that's accessible..

Okay. Great. And maybe just then on the [SIMD RASP] (ph) program.

Can you just discuss 246 and differentiation compared to 629? Just sort of any thoughts on indications that maybe better suited for the sort of earlier-stage asset with safety and tol?.

Right. ADX-246 is our most potent RASP modulator yet. It is a direct product of our RASP modulator platform, which is really designed to select for new candidates that -- or effective RASP modulators, but also exhibit the kinds of pharmacokinetic properties we would desire for an orally administered drug.

ADX-629, as you know, has been administered twice daily. There's the potential for 246 to be administered once daily, because not only is 246 more potent than 629, it also could have a more favorable dosage administration profile.

248 is similar, also a very potent RASP trap, but, in this case, will be formulated specifically for intravitreal injection for geographic atrophy and dark adaptation in patients with the dry form of AMD..

Great. Thanks..

Thanks, Justin..

Thank you. Our next question is from Kelly Shi from Jefferies. Kelly, please go ahead. Your line is open..

[Technical Difficulty] our questions. So, I want to follow-up on the 246. Todd, can you give us more color on the systemic immune-mediated diseases? Any details on specific indications you are pursuing? My second question is on the runway.

I just want to confirm that the runway to second half 2024 includes both the launch plan for Repro and 2191 and the projected revenue of both assets? Thank you..

Good morning, [Sean] (ph). Thanks for your question. And I think your 246 question relates to Justin's question about indications for 246. ADX-246, we'll initiate a Phase 1 clinical trial first. The idea there is to confirm safety and some of the pharmacokinetic advantages that I was highlighting in response to Justin's question.

My expectation is that ADX-246 will inherit some of the indications where ADX-629 is being trialed today. Examples might include chronic cough or atopic dermatitis or alcohol-associated hepatitis.

I think we need to see the results from the ADX-629 trial and then to the extent there is activity that we could consider shifting molecules to 246, particularly for some of the mass market indications. I'd also expect that ADX-629 will remain on the orphan side of the equation.

So, as you know, we have two orphan indications that are being tested currently; one is idiopathic nephrotic syndrome and the other one is Sjogren-Larsson syndrome. Happy to briefly comment on cash, and Bruce feel free to fill in as well. But the guidance is very clear. We have cash into the second half of next year.

That cash supports initial commercialization for both Reproxalap and ADX-2191. And I hope the answers to the prior questions have given you a sense of how we're approaching those launches..

Yeah. And I would just add that....

Thank you..

...forecast is conservative and does not include any revenue nor does it include expect -- any revenue from a license arrangement..

Terrific. Thank you..

Thank you, Sean..

Thank you. Our next question is from Tom Shrader from BTIG. Tom, please go ahead. Your line is open..

Hey, good morning. This is [Sung] (ph) on for Tom. Just -- thanks for taking our question. So, just two for us.

So, for ADX-2191, could you provide additional color on how the recent priority review for ocular lymphoma may help other indications such as PVRL and retinitis pigmentosa? And for the second question, so for the visual acuity data, what will be the best strategy moving forward? Is this something you will try to include when you submit the safety data? Thanks..

Hi, Sung. Good morning. Both of those are superb questions. Our regulatory strategy for ADX-2191 was quite intentional, and that is the idea is to get -- submit an NDA for ocular lymphoma first. The reason is that methotrexate, which is the active ingredient of 2191, is standard of care for treatment of ocular lymphoma.

It's been injected in eyes for 30 years with acceptable safety and activity. After that, subsequent NDA submissions or so-called supplemental NDAs, where the bar is somewhat lower, because safety and the chemistry manufacturing controls aspects of ADX-2191 have already been evaluated in the original NDA submission.

That's why I highlighted this morning the safety results from the Phase 3 GUARD trial in proliferative vitreoretinopathy. Those are particularly important for the lymphoma submission, because the FDA always assesses not only activity, but also safety.

And in this case, we have a new formulation designed to be vitreous compatible with a lower volume and a higher density and so forth, and all that will be assessed from a safety standpoint as part of the lymphoma review. We were absolutely thrilled with the Phase 3 GUARD results in terms of safety.

In terms of proliferative vitreoretinopathy, it appeared to be actually safer to administer methotrexate 2191 than it was not to administer 2191, which makes sense because methotrexate is a compound, is anti-inflammatory and may mitigate some of the trauma associated with surgery.

But by and large, I think we have a compelling submission for lymphoma based not only on the safety, but also on the activity from the scientific literature. The visual acuity data was quite remarkable and unexpected from the 12-month safety trial of Reproxalap.

There is a 120-day update as part of a standard NDA review, which focuses on safety in particular. Obviously, the 12-month safety trial, the final data from the 12-month safety trial will be highlighted in that safety update, including the visual acuity data.

What actually winds up in the label, I think, depends on negotiation with the FDA, but also we intend to publish the results of the safety trial. I think relative to other 12-month safety trials in dry disease, the visual acuity results are quite remarkable.

And as I mentioned in my prepared comments, should stand to differentiate Reproxalap from our potential competition in the dry eye space..

Great. Thank you..

Thanks, Sung..

Thank you. Our next question is from Catherine Novack from Jones Research. Catherine, please go ahead. Your line is open..

Hi, good morning. Thanks for taking my question. Just wanted to kind of extend on the last question.

Can you -- what was the change in visual acuity for the vehicle group in the safety study? And how clinically significant is this 37% improvement in [indiscernible] in the treatment group?.

Good morning, Catherine. Both vehicle and drug improved vision from baseline. The improvement in the drug arm, the Reproxalap arm, was statistically significantly greater than that of vehicle. I think that speaks to a couple of phenomena. One is dry eye patients are inflamed. There is edema or swelling in the cornea, which affects visual acuity.

As we're treating these patients either with vehicle or drug, we would expect that inflammation to improve. What's remarkable is, again, if you go back to other 12-month safety trials in dry disease, it's never been shown that either drug or vehicle can improve visual acuity.

And I think in this case, the improvement of visual acuity speaks to the activity of our drug product that is the drug itself, Reproxalap plus the vehicle, in calming down the eye and potentially reducing that edema and improving inflammation broadly that facilitates an improvement in visual acuity.

Most of these patients, by design, in enrollment, Catherine, have normal acuity. In other words, if patients have best corrected visual acuity, I think, it's more than 2100 or worse than 2100, they are not enrolled for obvious reasons.

So, to see any change, any improvement in visual acuity in a group of patients that are essentially normal, I think it's quite remarkable.

As I mentioned in response to another question, as we age over 12 months, you would expect to see visual acuity worsen slightly, particularly in the age group that is characteristic of dry disease, which is, on average, in your 60s. So, all in all, I think these findings are quite remarkable.

It's not something you would see with massively visually impaired populations. But here, any improvement, I think, speaks to the activity of the drug and, frankly, there's little that's more clinically relevant in ocular disease than acuity.

We have eyeballs to see, and if we see a little bit better, I think that speaks volumes for the activity of drug..

Got it. Thank you. That's very helpful. And then, one last question. I'm wondering if you can talk about the rationale for RASP modulators in geographic atrophy. We know that inflammation, oxidative stress, et cetera, have been implicated AMD, but at this point, most of the therapeutic approaches have focused on the complement cascade.

So, what led to the initiation of the study? And what do you think is differentiating about your approach?.

Well, I could talk about this one for an hour. We're particularly excited about geographic atrophy and dry AMD broadly as it relates to RASP modulation.

It could be that we look backwards in time, decades from now and are somewhat embarrassed that we tried to treat a complicated inflammatory disease by targeting a single aspect of the complement cascade. RASP modulation is entirely different.

As I mentioned in my prepared comments, the idea of RAS modulation is to influence a broad group of proteins and, said in another way, reduce inflammation from a variety of different fronts simultaneously, and that's exactly how RASP behave. They are broadly pro-inflammatory.

They affect many different proteins, not just a single aspect of the complement cascade. That's part one of why we're excited about RASP modulation in geographic atrophy.

Part two is characteristic of dry AMD and GA and related diseases such as Stargardt disease is the accumulation of undigestible metabolites or macromolecules that build up in the back of the eye. These are the so-called drusen, which are comprised of a compound or group of compounds called lipofuscin, which are directly derived from RASP.

So, RASP are not only pro-inflammatory in GA, but they also lead to the accumulation of these macromolecules, which the retina is not capable of getting rid of. And what happens is this accumulation of indigestible metabolites over time that lead to lipofuscin and drusen.

So, we have two mechanisms with RASP modulation, a broad anti-inflammatory approach, and I think, it's very clear that GA and dry MD and Stargardt are related inflammation, but also the prevention of the formation of these metabolites that buildup in the back of the eye as we age..

Got it. Thank you so much for taking my questions..

My pleasure, Catherine..

Thank you. We will now take our last question from Yale Jen from Laidlaw & Company. Yale, please go ahead. Your line is open..

Good morning, and thanks for taking the questions. In terms of INVIGORATE-2 study, that you will report the data this half, but could you give us a little bit update in terms of the -- when the study started and what's the current status of patient enrollment and others? And then, I have a follow-up. Thanks..

Thanks, Yale. It wouldn't be an Aldeyra earnings call, if I didn't thank you for all your support over the years. It's just been an absolute pleasure. INVIGORATE-2, I think, we started almost two years ago. And the reason I say that is because for allergen chamber trials, you cannot treat patients when there's pollen in the air.

When there's ambient pollen, that ambient pollen compounds the activity you may or may not observe in the allergen chamber, and thus most of these allergen chamber trials are run during the winter. So, we had last year's winter season. We have this year's winter season.

The reason why we're guiding this half for INVIGORATE-2 is that pollen will arrive again early spring in the next month or two. We will no longer be able to enroll patients and thus enrollment we would expect will be complete relatively soon.

As a reminder, the primary endpoint, really the only FDA approved endpoint, in ocular allergy is itching, that is a patient reported itching scale, typically 0 to 4.

As you know, across the Phase 3 ALLEVIATE trial, across our Phase 2 allergen chamber trial, across the INVIGORATE allergen chamber trial, the itching was significantly reduced relative to vehicle, and we've performed many analyses to confirm the clinical relevance of those findings. We hope to see the same thing in INVIGORATE-2.

As far as we know, assuming positive data INVIGORATE-2, INVIGORATE-2 would conclude our efficacy trials for allergic conjunctivitis..

Okay, great. That's very helpful. Maybe one more here, which is for 2191 with retinitis pigmentosa data readout.

What should we anticipate from that data once you report it?.

Well, thanks for highlighting retinitis pigmentosa. There are three major milestones for our company in this half. We just talked about INVIGORATE-2. I've discussed chronic cough previously. And then, retinitis pigmentosa is the third. What I think is remarkable about those three milestones is each milestone highlights a different aspect of our business.

I like to think of Aldeyra in three parts, Reproxalap being one, ADX-2191 being two, and the third being the oral pipeline, and each of those aspects of our business are representative of milestones that we expect this half. Retinitis pigmentosa is particularly interesting.

It is the largest of the three indications we're currently testing with ADX-2191.

To pick round numbers, one might think of roughly 400 incident patients with lymphoma, 4,000 incident patients with proliferative vitreoretinopathy and something like 40,000 incident patients with retinitis pigmentosa that relate to the particular mutations that appear to be sensitive to methotrexate administration.

The basis for using ADX-2191 and methotrexate in retinitis pigmentosa is cited in our clinical deck. It's been a remarkable series of experiments, spanning many thousands of molecules in animal models of retinitis pigmentosa, the winner was methotrexate.

And thus, investigators and many patients and certainly the staff here at Aldeyra are excited about the potential for ADX-2191 in retinitis pigmentosa. This is an open label trial. This is the first time methotrexate has been administered to retinitis pigmentosa patients. And we, as I mentioned, would expect to be able to announce results this half..

Okay, great. That's very helpful. And again, congrats for all these catalysts of this year..

Exciting time, Yale. Thank you..

Thank you. I'll now turn the call back to Dr. Brady for closing comments..

Thank you for joining us this morning. We are positioned for an exciting year in 2023. And as always, we look forward to bringing our novel therapies to patients with significant unmet medical need..

Thank you everyone for joining today's call. You may now disconnect your lines, and have a lovely day..